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Sample records for acylated ghrelin concentrations

  1. 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.

    PubMed

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

    2016-10-01

    Ghrelin is a peptide hormone produced in the gut that is implicated in signaling appetite and regulating dry matter intake (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 average daily BW gain (ADG) measurement period and to determine the association of those ghrelin measurements with DMI, ADG, ADG:DMI ratio (G:F), and residual feed intake in finishing beef steers and heifers. Blood samples were collected on day 0 and day 83 before feeding and between 0730 h and 1130 h. Samples were analyzed for acyl and total ghrelin using commercially available RIA. DMI in steers was greater during the last 35-d period of the experiment compared with the first 35 d (P < 0.01) and was greater than heifers regardless of period (P < 0.01). Steers had greater acyl ghrelin concentrations on day 0 than heifers, but concentrations decreased by day 83 to equal concentrations in heifers (P < 0.01). Total ghrelin concentrations were lower on day 0 in heifers but increased by day 83 and did not differ from steers on day 83 (P < 0.01). A mixed model analysis was used to determine the association of ghrelin concentrations and ratio with production traits, independent of breed and sire effects. There was an interaction of day 0 acyl ghrelin concentrations with time of sample collection for 84-d DMI (P < 0.01), ADG (P < 0.01), and G:F (P = 0.09), indicating a general positive association of acyl ghrelin with production traits, but the association weakened as time of sample collection increased. The mean ghrelin ratio tended (P = 0.08) to be positively associated with DMI in the last 35-d period. The ghrelin ratio on day 0 interacted with time of sample collection for ADG and G:F (P < 0.05), indicating an overall positive association of the ghrelin ratio with ADG and G:F. Results indicate that ghrelin is associated with DMI, ADG, and feed efficiency of finishing beef

  2. 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...

  3. 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 ...

  4. Antifibrotic Activity of Acylated and Unacylated Ghrelin

    PubMed Central

    Angelino, Elia; Reano, Simone; Ferrara, Michele; Agosti, Emanuela; Graziani, Andrea; Filigheddu, Nicoletta

    2015-01-01

    Fibrosis can affect almost all tissues and organs, it often represents the terminal stage of chronic diseases, and it is regarded as a major health issue for which efficient therapies are needed. Tissue injury, by inducing necrosis/apoptosis, triggers inflammatory response that, in turn, promotes fibroblast activation and pathological deposition of extracellular matrix. Acylated and unacylated ghrelin are the main products of the ghrelin gene. The acylated form, through its receptor GHSR-1a, stimulates appetite and growth hormone (GH) release. Although unacylated ghrelin does not bind or activate GHSR-1a, it shares with the acylated form several biological activities. Ghrelin peptides exhibit anti-inflammatory, antioxidative, and antiapoptotic activities, suggesting that they might represent an efficient approach to prevent or reduce fibrosis. The aim of this review is to summarize the available evidence regarding the effects of acylated and unacylated ghrelin on different pathologies and experimental models in which fibrosis is a predominant characteristic. PMID:25960743

  5. GOAT induced ghrelin acylation regulates hedonic feeding.

    PubMed

    Davis, J F; Perello, M; Choi, D L; Magrisso, I J; Kirchner, H; Pfluger, P T; Tschoep, M; Zigman, J M; Benoit, S C

    2012-11-01

    Ghrelin is an orexigenic hormone that regulates homeostatic and reward-related feeding behavior. Recent evidence indicates that acylation of ghrelin by the gut enzyme ghrelin O-acyl transferase (GOAT) is necessary to render ghrelin maximally active within its target tissues. Here we tested the hypothesis that GOAT activity modulates food motivation and food hedonics using behavioral pharmacology and mutant mice deficient for GOAT and the ghrelin receptor (GHSR). We evaluated operant responding following pharmacological administration of acyl-ghrelin and assessed the necessity of endogenous GOAT activity for operant responding in GOAT and GHSR-null mice. Hedonic-based feeding behavior also was examined in GOAT-KO and GHSR-null mice using a "Dessert Effect" protocol in which the intake of a palatable high fat diet "dessert" was assessed in calorically-sated mice. Pharmacological administration of acyl-ghrelin augmented operant responding; notably, this effect was dependent on intact GHSR signaling. GOAT-KO mice displayed attenuated operant responding and decreased hedonic feeding relative to controls. These behavioral results correlated with decreased expression of the orexin-1 receptor in reward-related brain regions in GOAT-KO mice. In summary, the ability of ghrelin to stimulate food motivation is dependent on intact GHSR signaling and modified by endogenous GOAT activity. Furthermore, GOAT activity is required for hedonic feeding behavior, an effect potentially mediated by forebrain orexin signaling. These data highlight the significance of the GOAT-ghrelin system for the mediation of food motivation and hedonic feeding.

  6. 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. PMID:27264721

  7. 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.

  8. 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...

  9. 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.

  10. 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.

  11. Acylated but not des-acyl ghrelin is neuroprotective in an MPTP mouse model of Parkinson's disease.

    PubMed

    Bayliss, Jacqueline A; Lemus, Moyra; Santos, Vanessa V; Deo, Minh; Elsworth, John D; Andrews, Zane B

    2016-05-01

    The gut hormone ghrelin is widely beneficial in many disease states. However, ghrelin exists in two distinctive isoforms, each with its own metabolic profile. In Parkinson's Disease (PD) acylated ghrelin administration is neuroprotective, however, the role of des-acylated ghrelin remains unknown. In this study, we wanted to identify the relative contribution each isoform plays using the MPTP model of PD. Chronic administration of acylated ghrelin in mice lacking both isoforms of ghrelin (Ghrelin KO) attenuated the MPTP-induced loss on tyrosine hydroxylase (TH) neuronal number and volume and TH protein expression in the nigrostriatal pathway. Moreover, acylated ghrelin reduced the increase in glial fibrillary acidic protein and Ionized calcium binding adaptor molecule 1 microglia in the substantia nigra. However, injection of acylated ghrelin also elevated plasma des-acylated ghrelin, indicating in vivo deacetylation. Next, we chronically administered des-acylated ghrelin to Ghrelin KO mice and observed no neuroprotective effects in terms of TH cell number, TH protein expression, glial fibrillary acidic protein and ionized calcium binding adaptor molecule 1 cell number. The lack of a protective effect was mirrored in ghrelin-O-acyltransferase KO mice, which lack the ability to acylate ghrelin and consequently these mice have chronically increased plasma des-acyl ghrelin. Plasma corticosterone was elevated in ghrelin-O-acyltransferase KO mice and with des-acylated ghrelin administration. Overall, our studies suggest that acylated ghrelin is the isoform responsible for in vivo neuroprotection and that pharmacological approaches preventing plasma conversion from acyl ghrelin to des-acyl ghrelin may have clinical efficacy to help slow or prevent the debilitating effects of PD. Ghrelin exists in the plasma as acyl and des-acyl ghrelin. We determined the form responsible for in vivo neuroprotection in a mouse model of Parkinson's disease. Although exogenous acyl ghrelin

  12. Des-acyl ghrelin attenuates pilocarpine-induced limbic seizures via the ghrelin receptor and not the orexin pathway.

    PubMed

    Portelli, Jeanelle; Coppens, Jessica; Demuyser, Thomas; Smolders, Ilse

    2015-06-01

    Des-acyl ghrelin, widely accepted to work independently of the ghrelin receptor, is increasingly being implicated in a number of biological functions. The involvement of des-acyl ghrelin in epilepsy has only been recently reported. In this study, apart from unravelling the effect of des-acyl ghrelin on seizure thresholds and seizure severity in two models of pilocarpine-induced seizures, we mainly attempted to unravel its anticonvulsant mechanism of action. Since it was found that des-acyl ghrelin administration affected food intake via the orexin pathway, we first determined whether this pathway was responsible for des-acyl ghrelin's seizure-attenuating properties using the dual orexin receptor antagonist almorexant. We noted that, while des-acyl ghrelin showed dose-dependent anticonvulsant effects against focal pilocarpine-evoked seizures in rats, almorexant did not affect seizure severity and did not reverse des-acyl ghrelin's anticonvulsant effect. Subsequently, to investigate whether the ghrelin receptor was implicated in des-acyl ghrelin's anticonvulsant properties, we tested this peptide in ghrelin receptor deficient mice and wild type mice, all infused with pilocarpine intravenously. Unexpectedly, we found that des-acyl ghrelin significantly elevated seizure thresholds in C57Bl/6 and wild type mice but not in ghrelin receptor knock-out mice. Taken together, our results indicate the involvement of the ghrelin receptor in the anticonvulsant effects of des-acyl ghrelin on pilocarpine-induced seizures. We also show for the first time that dual antagonism of hippocampal orexin receptors does not affect seizure severity.

  13. 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.

  14. Paradoxical post-exercise responses of acylated ghrelin and leptin during a simulated night shift.

    PubMed

    Morris, Christopher J; Fullick, Sarah; Gregson, Warren; Clarke, Neil; Doran, Dominic; MacLaren, Don; Atkinson, Greg

    2010-05-01

    Approximately 10% of employees undertake night work, which is a significant predictor of weight gain, possibly because responses to activity and eating are altered at night. It is known that the appetite-related hormone, acylated ghrelin, is suppressed after an acute bout of exercise during the day, but no researcher has explored whether evening exercise alters acylated ghrelin and other appetite-related outcomes during a subsequent night shift. Six healthy men (mean +/- SD: age 30 +/- 8 yrs, body mass index 23.1 +/- 1.1 kg/m(2)) completed two crossover trials (control and exercise) in random order. Participants fasted from 10:00 h, consumed a test meal at 18:00 h, and then cycled at 50% peak oxygen uptake or rested between 19:00-20:00 h. Participants then completed light activities during a simulated night shift which ended at 05:00 h. Two small isocaloric meals were consumed at 22:00 and 02:00 h. Venous blood samples were drawn via cannulation at 1 h intervals between 19:00-05:00 h for the determination of acylated ghrelin, leptin, insulin, glucose, triglyceride, and non-esterified fatty acids concentrations. Perceived hunger and wrist actimetry were also recorded. During the simulated night shift, mean +/- SD acylated ghrelin concentration was 86.5 +/- 40.8 pg/ml following exercise compared with 71.7 +/- 37.7 pg/ml without prior exercise (p = 0.015). Throughout the night shift, leptin concentration was 263 +/- 242 pg/ml following exercise compared with 187 +/- 221 pg/ml without prior exercise (p = 0.017). Mean levels of insulin, triglyceride, non-esterified fatty acids, and wrist actimetry level were also higher during the night shift that followed exercise (p < 0.05). These data indicate that prior exercise increases acylated ghrelin and leptin concentrations during a subsequent simulated night shift. These findings differ from the known effects of exercise on acylated ghrelin and leptin during the day, and therefore have implications for energy balance during

  15. Jejunal administration of glucose enhances acyl ghrelin suppression in obese humans.

    PubMed

    Tamboli, Robyn A; Sidani, Reem M; Garcia, Anna E; Antoun, Joseph; Isbell, James M; Albaugh, Vance L; Abumrad, Naji N

    2016-07-01

    Ghrelin is a gastric hormone that stimulates hunger and worsens glucose metabolism. Circulating ghrelin is decreased after Roux-en-Y gastric bypass (RYGB) surgery; however, the mechanism(s) underlying this change is unknown. We tested the hypothesis that jejunal nutrient exposure plays a significant role in ghrelin suppression after RYGB. Feeding tubes were placed in the stomach or jejunum in 13 obese subjects to simulate pre-RYGB or post-RYGB glucose exposure to the gastrointestinal (GI) tract, respectively, without the confounding effects of caloric restriction, weight loss, and surgical stress. On separate study days, the plasma glucose curves obtained with either gastric or jejunal administration of glucose were replicated with intravenous (iv) infusions of glucose. These "isoglycemic clamps" enabled us to determine the contribution of the GI tract and postabsorptive plasma glucose to acyl ghrelin suppression. Plasma acyl ghrelin levels were suppressed to a greater degree with jejunal glucose administration compared with gastric glucose administration (P < 0.05). Jejunal administration of glucose also resulted in a greater suppression of acyl ghrelin than the corresponding isoglycemic glucose infusion (P ≤ 0.01). However, gastric and isoglycemic iv glucose infusions resulted in similar degrees of acyl ghrelin suppression (P > 0.05). Direct exposure of the proximal jejunum to glucose increases acyl ghrelin suppression independent of circulating glucose levels. The enhanced suppression of acyl ghrelin after RYGB may be due to a nutrient-initiated signal in the jejunum that regulates ghrelin secretion. PMID:27279247

  16. The Acute Effects of Swimming on Appetite, Food Intake, and Plasma Acylated Ghrelin

    PubMed Central

    King, James A.; Wasse, Lucy K.; Stensel, David J.

    2011-01-01

    Swimming may stimulate appetite and food intake but empirical data are lacking. This study examined appetite, food intake, and plasma acylated ghrelin responses to swimming. Fourteen healthy males completed a swimming trial and a control trial in a random order. Sixty min after breakfast participants swam for 60 min and then rested for six hours. Participants rested throughout the control trial. During trials appetite was measured at 30 min intervals and acylated ghrelin was assessed periodically (0, 1, 2, 3, 4, 6, and 7.5 h. N = 10). Appetite was suppressed during exercise before increasing in the hours after. Acylated ghrelin was suppressed during exercise. Swimming did not alter energy or macronutrient intake assessed at buffet meals (total trial energy intake: control 9161 kJ, swimming 9749 kJ). These findings suggest that swimming stimulates appetite but indicate that acylated ghrelin and food intake are resistant to change in the hours afterwards. PMID:20953411

  17. 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. PMID:25535832

  18. 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

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

    PubMed

    Hatef, Azadeh; Yufa, Roman; Unniappan, Suraj

    2015-10-01

    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.

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

    PubMed

    Porporato, Paolo E; Filigheddu, Nicoletta; Reano, Simone; Ferrara, Michele; Angelino, Elia; Gnocchi, Viola F; Prodam, Flavia; Ronchi, Giulia; Fagoonee, Sharmila; Fornaro, Michele; Chianale, Federica; Baldanzi, Gianluca; Surico, Nicola; Sinigaglia, Fabiola; Perroteau, Isabelle; Smith, Roy G; Sun, Yuxiang; Geuna, Stefano; Graziani, Andrea

    2013-02-01

    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. Ghrelin is a peptide hormone that stimulates growth hormone (GH) release and positive energy balance through binding to the receptor GHSR-1a. Only acylated ghrelin (AG), but not the unacylated form (UnAG), can bind GHSR-1a; however, UnAG and AG share several GHSR-1a-independent biological activities. Here we investigated whether UnAG and AG could protect against skeletal muscle atrophy in a GHSR-1a-independent manner. We found that both AG and UnAG inhibited dexamethasone-induced skeletal muscle atrophy and atrogene expression through PI3Kβ-, mTORC2-, and p38-mediated pathways in myotubes. Upregulation of circulating UnAG in mice impaired skeletal muscle atrophy induced by either fasting or denervation without stimulating muscle hypertrophy and GHSR-1a-mediated activation of the GH/IGF-1 axis. In Ghsr-deficient mice, both AG and UnAG induced phosphorylation of Akt in skeletal muscle and impaired fasting-induced atrophy. These results demonstrate that AG and UnAG act on a common, unidentified receptor to block skeletal muscle atrophy in a GH-independent manner.

  1. 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.

  2. Intravenous glucose administration in fasting rats has differential effects on acylated and unacylated ghrelin in the portal and systemic circulation: a comparison between portal and peripheral concentrations in anesthetized rats.

    PubMed

    Gauna, Carlotta; Uitterlinden, Piet; Kramer, Piet; Kiewiet, Rosalie M; Janssen, Joop A M J L; Delhanty, Patric J D; van Aken, Maarten O; Ghigo, Ezio; Hofland, Leo J; Themmen, Axel P N; van der Lely, Aart Jan

    2007-11-01

    Ghrelin is produced by the gastrointestinal tract, and its systemic concentrations are mainly regulated by nutritional factors. Our aim was to investigate: 1) endogenous portal and systemic acylated and unacylated ghrelin levels (AG and UAG, respectively); 2) whether an iv glucose tolerance test (IVGTT) modifies AG and UAG; and 3) whether the liver passage plays a role in regulating systemic AG and UAG. To elucidate this, we evaluated the effects of IVGTT or saline injection on endogenous portal and systemic concentrations of glucose, insulin, AG, and UAG in anesthetized fasting rats. Hepatic extraction of insulin, AG, and UAG and the ratio of AG to UAG were also measured. IVGTT suppressed both portal (P < 0.03) and peripheral (P < 0.05) UAG, whereas it only blunted prehepatic, but not peripheral, AG. During fasting, hepatic clearance of UAG was 11%, and it was decreased to 8% by IVGTT. AG was cleared by the liver by 38% but unaffected by glucose. The AG to UAG ratio was higher in the portal than the systemic circulation, both in the saline (P < 0.004) and IVGTT (P < 0.0005) rats. In conclusion, this study shows that: 1) the ratio of AG to UAG is very low in the portal vein and decreases further in the systemic circulation; 2) IVGTT in anesthetized fasting rats inhibits UAG, whereas it only blunts prehepatic, but not systemic, AG; and 3) hepatic clearance of AG is much higher than that of UAG. Thus, our results suggest that peripheral AG metabolic regulation and action are mainly confined within the gastrointestinal tract.

  3. 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...

  4. 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

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

    PubMed

    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

  6. 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. PMID:26773867

  7. 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.

  8. 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.

  9. 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

  10. Role of intraamygdaloid acylated-ghrelin in spatial learning.

    PubMed

    Tóth, Krisztián; László, Kristóf; Lénárd, László

    2010-01-15

    According to recently published papers acylated-ghrelin (A-Ghr) modifies memory and learning. The basolateral nucleus of amygdala (ABL) participates in the regulation of memory and learning mechanisms. Previously we verified A-Ghr responsive neurons in the ABL by electrophysiological methods. In male Wistar rats effects of bilateral intraamygdaloid microinfusion of 50 ng, 100 ng A-Ghr, 15 ng Ghr receptor antagonist d-Lys3-GHRP-6 (ANT) or ANT+50 ng A-Ghr [dissolved in 0.15M sterile saline], or vehicle in 0.4 microl volume were investigated in Morris water maze paradigm. 50 ng A-Ghr significantly reduced latency to find the platform located in one of the quadrants of the maze. Effect of 50 ng A-Ghr was blocked by ANT pretreatment. ANT alone had no effect. Our results show that place learning linked memory processes are facilitated by A-Ghr in the rat ABL. It is a specific effect, because it could be eliminated by ANT pretreatment.

  11. 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.

  12. Novel Regulator of Acylated Ghrelin, CF801, Reduces Weight Gain, Rebound Feeding after a Fast, and Adiposity in Mice.

    PubMed

    Wellman, Martin K; Patterson, Zachary R; MacKay, Harry; Darling, Joseph E; Mani, Bharath K; Zigman, Jeffrey M; Hougland, James L; Abizaid, Alfonso

    2015-01-01

    Ghrelin is a 28 amino acid hormonal peptide that is intimately related to the regulation of food intake and body weight. Once secreted, ghrelin binds to the growth hormone secretagogue receptor-1a, the only known receptor for ghrelin and is capable of activating a number of signaling cascades, ultimately resulting in an increase in food intake and adiposity. Because ghrelin has been linked to overeating and the development of obesity, a number of pharmacological interventions have been generated in order to interfere with either the activation of ghrelin or interrupting ghrelin signaling as a means to reducing appetite and decrease weight gain. Here, we present a novel peptide, CF801, capable of reducing circulating acylated ghrelin levels and subsequent body weight gain and adiposity. To this end, we show that IP administration of CF801 is sufficient to reduce circulating plasma acylated ghrelin levels. Acutely, intraperitoneal injections of CF801 resulted in decreased rebound feeding after an overnight fast. When delivered chronically, they decreased weight gain and adiposity without affecting caloric intake. CF801, however, did cause a change in diet preference, decreasing preference for a high-fat diet and increasing preference for regular chow diet. Given the complexity of ghrelin receptor function, we propose that CF801, along with other compounds that regulate ghrelin secretion, may prove to be a beneficial tool in the study of the ghrelin system, and potential targets for ghrelin-based obesity treatments without altering the function of ghrelin receptors.

  13. Novel Regulator of Acylated Ghrelin, CF801, Reduces Weight Gain, Rebound Feeding after a Fast, and Adiposity in Mice

    PubMed Central

    Wellman, Martin K.; Patterson, Zachary R.; MacKay, Harry; Darling, Joseph E.; Mani, Bharath K.; Zigman, Jeffrey M.; Hougland, James L.; Abizaid, Alfonso

    2015-01-01

    Ghrelin is a 28 amino acid hormonal peptide that is intimately related to the regulation of food intake and body weight. Once secreted, ghrelin binds to the growth hormone secretagogue receptor-1a, the only known receptor for ghrelin and is capable of activating a number of signaling cascades, ultimately resulting in an increase in food intake and adiposity. Because ghrelin has been linked to overeating and the development of obesity, a number of pharmacological interventions have been generated in order to interfere with either the activation of ghrelin or interrupting ghrelin signaling as a means to reducing appetite and decrease weight gain. Here, we present a novel peptide, CF801, capable of reducing circulating acylated ghrelin levels and subsequent body weight gain and adiposity. To this end, we show that IP administration of CF801 is sufficient to reduce circulating plasma acylated ghrelin levels. Acutely, intraperitoneal injections of CF801 resulted in decreased rebound feeding after an overnight fast. When delivered chronically, they decreased weight gain and adiposity without affecting caloric intake. CF801, however, did cause a change in diet preference, decreasing preference for a high-fat diet and increasing preference for regular chow diet. Given the complexity of ghrelin receptor function, we propose that CF801, along with other compounds that regulate ghrelin secretion, may prove to be a beneficial tool in the study of the ghrelin system, and potential targets for ghrelin-based obesity treatments without altering the function of ghrelin receptors. PMID:26441834

  14. 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

  15. 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...

  16. An Evaluation of Acylated Ghrelin and Obestatin Levels in Childhood Obesity and Their Association with Insulin Resistance, Metabolic Syndrome, and Oxidative Stress

    PubMed Central

    Razzaghy-Azar, Maryam; Nourbakhsh, Mitra; Pourmoteabed, Abdolreza; Nourbakhsh, Mona; Ilbeigi, Davod; Khosravi, Mohsen

    2016-01-01

    Background: Ghrelin is a 28-amino acid peptide with an orexigenic property, which is predominantly produced by the stomach. Acylated ghrelin is the active form of this hormone. Obestatin is a 23-amino acid peptide which is produced by post-translational modification of a protein precursor that also produces ghrelin. Obestatin has the opposite effect of ghrelin on food intake. The aim of this study was to evaluate acylated ghrelin and obestatin levels and their ratio in obese and normal-weight children and adolescents, and their association with metabolic syndrome (MetS) parameters. Methods: Serum acyl-ghrelin, obestatin, leptin, insulin, fasting plasma glucose (FPG), lipid profile, and malondialdehyde (MDA) were evaluated in 73 children and adolescents (42 obese and 31 control). Insulin resistance was calculated by a homeostasis model assessment of insulin resistance (HOMA-IR). MetS was determined according to IDF criteria. Results: Acyl-ghrelin levels were significantly lower in obese subjects compared to the control group and lower in obese children with MetS compared to obese subjects without MetS. Obestatin was significantly higher in obese subjects compared to that of the control, but it did not differ significantly among those with or without MetS. Acyl-ghrelin to obestatin ratio was significantly lower in obese subjects compared to that in normal subjects. Acyl-ghrelin showed significant negative and obestatin showed significant positive correlations with body mass index (BMI), BMI Z-score, leptin, insulin, and HOMA-IR. Acyl-ghrelin had a significant negative correlation with MDA as an index of oxidative stress. Conclusion: Ghrelin is decreased and obestatin is elevated in obesity. Both of these hormones are associated with insulin resistance, and ghrelin is associated with oxidative stress. The balance between ghrelin and obestatin seems to be disturbed in obesity. PMID:27348010

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

    PubMed

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

    2016-07-01

    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

  18. 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.

  19. Acylated and Desacylated Ghrelin, Preptin, Leptin, and Nesfatin-1 Peptide Changes Related to the Body Mass Index

    PubMed Central

    Ozkan, Yusuf; Timurkan, Esra Suay; Sahin, İbrahim; Timurkan, Mustafa; Citil, Cihan; Kalayci, Mehmet; Yilmaz, Musa; Catak, Zekiye

    2013-01-01

    This study examines the levels of acylated and desacylated ghrelin, preptin, leptin, and nesfatin-1 peptide changes related to the body mass index (BMI). The subjects were allocated to 5 groups depending on their BMIs as follows: Group I (BMI <18.5 kg/m2); Group II (BMI 18.5–24.9 kg/m2); Group III (BMI 25–29.9 kg/m2); Group IV (BMI 30–39.9 kg/m2); Group V (BMI >40 kg/m2). Serum acylated and desacylated ghrelin, preptin, and leptin levels were measured by the enzyme-linked immunosorbent assay (ELISA) and nesfatin-1 was measured by the enzyme immunoassay (EIA). Desacylated ghrelin levels showed a gradual and statistically significant drop from Group I to Group V, while preptin and leptin levels exhibited a gradual and significant increase from Group I to Group IV. Serum nesfatin-1 levels gradually, but not significantly, increased from Group I to Group III and showed a significant decrease in Groups IV and V. In conclusion, leptin, preptin, and acylated ghrelin (AG) levels increased with higher BMI, whereas desacylated ghrelin (DAG) decreased and nesfatin-1 showed no clear relationship to BMI. PMID:24371438

  20. 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. PMID:26381714

  1. 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.

  2. 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

  3. Plasma ghrelin levels in healthy elderly volunteers: the levels of acylated ghrelin in elderly females correlate positively with serum IGF-I levels and bowel movement frequency and negatively with systolic blood pressure.

    PubMed

    Akamizu, T; Murayama, T; Teramukai, S; Miura, K; Bando, I; Irako, T; Iwakura, H; Ariyasu, H; Hosoda, H; Tada, H; Matsuyama, A; Kojima, S; Wada, T; Wakatsuki, Y; Matsubayashi, K; Kawakita, T; Shimizu, A; Fukushima, M; Yokode, M; Kangawa, K

    2006-02-01

    Aging is associated with a decrease in growth hormone (GH) secretion, appetite and energy intake. As ghrelin stimulates both GH secretion and appetite, reductions in ghrelin levels may be involved in the reductions in GH secretion and appetite observed in the elderly. However, only preliminary studies have been performed on the role of ghrelin in elderly subjects. In this study, we sought to clarify the physiologic implications of the age-related alterations in ghrelin secretion by determining plasma ghrelin levels and other clinical parameters in healthy elderly subjects. Subjects were > or = 65 years old, corresponding to the SENIEUR protocol, had not had a resection of the upper gastrointestinal tract and had not been treated with hormones. One hundred and five volunteers (49 men and 56 women) were admitted to this study (73.4 +/- 6.3 years old). Plasma levels of acylated ghrelin in elderly female subjects positively correlated with serum IGF-I levels and bowel movement frequency and negatively with systolic blood pressure. In elderly men, desacyl ghrelin levels correlated only weakly with bowel movement frequency. These findings suggest that the plasma levels of the acylated form of ghrelin may influence the age-related alterations in GH/IGF-I regulation, blood pressure and bowel motility. These observational associations warrant further experimental studies to clarify the physiologic significance of these effects.

  4. 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

  5. Plasma ghrelin concentrations change with physiological state in a sciurid hibernator (Spermophilus lateralis).

    PubMed

    Healy, Jessica E; Ostrom, Cara E; Wilkerson, Gregory K; Florant, Gregory L

    2010-04-01

    Ghrelin is a recently discovered hormone which has profound effects on food intake and lipogenesis in mammals. In all mammals studied thus far, plasma ghrelin concentrations are increased before a meal and decrease immediately following a meal; ghrelin levels increase with fasting. The golden-mantled ground squirrel Spermophilus lateralis (also known as Callospermophilus lateralis (see Helgen et al., 2009) is a diurnal hibernator which has a robust annual cycle of body mass gain and loss that is primarily controlled by food intake. We hypothesized that in spring, summer, and autumn, the endogenous ghrelin concentrations of hibernators would be similar to those of non-hibernators, but that during the winter hibernation season, plasma ghrelin concentrations would be low or undetectable. We found that peripherally injected ghrelin significantly increased food intake in June. Plasma ghrelin concentrations were significantly increased through 5 days of fasting during a short-term fast in summer. Over a 24h period, ghrelin concentrations increased at night and decreased during the day with drops corresponding to times when squirrels were eating. In January, ghrelin concentrations are low but measurable even while animals are at low body temperature (Tb). This is the first report of ghrelin concentrations in a non-photoperiodic hibernator. We suggest that ghrelin may be important for the regulation of food intake and the body mass cycle in mammals that hibernate.

  6. Plasma ghrelin concentrations change with physiological state in a sciurid hibernator (Spermophilus lateralis).

    PubMed

    Healy, Jessica E; Ostrom, Cara E; Wilkerson, Gregory K; Florant, Gregory L

    2010-04-01

    Ghrelin is a recently discovered hormone which has profound effects on food intake and lipogenesis in mammals. In all mammals studied thus far, plasma ghrelin concentrations are increased before a meal and decrease immediately following a meal; ghrelin levels increase with fasting. The golden-mantled ground squirrel Spermophilus lateralis (also known as Callospermophilus lateralis (see Helgen et al., 2009) is a diurnal hibernator which has a robust annual cycle of body mass gain and loss that is primarily controlled by food intake. We hypothesized that in spring, summer, and autumn, the endogenous ghrelin concentrations of hibernators would be similar to those of non-hibernators, but that during the winter hibernation season, plasma ghrelin concentrations would be low or undetectable. We found that peripherally injected ghrelin significantly increased food intake in June. Plasma ghrelin concentrations were significantly increased through 5 days of fasting during a short-term fast in summer. Over a 24h period, ghrelin concentrations increased at night and decreased during the day with drops corresponding to times when squirrels were eating. In January, ghrelin concentrations are low but measurable even while animals are at low body temperature (Tb). This is the first report of ghrelin concentrations in a non-photoperiodic hibernator. We suggest that ghrelin may be important for the regulation of food intake and the body mass cycle in mammals that hibernate. PMID:20005230

  7. Plasma ghrelin concentrations change with physiological state in a sciurid hibernator (Spermophilus lateralis)

    PubMed Central

    Healy, Jessica E.; Ostrom, Cara E.; Wilkerson, Gregory K.; Florant, Gregory L.

    2009-01-01

    Ghrelin is a recently discovered hormone which has profound effects on food intake and lipogenesis in mammals. In all mammals studied thus far, plasma ghrelin concentrations are increased before a meal and decrease immediately following a meal; ghrelin levels increase with fasting. The golden-mantled ground squirrel Spermophilus lateralis (also known as Callospermophilus lateralis (see Helgen et al., 2009)) is a diurnal hibernator which has a robust annual cycle of body mass gain and loss that is primarily controlled by food intake. We hypothesized that in spring, summer, and autumn, the endogenous ghrelin concentrations of hibernators would be similar to those of non-hibernators, but that during the winter hibernation season, plasma ghrelin concentrations would be low or undetectable. We found that peripherally injected ghrelin significantly increased food intake in June. Plasma ghrelin concentrations were significantly increased through 5 days of fasting during a short-term fast in summer. Over a 24 hour period, ghrelin concentrations increased at night and decreased during the day with drops corresponding to times when squirrels were eating. In January, ghrelin concentrations are low but measurable even while animals are at low body temperature (Tb). The reason for the persistence of ghrelin in plasma at this time is unclear, but circulating ghrelin in hibernators may be involved with the control of sleep in these animals. This is the first report of ghrelin concentrations in a non-photoperiodic hibernator. We suggest that ghrelin may be important for the regulation of food intake and the body mass cycle in mammals that hibernate. PMID:20005230

  8. Effects of prolonged nutrient restriction on baseline and periprandial plasma ghrelin concentrations of postpubertal Holstein heifers.

    PubMed

    Field, M E; Deaver, S E; Rhoads, R P; Collier, R J; Rhoads, M L

    2013-10-01

    Objectives of this study were to measure both daily and periprandial plasma ghrelin concentrations of postpubertal Holstein heifers during prolonged undernutrition. Following an acclimation period, Holstein heifers [n=10; 339.5 ± 8.6 kg of body weight (BW)] were fed ad libitum [well fed (WF); n=5] or restricted to 50% of ad libitum intake [underfed (UF); n=5) for 8 wk. Body condition scores (BCS) were recorded at the beginning and end of the treatment period, and weekly measurements of BW, plasma ghrelin, progesterone, and nonesterified fatty acids (NEFA) concentrations were obtained. Ovarian follicular and luteal structures were measured twice weekly via transrectal ultrasonography. Plasma ghrelin concentrations were also measured during a periprandial window bleed conducted at the end of the experiment. During the window bleed, samples were collected every 15 min between 0500 and 0900 h, with feed offered at 0700 h. Underfed heifers lost BW and BCS, whereas WF heifers gained weight and either increased or maintained BCS. Chronic underfeeding increased circulating ghrelin and NEFA concentrations. By wk 4 of the treatment period, circulating ghrelin concentrations of the UF heifers reached a plateau. Periprandial fluctuations in ghrelin concentrations were apparent as plasma ghrelin concentrations changed over time. Overall differences in periprandial plasma ghrelin concentrations were primarily due to prefeeding effects of plane of nutrition. Plasma ghrelin concentrations and change in BCS were negatively correlated such that heifers that lost the most BCS had the highest concentrations of circulating ghrelin. Two of the 5 UF heifers became anestrus by wk 3 of the treatment period. Despite being of similar age, the heifers that became anestrus had lower BW and plasma ghrelin concentrations than the UF heifers that continued to ovulate. In the current experiment, long-term undernutrition elicited ghrelin responses similar to those reported for shorter durations of

  9. 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.

  10. 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. PMID:25989955

  11. 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.

  12. Impact of visual, olfactory, and auditory cues on circulating concentrations of ghrelin in wethers.

    PubMed

    Stockwell-Goering, M G; Benavides, E A; Keisler, D H; Daniel, J A

    2015-08-01

    Ghrelin is a hormone that stimulates feed intake and regulates energy homeostasis. A link has been observed in sheep, in which simulated feedings at scheduled meal times resulted in an increase in ghrelin concentrations. The present study sought to characterize the effect of feeding cues outside of scheduled meal times on circulating ghrelin concentrations in sheep. Katahdin wethers (age 201 ± 4.9 d; weight 35 ± 1.2 kg) were not offered feed (CONT; = 5), offered 275 g of feed (FED; = 5), or fitted with a muzzle and offered 275 g of feed (SHAM; = 5) during the sampling period, which began 2.5 h after normally scheduled daily feeding time. Blood samples were collected via jugular catheter every 15 min for 2.5 h. Feed was offered for 15 min 0.5 h after the start of blood sampling. The CONT samples were collected on d 1, and FED and SHAM samples were collected on d 2. The active ghrelin present in the plasma was then analyzed by RIA. After the Shapiro-Wilk W goodness of fit test demonstrated that 1 SHAM wether was an outlier and it was removed, data were tested for effect of treatment (FED, SHAM, or CONT), time, and treatment × time interaction using procedures for repeated measures with JMP Software (SAS Inst. Inc., Cary, NC). There was no treatment or time effect ( > 0.05); however, there was a treatment × time interaction on plasma ghrelin concentrations ( = 0.0028) such that ghrelin concentrations in SHAM wethers were greater than in CONT wethers 15, 60, and 90 min after feeding, whereas ghrelin concentrations in SHAM wethers were greater than those in FED wethers 30, 60, 90, and 120 min after feeding ( < 0.05). Within the SHAM treatment, ghrelin concentrations were greater at 15 min than at -30 min. Moreover, ghrelin concentrations within the FED treatment were greater at -30 min than at 30, 45, 60, 90, 105, and 120 min and at -15 min than at 15 through 120 min. The area under the curve representing circulating concentrations of ghrelin in CONT, FED, and SHAM

  13. 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.

  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. 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

  16. 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.

  17. Plane of nutrition affects plasma ghrelin concentrations in neonatal calves

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Investigating different planes of nutrition on appetite-related hormones could provide knowledge into the role of these hormones on growth performance in neonatal calves. The objective of the current study was to investigate the effects of feeding rates on ghrelin in plasma from preruminant calves....

  18. 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.

  19. High-fat diet with acyl-ghrelin treatment leads to weight gain with low inflammation, high oxidative capacity and normal triglycerides in rat muscle.

    PubMed

    Barazzoni, Rocco; Zanetti, Michela; Semolic, Annamaria; Cattin, Maria Rosa; Pirulli, Alessia; Cattin, Luigi; Guarnieri, Gianfranco

    2011-01-01

    Obesity is associated with muscle lipid accumulation. Experimental models suggest that inflammatory cytokines, low mitochondrial oxidative capacity and paradoxically high insulin signaling activation favor this alteration. The gastric orexigenic hormone acylated ghrelin (A-Ghr) has antiinflammatory effects in vitro and it lowers muscle triglycerides while modulating mitochondrial oxidative capacity in lean rodents. We tested the hypothesis that A-Ghr treatment in high-fat feeding results in a model of weight gain characterized by low muscle inflammation and triglycerides with high muscle mitochondrial oxidative capacity. A-Ghr at a non-orexigenic dose (HFG: twice-daily 200-µg s.c.) or saline (HF) were administered for 4 days to rats fed a high-fat diet for one month. Compared to lean control (C) HF had higher body weight and plasma free fatty acids (FFA), and HFG partially prevented FFA elevation (P<0.05). HFG also had the lowest muscle inflammation (nuclear NFkB, tissue TNF-alpha) with mitochondrial enzyme activities higher than C (P<0.05 vs C, P = NS vs HF). Under these conditions HFG prevented the HF-associated muscle triglyceride accumulation (P<0.05). The above effects were independent of changes in redox state (total-oxidized glutathione, glutathione peroxidase activity) and were not associated with changes in phosphorylation of AKT and selected AKT targets. Ghrelin administration following high-fat feeding results in a novel model of weight gain with low inflammation, high mitochondrial enzyme activities and normalized triglycerides in skeletal muscle. These effects are independent of changes in tissue redox state and insulin signaling, and they suggest a potential positive metabolic impact of ghrelin in fat-induced obesity.

  20. Plasma ghrelin in anorexia, bulimia, and binge-eating disorder: relations with eating patterns and circulating concentrations of cortisol and thyroid hormones.

    PubMed

    Troisi, Alfonso; Di Lorenzo, Giorgio; Lega, Ilaria; Tesauro, Manfredi; Bertoli, Aldo; Leo, Roberto; Iantorno, Micaela; Pecchioli, Chiara; Rizza, Stefano; Turriziani, Mario; Lauro, Renato; Siracusano, Alberto

    2005-01-01

    The present study was designed to investigate the relations between plasma ghrelin concentrations, eating patterns, and circulating concentrations of cortisol and thyroid hormones in women with anorexia nervosa, bulimia nervosa, and binge-eating disorder. The patterns of disordered eating behavior were assessed using the Eating Attitudes Test (EAT-26) and the Bulimia Test-Revised (BULIT-R). In women with eating disorders, but not in healthy control women, plasma ghrelin concentrations were negatively correlated with body mass index (BMI) and plasma concentrations of thyreotropin (TSH), free T3 and free T4, and positively correlated with plasma concentrations of cortisol. The ghrelin concentrations of women with binge-eating and purging behavior were significantly lower than those of women with anorexia nervosa, restricting type, and there was a negative relation between the frequency and severity of binge-eating and purging behavior, as measured by the BULIT-R total score, and ghrelin concentrations. In a multivariate regression model controlling for the confounding effects of body mass index (BMI) and age, higher ghrelin concentrations were correlated with lower BULIT-R total scores. The results of this study did not confirm the hypothesis advanced in previous studies that ghrelin concentrations are higher in patients with binge-eating/purging forms of eating disorders. Based on these data, we suggest that, in women with eating disorders, ghrelin concentrations best reflect nutritional status rather than specific patterns of disordered eating behavior.

  1. 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

  2. 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 Central

    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. PMID:27127509

  3. 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

  4. 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.

  5. 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.

  6. Seasonal and parity effects on ghrelin levels throughout the estrous cycle in dairy cows.

    PubMed

    Honig, Hen; Ofer, Lior; Elbaz, Michal; Kaim, Moshe; Shinder, Dima; Gershon, Eran

    2016-09-01

    In dairy cows, heat stress depresses appetite, leading to decreased food intake, a negative energy balance, and modifies ghrelin levels. Ghrelin is a gut-brain peptide with two major forms: acylated, with an O-n-octanoylated serine in position 3, and nonacylated. To date, the effect of heat stress and estrous cycle on ghrelin secretion in dairy cows has not been studied. We characterized ghrelin secretion during the estrous cycle in each, the winter and the summer seasons. We further examined the effects of parity on ghrelin secretion. Blood was collected from 10 primiparous or multiparous Israeli-Holstein dairy cows throughout the estrous cycle, in both, the hot and cold seasons. The levels of acylated and total ghrelin were measured in the blood samples. We found that both acylated and total ghrelin levels during heat stress were lower than their respective levels in the winter in both, primiparous and multiparous cows. No differences in acylated and total ghrelin levels were found between primiparous and multiparous cows in both seasons. We further found that in multiparous but not primiparous cows acylated ghrelin secretion oscillated during the estrous cycle in both seasons. Its levels peaked on the last days of the first follicular wave and on the days before and during ovulation. Interestingly, we found that elevated acylated ghrelin levels correlated with conception success and increased total ghrelin levels were associated with successful conception from first insemination. Our data is the first to demonstrate seasonal variation in ghrelin secretion. This study provides evidence for the yet unfamiliar link between heat stress, ghrelin and fertility. Increased circulating acylated ghrelin may contribute to improved fertility in dairy cows. It further raises the possibility of a link between ghrelin levels and successful inseminations. Further research is required to determine the effects of ghrelin on dairy cow performance.

  7. Seasonal and parity effects on ghrelin levels throughout the estrous cycle in dairy cows.

    PubMed

    Honig, Hen; Ofer, Lior; Elbaz, Michal; Kaim, Moshe; Shinder, Dima; Gershon, Eran

    2016-09-01

    In dairy cows, heat stress depresses appetite, leading to decreased food intake, a negative energy balance, and modifies ghrelin levels. Ghrelin is a gut-brain peptide with two major forms: acylated, with an O-n-octanoylated serine in position 3, and nonacylated. To date, the effect of heat stress and estrous cycle on ghrelin secretion in dairy cows has not been studied. We characterized ghrelin secretion during the estrous cycle in each, the winter and the summer seasons. We further examined the effects of parity on ghrelin secretion. Blood was collected from 10 primiparous or multiparous Israeli-Holstein dairy cows throughout the estrous cycle, in both, the hot and cold seasons. The levels of acylated and total ghrelin were measured in the blood samples. We found that both acylated and total ghrelin levels during heat stress were lower than their respective levels in the winter in both, primiparous and multiparous cows. No differences in acylated and total ghrelin levels were found between primiparous and multiparous cows in both seasons. We further found that in multiparous but not primiparous cows acylated ghrelin secretion oscillated during the estrous cycle in both seasons. Its levels peaked on the last days of the first follicular wave and on the days before and during ovulation. Interestingly, we found that elevated acylated ghrelin levels correlated with conception success and increased total ghrelin levels were associated with successful conception from first insemination. Our data is the first to demonstrate seasonal variation in ghrelin secretion. This study provides evidence for the yet unfamiliar link between heat stress, ghrelin and fertility. Increased circulating acylated ghrelin may contribute to improved fertility in dairy cows. It further raises the possibility of a link between ghrelin levels and successful inseminations. Further research is required to determine the effects of ghrelin on dairy cow performance. PMID:27288640

  8. Higher habitual intake of dietary fat and carbohydrates are associated with lower leptin and higher ghrelin concentrations in overweight and obese postmenopausal women with elevated insulin levels.

    PubMed

    Kong, Angela; Neuhouser, Marian L; Xiao, Liren; Ulrich, Cornelia M; McTiernan, Anne; Foster-Schubert, Karen E

    2009-11-01

    A highly regulated homeostatic system governs body weight; however, it is possible that this system might be impaired by the sustained intake of highly palatable foods. Short-term feeding studies suggest that the appetite-stimulating hormone ghrelin is suppressed less effectively by dietary fat intake, and diets high in sucrose decrease levels of the adipose hormone leptin. We hypothesized that higher habitual intake of dietary fat and carbohydrate (CHO) would be associated with elevated concentrations of circulating plasma ghrelin and lower circulating leptin in humans, a hormonal profile that could promote weight gain. To test our hypothesis, we examined the cross-sectional associations of ghrelin and leptin with the habitual macronutrient intake of 165 healthy overweight and obese sedentary women and tested the modifying role of insulin in these associations. We observed a significant inverse association between leptin concentrations and percentage energy from CHO independent of body mass index, percentage body fat, age, and intraabdominal fat (beta = -0.11 P = .04). No significant associations were observed between ghrelin and macronutrients or their subtypes among the total cohort. Among women with insulin concentrations at or greater than the median, we found a statistically significant positive association between intake of saturated fat and ghrelin concentrations, as well as additional statistically significant associations between leptin concentrations and macronutrients not observed among the total cohort. Our results provide some evidence that diets higher in fat and CHO are associated with a hormonal profile (ie, lower leptin and higher ghrelin concentrations), which could enhance weight gain, particularly among individuals with higher circulating insulin concentrations.

  9. Circulating ghrelin and leptin concentrations and growth hormone secretagogue receptor abundance in liver, muscle, and adipose tissue of beef cattle exhibiting differences in composition of gain.

    PubMed

    Jennings, J S; Wertz-Lutz, A E; Pritchard, R H; Weaver, A D; Keisler, D H; Bruns, K

    2011-12-01

    Data from species other than cattle indicate that ghrelin and GH secretagogue receptor (GHS-R) could play a key role in fat deposition, energy homeostasis, or glucose metabolism by directly affecting liver and adipose tissue metabolism. Beef steers (n = 72) were used to test the hypothesis that plasma ghrelin and leptin concentrations and abundance of the GHS-R in liver, muscle, and adipose tissues differ in steers exhibiting differences in composition of gain. At trial initiation (d 0), 8 steers were slaughtered for initial carcass composition. The remaining 64 steers were stratified by BW, allotted to pen, and treatment was assigned randomly to pen. Steers were not implanted with anabolic steroids. Treatments were 1) a low-energy (LE) diet fed during the growing period (0 to 111 d) followed by a high-energy (HE) diet during the finishing period (112 to 209 d; LE-HE) or 2) the HE diet for the duration of the trial (1 to 209 d; HE-HE). Eight steers per treatment were slaughtered on d 88, 111, 160, and 209. Carcass ninth, tenth, and eleventh rib sections were dissected for chemical composition and regression equations were developed to predict compositional gain. Liver, muscle, and subcutaneous adipose tissues were frozen in liquid nitrogen for subsequent Western blotting for GHS-R. Replicate blood samples collected before each slaughter were assayed for ghrelin and leptin concentrations. When compared at a common compositional fat end-point, the rate of carcass fat accretion (g·kg of shrunk BW(-1)) was greater (P < 0.001) in HE-HE steers whereas the rate of carcass protein accretion (g·kg of shrunk BW(-1)) was less (P < 0.001) compared with LE-HE steers. When compared at a common compositional fat end-point, plasma leptin, ghrelin, and insulin concentrations were greater (P < 0.05) for HE-HE compared with LE-HE steers. Abundance of the GHS-R, to which ghrelin binds, increased over time in liver and adipose tissue but did not differ as a result of treatment

  10. Impact of maternal BMI and sampling strategy on the concentration of leptin, insulin, ghrelin and resistin in breast milk across a single feed: a longitudinal cohort study

    PubMed Central

    Andreas, Nicholas J; Hyde, Matthew J; Herbert, Bronwen R; Jeffries, Suzan; Santhakumaran, Shalini; Mandalia, Sundhiya; Holmes, Elaine; Modi, Neena

    2016-01-01

    Objectives We tested the hypothesis that there is a positive association between maternal body mass index (BMI) and the concentration of appetite-regulating hormones leptin, insulin, ghrelin and resistin in breast milk. We also aimed to describe the change in breast milk hormone concentration within each feed, and over time. Setting Mothers were recruited from the postpartum ward at a university hospital in London. Breast milk samples were collected at the participants’ homes. Participants We recruited 120 healthy, primiparous, breastfeeding mothers, aged over 18 years. Mothers who smoked, had multiple births or had diabetes were excluded. Foremilk and hindmilk samples were collected from 105 women at 1 week postpartum and 92 women at 3 months postpartum. Primary and secondary outcome measures We recorded maternal and infant anthropometric measurements at each sample collection and measured hormone concentrations using a multiplex assay. Results The concentration of leptin in foremilk correlated with maternal BMI at the time of sample collection, at 7 days (r=0.31, p=0.02) and 3 months postpartum (r=0.30, p=<0.00). Foremilk insulin correlated with maternal BMI at 3 months postpartum (r=0.22, p=0.04). Breast milk ghrelin and resistin were not correlated with maternal BMI. Ghrelin concentrations at 3 months postpartum were increased in foremilk compared with hindmilk (p=0.01). Concentrations of ghrelin were increased in hindmilk collected at 1  week postpartum compared with samples collected at 3 months postpartum (p=0.03). A trend towards decreased insulin concentrations in hindmilk was noted. Concentrations of leptin and resistin were not seen to alter over a feed. Conclusions A positive correlation between maternal BMI and foremilk leptin concentration at both time points studied, and foremilk insulin at 3 months postpartum was observed. This may have implications for infant appetite regulation and obesity risk. PMID:27388351

  11. Ghrelin gene products and the regulation of food intake and gut motility.

    PubMed

    Chen, Chih-Yen; Asakawa, Akihiro; Fujimiya, Mineko; Lee, Shou-Dong; Inui, Akio

    2009-12-01

    A breakthrough using "reverse pharmacology" identified and characterized acyl ghrelin from the stomach as the endogenous cognate ligand for the growth hormone (GH) secretagogue receptor (GHS-R) 1a. The unique post-translational modification of O-n-octanoylation at serine 3 is the first in peptide discovery history and is essential for GH-releasing ability. Des-acyl ghrelin, lacking O-n-octanoylation at serine 3, is also produced in the stomach and remains the major molecular form secreted into the circulation. The third ghrelin gene product, obestatin, a novel 23-amino acid peptide identified from rat stomach, was found by comparative genomic analysis. Three ghrelin gene products actively participate in modulating appetite, adipogenesis, gut motility, glucose metabolism, cell proliferation, immune, sleep, memory, anxiety, cognition, and stress. Knockdown or knockout of acyl ghrelin and/or GHS-R1a, and overexpression of des-acyl ghrelin show benefits in the therapy of obesity and metabolic syndrome. By contrast, agonism of acyl ghrelin and/or GHS-R1a could combat human anorexia-cachexia, including anorexia nervosa, chronic heart failure, chronic obstructive pulmonary disease, liver cirrhosis, chronic kidney disease, burn, and postsurgery recovery, as well as restore gut dysmotility, such as diabetic or neurogenic gastroparesis, and postoperative ileus. The ghrelin acyl-modifying enzyme, ghrelin O-Acyltransferase (GOAT), which attaches octanoate to serine-3 of ghrelin, has been identified and characterized also from the stomach. To date, ghrelin is the only protein to be octanylated, and inhibition of GOAT may have effects only on the stomach and is unlikely to affect the synthesis of other proteins. GOAT may provide a critical molecular target in developing novel therapeutics for obesity and type 2 diabetes. PMID:20038570

  12. 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.

  13. Dietary Mannoheptulose Increases Fasting Serum Glucagon Like Peptide-1 and Post-Prandial Serum Ghrelin Concentrations in Adult Beagle Dogs

    PubMed Central

    McKnight, Leslie L.; Eyre, Ryan; Gooding, Margaret A.; Davenport, Gary M.; Shoveller, Anna Kate

    2015-01-01

    Simple Summary There is increased interest in the use of nutraceuticals for weight management in companion animals. A nutraceutical can broadly be considered a food (or a part of) that provides a health benefit. Mannoheptulose (MH), a sugar found in avocados, is being investigated as a nutraceutical for dogs. In this study, dogs fed a diet containing MH had increased concentrations of blood biomarkers related to energy intake. In addition, dogs fed MH were less physically active than dogs fed a control diet. These findings suggest that dietary MH has the ability to alter energy intake and lower daily energy expenditure. Abstract There is a growing interest in the use of nutraceuticals for weight management in companion animals. The purpose of this study was to determine the effects of mannoheptulose (MH), a sugar in avocados that inhibits glycolysis, on energy metabolism in adult Beagle dogs. The study was a double-blind, randomized controlled trial where dogs were allocated to a control (CON, n = 10, 10.1 ± 0.4 kg) or MH containing diet (168 mg/kg, n = 10, 10.3 ± 0.4 kg). Blood was collected after an overnight fast and 1 h post-feeding (week 12) to determine serum satiety related hormones and biochemistry. Resting and post-prandial energy expenditure and respiratory quotient were determined by indirect calorimetry (weeks 4 and 8). Physical activity was measured using an accelerometer (weeks 3, 7, 11). Body composition was assessed using dual X-ray absorptiometry (week 12). MH significantly (p < 0.05) increased fasting serum glucagon-like peptide-1 and post-prandial serum ghrelin. MH tended (p < 0.1) to increase fasting serum gastric inhibitory peptide and decrease physical activity. Together, these findings suggest that dietary MH has the ability to promote satiation and lowers daily energy expenditure. PMID:26479244

  14. 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.

  15. Altered hepatic retinyl ester concentration and acyl composition in response to alcohol consumption.

    PubMed

    Clugston, Robin D; Jiang, Hongfeng; Lee, Man Xia; Berk, Paul D; Goldberg, Ira J; Huang, Li-Shin; Blaner, William S

    2013-07-01

    Retinoids (vitamin A and its metabolites) are essential micronutrients that regulate many cellular processes. Greater than 70% of the body's retinoid reserves are stored in the liver as retinyl ester (RE). Chronic alcohol consumption induces depletion of hepatic retinoid stores, and the extent of this has been correlated with advancing stages of alcoholic liver disease. The goal of this study was to analyze the mechanisms responsible for depletion of hepatic RE stores by alcohol consumption A change in the fatty-acyl composition of RE in alcohol-fed mice was observed within two weeks after the start of alcohol consumption. Specifically, alcohol-feeding was associated with a significant decline in hepatic retinyl palmitate levels; however, total RE levels were maintained by a compensatory increase in levels of usually minor RE species, particularly retinyl oleate. Our data suggests that alcohol feeding initially stimulates a futile cycle of RE hydrolysis and synthesis, and that the change in RE acyl composition is associated with a change in the acyl composition of hepatic phosphatidylcholine. The alcohol-induced change in RE acyl composition was specific to the liver, and was not seen in lung or white adipose tissue. This shift in hepatic RE fatty acyl composition is a sensitive indicator of alcohol consumption and may be an early biomarker for events associated with the development of alcoholic liver disease. PMID:24046868

  16. Altered hepatic retinyl ester concentration and acyl composition in response to alcohol consumption.

    PubMed

    Clugston, Robin D; Jiang, Hongfeng; Lee, Man Xia; Berk, Paul D; Goldberg, Ira J; Huang, Li-Shin; Blaner, William S

    2012-07-01

    Retinoids (vitamin A and its metabolites) are essential micronutrients that regulate many cellular processes. Greater than 70% of the body's retinoid reserves are stored in the liver as retinyl ester (RE). Chronic alcohol consumption induces depletion of hepatic retinoid stores, and the extent of this has been correlated with advancing stages of alcoholic liver disease. The goal of this study was to analyze the mechanisms responsible for depletion of hepatic RE stores by alcohol consumption. A change in the fatty-acyl composition of RE in alcohol-fed mice was observed within two weeks after the start of alcohol consumption. Specifically, alcohol-feeding was associated with a significant decline in hepatic retinyl palmitate levels; however, total RE levels were maintained by a compensatory increase in levels of usually minor RE species, particularly retinyl oleate. Our data suggests that alcohol feeding initially stimulates a futile cycle of RE hydrolysis and synthesis, and that the change in RE acyl composition is associated with a change in the acyl composition of hepatic phosphatidylcholine. The alcohol-induced change in RE acyl composition was specific to the liver, and was not seen in lung or white adipose tissue. This shift in hepatic RE fatty acyl composition is a sensitive indicator of alcohol consumption and may be an early biomarker for events associated with the development of alcoholic liver disease. PMID:23583843

  17. Plasma butyrylcholinesterase regulates ghrelin to control aggression.

    PubMed

    Chen, Vicky Ping; Gao, Yang; Geng, Liyi; Parks, Robin J; Pang, Yuan-Ping; Brimijoin, Stephen

    2015-02-17

    Ongoing mouse studies of a proposed therapy for cocaine abuse based on viral gene transfer of butyrylcholinesterase (BChE) mutated for accelerated cocaine hydrolysis have yielded surprising effects on aggression. Further investigation has linked these effects to a reduction in circulating ghrelin, driven by BChE at levels ∼ 100-fold above normal. Tests with human BChE showed ready ghrelin hydrolysis at physiologic concentrations, and multiple low-mass molecular dynamics simulations revealed that ghrelin's first five residues fit sterically and electrostatically into BChE's active site. Consistent with in vitro results, male BALB/c mice with high plasma BChE after gene transfer exhibited sharply reduced plasma ghrelin. Unexpectedly, such animals fought less, both spontaneously and in a resident/intruder provocation model. One mutant BChE was found to be deficient in ghrelin hydrolysis. BALB/c mice transduced with this variant retained normal plasma ghrelin levels and did not differ from untreated controls in the aggression model. In contrast, C57BL/6 mice with BChE gene deletion exhibited increased ghrelin and fought more readily than wild-type animals. Collectively, these findings indicate that BChE-catalyzed ghrelin hydrolysis influences mouse aggression and social stress, with potential implications for humans.

  18. Ghrelin and its promoter variant associated with cardiac hypertrophy.

    PubMed

    Ukkola, O; Pääkkö, T; Kesäniemi, Y A

    2012-07-01

    The roles of ghrelin, a peptide hormone that has a role in regulating food intake and energy homeostasis, in the cardiovascular system have not yet been unambiguously established. We evaluated the association between plasma ghrelin concentrations and -501A>C single-nucleotide polymorphism (SNP) in the ghrelin gene 5' flanking area and echocardiographic measurements in 1037 middle-aged subjects. Left ventricular mass index (LVMI) was calculated according to Devereux's method. The ambulatory blood pressure (BP) was recorded using the fully automatic SpaceLabs 90207 oscillometric unit. Results suggested that plasma ghrelin was not related to mean ambulatory BP values. However, the highest plasma ghrelin tertile was associated with increased intraventricular septum (P=0.043) and posterior ventricular wall (P=0.002) thicknesses as well as left ventricular mass (P=0.05). After adjustment for age, sex, body mass index and systolic BP, the association persisted between ghrelin tertiles and intraventricular septum (P=0.05) and posterior ventricular wall (P=0.001) thicknesses. The SNP -501A>C polymorphism was associated with LVMI after adjustments for age, sex and systolic BP. In conclusion, ghrelin and its promoter variant are associated with cardiac hypertrophy indexes independent of BP. Positive correlation between ghrelin levels and increased wall thickness parameters may reflect compensatory up-regulation of ghrelin concentrations or direct effects of ghrelin on myocardium. The effects of the SNP seem not to be mediated through its effects on ghrelin plasma levels. PMID:21614024

  19. 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.

  20. Effects of capsaicin on testis ghrelin expression in mice.

    PubMed

    Ilhan, T; Erdost, H

    2013-01-01

    Capsaicin (CAP), the active substance of red hot peppers, has been reported to stimulate development of the gonad. Ghrelin is an acylated polypeptide hormone that is secreted predominantly by endocrine cells of the stomach. There is evidence that ghrelin is involved in reproductive function. Ghrelin significantly inhibits testosterone secretion in a dose-dependent manner. We investigated the effect of CAP on ghrelin expression in testes of mice and on testosterone levels during pubertal and adult periods. We used a variety of morphometric, immunohistochemical and biochemical methods, and western blot analysis. The animals were divided into two age groups: puberty and adult. Control groups for both age groups were fed with standard diet and experimental groups were fed with a diet containing 0.02% CAP. Testes were collected quickly after sacrifice. After dehydration, the specimens were embedded in paraffin and 5 μm sections were cut, and Crossman's triple staining and immunohistochemical staining for ghrelin were applied. Immunohistochemical staining with ghrelin antibody for both age groups demonstrated immunoreaction especially in Leydig and Sertoli cells, but no reaction was observed in spermatogenic cells. Ghrelin immunoreaction was less intense in the experimental groups. Serum testosterone levels were increased in both experimental groups, especially in adults. More spermatocytes were observed in the experimental group compared to the control group. In both pubertal and adult experimental groups, the seminiferous epithelium was thick. CAP appears to enhance testicular cell proliferation and can affect the release of ghrelin and testosterone directly or indirectly.

  1. Concentrations of long-chain acyl-acyl carrier proteins during fatty acid synthesis by chloroplasts isolated from pea (Pisum sativum), safflower (Carthamus tinctoris), and amaranthus (Amaranthus lividus) leaves

    SciTech Connect

    Roughan, G.; Nishida, I. )

    1990-01-01

    Fatty acid synthesis from (1-14C)acetate by chloroplasts isolated from peas and amaranthus was linear for at least 15 min, whereas incorporation of the tracer into long-chain acyl-acyl carrier protein (ACP) did not increase after 2-3 min. When reactions were transferred to the dark after 3-5 min, long-chain acyl-ACPs lost about 90% of their radioactivity and total fatty acids retained all of theirs. Half-lives of the long-chain acyl-ACPs were estimated to be 10-15 s. Concentrations of palmitoyl-, stearoyl-, and oleoyl-ACP as indicated by equilibrium labeling during steady-state fatty acid synthesis, ranged from 0.6-1.1, 0.2-0.7, and 0.4-1.6 microM, respectively, for peas and from 1.6-1.9, 1.3-2.6, and 0.6-1.4 microM, respectively, for amaranthus. These values are based on a chloroplast volume of 47 microliters/mg chlorophyll and varied according to the mode of the incubation. A slow increase in activity of the fatty acid synthetase in safflower chloroplasts resulted in long-chain acyl-ACPs continuing to incorporate labeled acetate for 10 min. Upon re-illumination following a dark break, however, both fatty acid synthetase activity and acyl-ACP concentrations increased very rapidly. Palmitoyl-ACP was present at concentrations up to 2.5 microM in safflower chloroplasts, whereas those of stearoyl- and oleoyl-ACPs were in the lower ranges measured for peas. Acyl-ACPs were routinely separated from extracts of chloroplasts that had been synthesising long-chain fatty acids from labeled acetate by a minor modification of the method of Mancha et al. The results compared favorably with those obtained using alternative analytical methods such as adsorption to filter paper and partition chromatography on silicic acid columns.

  2. Effect of preduodenal lipase inhibition in suckling rats on dietary octanoic acid (C8:0) gastric absorption and plasma octanoylated ghrelin concentration.

    PubMed

    Lemarié, F; Cavalier, J-F; Garcia, C; Boissel, F; Point, V; Catheline, D; Legrand, P; Carrière, F; Rioux, V

    2016-09-01

    Part of medium chain fatty acids (MCFAs) coming from dietary triglycerides (TGs) can be directly absorbed through the gastric mucosa after the action of preduodenal lipase (lingual lipase in the rat). MCFA gastric absorption, particularly that of octanoic acid (C8:0), may have a physiological importance in the octanoylation of ghrelin, the orexigenic gastric peptide acting as an endogenous ligand of the hypothalamic growth hormone secretagogue receptor 1a (GHSR-1a). However, the amount of C8:0 absorbed in the stomach and its metabolic fate still haven't been clearly characterized. The purpose of the present study was to further characterize and quantify the importance of preduodenal lipase activity on the release and gastric absorption of dietary C8:0 and on the subsequent ghrelin octanoylation in the stomach mucosa. Fifteen days old rats received fat emulsions containing triolein or [1,1,1-(13)C]-Tri-C8:0 and a specific inhibitor of preduodenal lipase, 5-(2-(benzyloxy)ethoxy)-3-(3-phenoxyphenyl)-1,3,4-oxadiazol-2(3H)-one or BemPPOX. The fate of the (13)C-C8:0 was followed in rat tissues after 30 and 120min of digestion and octanoylated ghrelin was measured in the plasma. This work (1) demonstrates that part of C8:0 coming from Tri-C8:0 is directly absorbed at the gastric level, (2) allows the estimation of C8:0 gastric absorption level (1.3% of the (13)C-C8:0 in sn-3 position after 30min of digestion), as well as (3) the contribution of rat lingual lipase to total lipolysis and to duodenal absorption of dietary FAs (at least 30%), (4) shows no short-term effect of dietary Tri-C8:0 consumption and subsequent increase of C8:0 gastric tissue content on plasma octanoylated ghrelin concentration. PMID:27317984

  3. 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.

  4. 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

  5. Change in intrarenal Ghrelin expression in immune complex-mediated glomerular disease in dogs

    PubMed Central

    YABUKI, Akira; MIZUKAMI, Keijiro; TOKUNAGA, Satoshi; YAMATO, Osamu

    2015-01-01

    Ghrelin is a peptide hormone that is mainly produced by the stomach. The kidney is a major source of local ghrelin, and maintaining body fluid balance is considered a critical role of renal ghrelin. However, there are no reports on renal ghrelin in small animal medicine. The present study investigated the intrarenal localization of and change in ghrelin expression in dogs with immune complex-mediated glomerulonephritis (ICGN). Ghrelin immunoreactivity (IR) was observed in the distal tubules of normal kidneys. Ghrelin IR was weak in ICGN kidneys, and the quantitative ghrelin IR score was significantly lower in ICGN kidneys than in normal kidneys. In cases of ICGN, plasma creatinine concentrations showed a positive correlation with the ghrelin IR score. PMID:26256231

  6. Role of ghrelin in the regulation of appetite in children.

    PubMed

    Savastio, S; Bellone, S; Baldelli, R; Ferraris, M; Lapidari, A; Zanetta, F; Sogni, S; Petri, A; Bona, G

    2006-02-01

    Ghrelin, the new recently discovered hormone, is a 28 amino-acid acylated peptide predominantly produced by the stomach characterized by a strong GH-releasing activity mediated by the hypothalamic-pituitary GH secretagogues (GHSs) receptors. Ghrelin and GHSs, acting on central and peripheral receptors, exert other actions such as stimulation of ACTH and prolactin secretion, influence on insulin secretion and glucose metabolism, orexigenic effect and modulatory activity on the neuroendocrine and metabolic response to starvation, influence on exocrine gastro-entero-pancreatic functions, cardiovascular activities and modulation of cell proliferation and apoptosis. The wide spectrum of ghrelin action requires further studies to provide critical information on the role of ghrelin and the potential perspectives of its analogues in the clinical practice. This point is of particular interest in the field of pediatric endocrinology and metabolism because the ghrelin story started focusing on GH deficiency and is now extending to aspects that once again are of major relevance such as obesity and eating disorders, regulation of the hypothalamus-pituitary-adrenal and gonadal axis. More studies are needed to evaluate the real impact of ghrelin in different non endocrine processes and the possible use of ghrelin analogues in different diseases condition.

  7. Nutritional and environmental factors affecting plasma ghrelin and leptin levels in rats.

    PubMed

    Nakahara, Keiko; Okame, Rieko; Katayama, Tetsuro; Miyazato, Mikiya; Kangawa, Kenji; Murakami, Noboru

    2010-10-01

    We examined which factors suppress the rise of ghrelin secretion under hunger in 16-h-starved rats, and compared the responses of plasma ghrelin and leptin levels to various exogenous and endogenous stimuli in intact rats. Although an acute expansion of the stomach by infusion of 6 ml air or 3 ml water in rats starved for 16 h did not change the level of plasma acyl-ghrelin 3 ml corn starch solution, corn oil, or 20% ethanol significantly decreased it. Vagotomy inhibited suppression by nutrients but not by ethanol. Chronic infusion of ethanol into the stomach for 3 weeks in free-feeding rats caused widespread injury of the stomach mucosa, and increased both plasma ghrelin levels and the number of ghrelin cells. In intact rats, low temperature did not change ghrelin levels, but increased leptin levels. On the other hand, restriction stress decreased plasma ghrelin levels, but had the reverse effect on plasma leptin levels. Although insulin decreased and 20% glucose increased plasma glucose levels, they both decreased plasma ghrelin levels. Insulin elevated plasma leptin levels, but glucose had no effect. These results indicate that 1) acyl-ghrelin secretion from the stomach under fasting condition is suppressed by nutrients but not by mechanical expansion of the stomach; 2) high and low environmental temperature, stress, or administration of insulin reciprocally affect plasma levels of ghrelin and leptin; and 3) an increase of stomach ghrelin cell number and plasma ghrelin levels after chronic ethanol treatment may be involved in restoration of gastric mucosae.

  8. Mole ghrelin: cDNA cloning, gene expression, and diverse molecular forms in Mogera imaizumii.

    PubMed

    Satou, Motoyasu; Kaiya, Hiroyuki; Nishi, Yoshihiro; Shinohara, Akio; Kawada, Shin-Ichiro; Miyazato, Mikiya; Kangawa, Kenji; Sugimoto, Hiroyuki

    2016-06-01

    Here, we describe cDNA cloning and purification of the ghrelin gene sequences and ghrelin peptides from the Japanese true mole, Mogera imaizumii. The gene spans >2.9kbp, has four exons and three introns, and shares structural similarity with those of terrestrial animals. Mature mole ghrelin peptide was predicted to be 28 amino acids long (GSSFLSPEHQKVQQRKESKKPPSKPQPR) and processed from a prepropeptide of 116 amino acids. To further elucidate molecular characteristics, we purified ghrelin peptides from mole stomach. By mass spectrometry, we found that the mole ghrelin peptides had higher ratios of the odd-number fatty acids (C9 and C11 as much as C8) attached to the third serine residue than other vertebrate ghrelin. Truncated forms of ghrelins such as [1-27], [1-19], [1-16] and [1-15], and that lacked the 14th glutamine residue (des-Gln14 ghrelin) were produced in the stomach. Marked expression of ghrelin mRNA in lung was observed as in stomach and brain. Phylogenetic analysis indicated that the branch of M. imaizumii has slightly higher dN/dS ratios (the nucleotide substitution rates at non-synonymous and synonymous sites) than did other eulipotyphlans. Peptide length was positively correlated with human ghrelin receptor activation, whereas the length of fatty-acyl chains showed no obvious functional correlation. The basal higher luciferase activities of the 5'-proximal promoter region of mole ghrelin were detected in ghrelin-negative C2C12 cells and hypoxic culture conditions impaired transcriptional activity. These results indicated that moles have acquired diverse species of ghrelin probably through distinctive fatty acid metabolism because of their food preferences. The results provide a gateway to understanding ghrelin metabolism in fossorial animals. PMID:27102942

  9. 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

  10. 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.

  11. 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

  12. Ghrelin protects infarcted myocardium by induction of autophagy and AMP-activated protein kinase pathway.

    PubMed

    Yuan, Ming-Jie; Kong, Bin; Wang, Tao; Wang, Xin; Huang, He; Maghsoudi, Taneen

    2016-08-01

    The majority of studies have reported that enhancing autophagy in the myocardium is cardioprotective. Here, we tested the hypothesis that ghrelin, a growth hormone-releasing peptide, will protect infarcted myocardium by inducing of autophagy. Myocardial infarction was induced in mice by left coronary artery ligation the surviving mice 24 h after surgical were started on 2 week treatments with one of the following: vehicle, acylated ghrelin(50 mg/kg per day) or acylated ghrelin plus 3-MA(an autophagy inhibitor, 15 mg/kg, per day). We found that ghrelin significantly improved the cardiac function, and autophagy was enhanced by elevated LC3-II/LC-I ratio and mRNA expression of autophagy related protein. In vitro, cultured neonatal rat ventricular cardiomyocytes were subjected to simulate ischemia/reperfusion, 3-MA significantly attenuated ghrelin-induced autophagy, which was associated with activated AMP-activated protein kinase (AMPK) signal pathway. Moreover, ghrelin reduced cell death, and RNAi-mediated knockdown of autophagy protein 5 (Atg5) partly abolished ghrelin's cardioprotective effect. It is the first time to demonstrate that the cardioprotective effect of ghrelin on ischemia myocardium in part through regulating of autophagy signal pathway. PMID:27235554

  13. Ghrelin and reproductive disorders.

    PubMed

    Repaci, Andrea; Gambineri, Alessandra; Pagotto, Uberto; Pasquali, Renato

    2011-06-20

    Ghrelin is an important factor involved in most of the metabolic and hormonal signals which adapt the reproductive functions in conditions of altered energy balance. Moreover, the coordinated role of leptin and ghrelin appears in fact to have a specific role in the regulation of puberty. Systemic action of ghrelin on the reproductive axis involves the control of the hypothalamic-pituitary-gondal axis. In addition, it has been shown that ghrelin may directly act at a gonadal level in both females and males. Available data also demonstrate that sex steroid hormones and gonadotropins may in turn regulate the gonadal effect of ghrelin, as documented by studies performed in females with the polycystic ovary syndrome and in hypogonadal men. Notably, recent studies also confirm a potentially important role for ghrelin in fetal and neonatal energy balance, and specifically in allowing fetal adaptation to an adverse intrauterine environment.

  14. 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.

  15. Abnormal ghrelin and pancreatic polypeptide responses in gastroparesis.

    PubMed

    Gaddipati, Kishore V; Simonian, Hrair P; Kresge, Karen M; Boden, Guenther H; Parkman, Henry P

    2006-08-01

    Vagal nerve dysfunction has been implicated in the pathogenesis of diabetic gastroparesis, but its role in idiopathic gastroparesis remains uncertain. The increase in pancreatic polypeptide with sham feeding is often used as a measure of vagal integrity. Ghrelin has been suggested to function as an appetite-stimulating hormone from the gut to the brain acting through vagal afferent pathways. Systemic ghrelin also rises in part due to vagal efferent pathways. Alterations in ghrelin and its effects on appetite could play a role in gastroparesis. In this study we aimed [1] to investigate the presence of vagal nerve dysfunction in patients with idiopathic and diabetic gastroparesis and [2] to determine if alterations in ghrelin concentrations occur in gastroparesis. Normal subjects and patients with diabetic, idiopathic, or postsurgical gastroparesis underwent a sham feeding protocol. Serial blood samples were obtained for plasma ghrelin and pancreatic polypeptide. Sham feeding was characterized by an increase in pancreatic polypeptide and ghrelin in normal controls and patients with idiopathic gastroparesis. The changes in pancreatic polypeptide and ghrelin levels in diabetic and postsurgical gastroparesis were significantly less than those in normal subjects. Vagal nerve dysfunction, as evidenced by an impaired pancreatic polypeptide response with sham feeding, is present in diabetic gastroparesis but not idiopathic gastroparesis. Systemic ghrelin concentrations increased with sham feeding in normal subjects and patients with idiopathic gastroparesis but not in diabetic or postsurgical gastroparesis. Vagal function and regulation of ghrelin levels are impaired in diabetic gastroparesis. PMID:16868831

  16. 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. PMID:26732975

  17. Dietary Mannoheptulose Increases Fasting Serum Glucagon Like Peptide-1 and Post-Prandial Serum Ghrelin Concentrations in Adult Beagle Dogs.

    PubMed

    McKnight, Leslie L; Eyre, Ryan; Gooding, Margaret A; Davenport, Gary M; Shoveller, Anna Kate

    2015-01-01

    There is a growing interest in the use of nutraceuticals for weight management in companion animals. The purpose of this study was to determine the effects of mannoheptulose (MH), a sugar in avocados that inhibits glycolysis, on energy metabolism in adult Beagle dogs. The study was a double-blind, randomized controlled trial where dogs were allocated to a control (CON, n = 10, 10.1 ± 0.4 kg) or MH containing diet (168 mg/kg, n = 10, 10.3 ± 0.4 kg). Blood was collected after an overnight fast and 1 h post-feeding (week 12) to determine serum satiety related hormones and biochemistry. Resting and post-prandial energy expenditure and respiratory quotient were determined by indirect calorimetry (weeks 4 and 8). Physical activity was measured using an accelerometer (weeks 3, 7, 11). Body composition was assessed using dual X-ray absorptiometry (week 12). MH significantly (p < 0.05) increased fasting serum glucagon-like peptide-1 and post-prandial serum ghrelin. MH tended (p < 0.1) to increase fasting serum gastric inhibitory peptide and decrease physical activity. Together, these findings suggest that dietary MH has the ability to promote satiation and lowers daily energy expenditure. PMID:26479244

  18. Identification and gene expression analyses of ghrelin in the stomach of Pacific bluefin tuna (Thunnus orientalis).

    PubMed

    Suda, Atsushi; Kaiya, Hiroyuki; Nikaido, Hideki; Shiozawa, Satoshi; Mishiro, Kenzo; Ando, Hironori

    2012-08-01

    Full length cDNA and gene encoding ghrelin precursor and mature ghrelin peptide were identified from the stomach of Pacific bluefin tuna, Thunnus orientalis, which has unique metabolic physiology and high commercial value at fishery markets. Quantitative expression analysis was conducted for the gastric ghrelin and pepsinogen 2 genes during the early stage of somatic growth from the underyearling to yearling fish. The full length cDNA of bluefin tuna ghrelin precursor has a length of 470bp and the deduced precursor is composed of 107 amino acids. The ghrelin gene is 1.9kbp in length and has a 4 exon-3 intron structure. The major form of mature ghrelin in the stomach was an octanoylated 20-amino acid peptide with C-terminal amidation, while overall 12 different forms of ghrelin peptides, including short form of 18-amino acid peptide and seven kinds of acyl modifications were identified. The expression profiles of the gastric ghrelin and pepsinogen 2 genes showed no significant changes related to the early growth stages. The present results suggest that digestive physiology has already been functional in this growth stage of the juvenile bluefin tuna and ghrelin may have a role in the sustained digestive and metabolic activities.

  19. High concentrations of aromatic acylated anthocyanins found in cauline hairs in Plectranthus ciliatus.

    PubMed

    Jordheim, Monica; Calcott, Kate; Gould, Kevin S; Davies, Kevin M; Schwinn, Kathy E; Andersen, Øyvind M

    2016-08-01

    Vegetative shoots of a naturalized population of purple-leaved plectranthus (Plectranthus ciliatus, Lamiaceae) were found to contain four main anthocyanins: peonidin 3-(6″-caffeoyl-β-glucopyranoside)-5-β-glucopyranoside, peonidin 3-(6″-caffeoyl-β-glucopyranoside)-5-(6‴-malonyl-β-glucopyranoside), peonidin 3-(6″-E-p-coumaroyl-β-glucopyranoside)-5-(6‴-malonyl-β-glucopyranoside), and peonidin 3-(6″-E-p-coumaroyl-β-glucopyranoside)-5-β-glucopyranoside. The first three of these pigments have not been reported previously from any plant. They all follow the typical anthocyanin pattern of Lamiaceae, with universal occurrence of anthocyanidin 3,5-diglucosides and aromatic acylation with p-coumaric and sometimes caffeic acids; however, they differ by being based on peonidin. The four anthocyanins were present in the leaves (22.2 mg g(-1) DW), and in the xylem and interfascicular parenchyma of the stem. They were exceptionally abundant, among the highest reported for any plant organ, in epidermal hairs on some of the stem internodes (101 mg g(-1) DW). Anthocyanin content in these hairs increased more than three-fold from the youngest to the fourth-youngest internodes. In situ absorbances (λmax ≈ 545 nm) were bathochromic in comparison to absorbances of the isolated anthocyanins in their flavylium form in acidified aqueous solutions (λmax = 525 nm), suggesting that the anthocyanins occur both in quinoidal and flavylium forms in constant proportions in the anthocyanic hair cells. The most distinctive observation with respect to relative proportions of individual anthocyanins was found in de-haired internodes, for which anthocyanin caffeoyl-derivatives decreased, and anthocyanin coumaroyl-derivatives increased, from the youngest to the fourth-youngest internode. PMID:27165277

  20. 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.

  1. Identification of the ghrelin-GHSR 1 system and its influence in the modulation of induced ocular hypertension in rabbit and rat eyes.

    PubMed

    Rocha-Sousa, A; Pereira-Silva, P; Tavares-Silva, M; Azevedo-Pinto, S; Rodrigues-Araújo, J; Pinho, S; Avelino, A; Falcão-Reis, F; Leite-Moreira, A

    2014-07-01

    Recent studies evidenced a decrease in ghrelin's aqueous humor levels in patients with glaucoma. The goal of our investigation was to study the effect of the ghrelin-GHSR-1a system in the modulation of intraocular pressure in acute ocular hypertension models and its expression and distribution in ocular tissues. Two animal models of acute ocular hypertension were used to study the effect of the ghrelin-GHSR-1a system in the modulation of intraocular pressure: the rabbit and the rat. Ocular hypertension was induced by an intravitreal injection of 20% NaCl. Ghrelin or des-acyl ghrelin were delivered subconjunctivally and the intraocular pressure was assessed by a rebound tonometer that was calibrated for each species. In addition, we have studied the influence of nitric oxide and prostaglandins on ghrelin's effect in the rabbit animal model. Finally, we determined by immunofluorescence the expression of ghrelin and GHSR-1 in the rat's ocular tissue. Ghrelin decreased the intraocular pressure in both animal models (maximum decrease: 43.8±12.0% in the rabbit and 29.0±7.46% in the rat). In the rabbit, this effect was blunted in the presence of l-NAME and ketorolac. Des-acyl ghrelin only decreased the intraocular pressure in the rat (maximum decrease: 34.9±8.15%). Ghrelin expression was detected in the ciliary processes and GHSR-1 expression was detected in the trabecular meshwork and ciliary body. The ghrelin-GHSR-1 system is expressed in the anterior segment of the eye. Ghrelin and des-acyl ghrelin are responsible for a hypotensive effect in acute ocular hypertension animal models.

  2. A link between FTO, ghrelin, and impaired brain food-cue responsivity

    PubMed Central

    Karra, Efthimia; O’Daly, Owen G.; Choudhury, Agharul I.; Yousseif, Ahmed; Millership, Steven; Neary, Marianne T.; Scott, William R.; Chandarana, Keval; Manning, Sean; Hess, Martin E.; Iwakura, Hiroshi; Akamizu, Takashi; Millet, Queensta; Gelegen, Cigdem; Drew, Megan E.; Rahman, Sofia; Emmanuel, Julian J.; Williams, Steven C.R.; Rüther, Ulrich U.; Brüning, Jens C.; Withers, Dominic J.; Zelaya, Fernando O.; Batterham, Rachel L.

    2013-01-01

    Polymorphisms in the fat mass and obesity-associated gene (FTO) are associated with human obesity and obesity-prone behaviors, including increased food intake and a preference for energy-dense foods. FTO demethylates N6-methyladenosine, a potential regulatory RNA modification, but the mechanisms by which FTO predisposes humans to obesity remain unclear. In adiposity-matched, normal-weight humans, we showed that subjects homozygous for the FTO “obesity-risk” rs9939609 A allele have dysregulated circulating levels of the orexigenic hormone acyl-ghrelin and attenuated postprandial appetite reduction. Using functional MRI (fMRI) in normal-weight AA and TT humans, we found that the FTO genotype modulates the neural responses to food images in homeostatic and brain reward regions. Furthermore, AA and TT subjects exhibited divergent neural responsiveness to circulating acyl-ghrelin within brain regions that regulate appetite, reward processing, and incentive motivation. In cell models, FTO overexpression reduced ghrelin mRNA N6-methyladenosine methylation, concomitantly increasing ghrelin mRNA and peptide levels. Furthermore, peripheral blood cells from AA human subjects exhibited increased FTO mRNA, reduced ghrelin mRNA N6-methyladenosine methylation, and increased ghrelin mRNA abundance compared with TT subjects. Our findings show that FTO regulates ghrelin, a key mediator of ingestive behavior, and offer insight into how FTO obesity-risk alleles predispose to increased energy intake and obesity in humans. PMID:23867619

  3. Cereal type and heat processing of the cereal affect nutrient digestibility and dynamics of serum insulin and ghrelin in weanling pigs.

    PubMed

    Menoyo, D; Serrano, M P; Barrios, V; Valencia, D G; Lázaro, R; Argente, J; Mateos, G G

    2011-09-01

    The effects of feeding corn or rice, either raw or heat processed (HP), on apparent total tract digestibility (ATTD) and apparent ileal digestibility (AID) of nutrients and on insulin and ghrelin concentrations in the serum were studied in young pigs. Pigs were weaned at approximately 23 ± 3 d of age and weighed 7.4 ± 1.2 kg. Each of the 4 treatments was replicated 9 times, and the experimental unit was a pig individually housed. Pigs (5 males and 4 females/treatment) were fed their respective diets ad libitum from 23 to 47 d of age. At 37 d of age, the effects of dietary treatments on the fasting and postprandial concentrations of insulin and total and acylated ghrelin were studied. The ATTD of OM, GE, and ether extract were, respectively, 4.3, 5.4, and 3.6% greater (P < 0.05) for the rice than for the corn diets, but CP digestibility was not affected. Similar results were observed for AID. Heat processing of the cereal increased (P < 0.05) the ATTD by 2.1% for OM, 3.2% for GE, 7.1% for ether extract, and 2.2% for CP and tended to increase the AID of CP (P = 0.06) and starch (P = 0.09). The postprandial serum insulin response was greater and was more prolonged in pigs fed raw rice than in pigs fed raw corn (P < 0.05). In addition, the effects of HP on serum insulin response were more pronounced with corn than with rice (cereal × HP, P < 0.05). Total ghrelin concentration was not affected by treatment, but acylated ghrelin was greater (P < 0.05) at 6 h postprandially in pigs fed rice than in pigs fed raw corn. Feeding rice and HP corn increased nutrient digestibility and insulin response in the early postprandial period and increased the acylated ghrelin response in the late postprandial period compared with feeding raw corn.

  4. 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.

  5. 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 Central

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

    2014-01-01

    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 3 day 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 3 days. 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. PMID:24462487

  6. Differential effects of methamphetamine on expression of neuropeptide Y mRNA in hypothalamus and on serum leptin and ghrelin concentrations in ad libitum-fed and schedule-fed rats.

    PubMed

    Crowley, W R; Ramoz, G; Keefe, K A; Torto, R; Kalra, S P; Hanson, G R

    2005-01-01

    Relatively little is known concerning the interaction of psychostimulants with hypothalamic neuropeptide systems or metabolic hormones implicated in regulation of energy balance. The present studies tested whether methamphetamine alters the expression of neuropeptide Y (NPY) and agouti-related peptide (AgRP), two important orexigenic neuropeptides, or proopiomelanocortin (POMC), the precursor for the anorexigenic peptide alpha-melanocyte-stimulating hormone, or the secretion of leptin, insulin and ghrelin, concomitant with inhibition of food intake. Female rats were either fed ad libitum (AL) or placed on a scheduled feeding (SF) regimen, with access to food limited to 4 h/day. Administration of (+/-)-methamphetamine (7.5 mg/kg, i.p.) 2 h prior to food presentation significantly inhibited food intake in SF animals, but did not affect intake in AL animals. In a separate study, AL and SF animals were killed just prior to expected food presentation, and expression of NPY, AgRP and POMC mRNAs in hypothalamus was determined using in situ hybridisation; concentrations of leptin, insulin and ghrelin in serum were determined with radioimmunoassays. In saline-treated, SF controls, NPY and AgRP mRNA expression in arcuate nucleus and serum ghrelin were significantly elevated, and serum leptin and insulin were significantly reduced. Methamphetamine reversed the up-regulation of NPY mRNA expression observed in the SF condition, without affecting AgRP mRNA or the serum concentrations of metabolic hormones. However, in AL animals, NPY mRNA expression in arcuate and dorsomedial nuclei was significantly increased by methamphetamine, which also reduced serum leptin and insulin and increased serum ghrelin concentrations. These findings suggest that the inhibition of NPY expression in SF animals may be a mechanism underlying the anorexigenic effect of methamphetamine seen in this condition. The increase in NPY expression produced by methamphetamine in AL animals may be mediated by the

  7. Molecular evolution of GPCRs: Ghrelin/ghrelin receptors.

    PubMed

    Kaiya, Hiroyuki; Kangawa, Kenji; Miyazato, Mikiya

    2014-06-01

    After the discovery in 1996 of the GH secretagogue-receptor type-1a (GHS-R1a) as an orphan G-protein coupled receptor, many research groups attempted to identify the endogenous ligand. Finally, Kojima and colleagues successfully isolated the peptide ligand from rat stomach extracts, determined its structure, and named it ghrelin. The GHS-R1a is now accepted to be the ghrelin receptor. The existence of the ghrelin system has been demonstrated in many animal classes through biochemical and molecular biological strategies as well as through genome projects. Our work, focused on identifying the ghrelin receptor and its ligand ghrelin in laboratory animals, particularly nonmammalian vertebrates, has provided new insights into the molecular evolution of the ghrelin receptor. In mammals, it is assumed that the ghrelin receptor evolution is in line with the plate tectonics theory. In contrast, the evolution of the ghrelin receptor in nonmammalian vertebrates differs from that of mammals: multiplicity of the ghrelin receptor isoforms is observed in nonmammalian vertebrates only. This multiplicity is due to genome duplication and polyploidization events that particularly occurred in Teleostei. Furthermore, it is likely that the evolution of the ghrelin receptor is distinct from that of its ligand, ghrelin, because only one ghrelin isoform has been detected in all species examined so far. In this review, we summarize current knowledge related to the molecular evolution of the ghrelin receptor in mammalian and nonmammalian vertebrates. PMID:24353285

  8. 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. PMID:26512025

  9. Periprandial changes and effects of short- and long-term fasting on ghrelin, GOAT, and ghrelin receptors in goldfish (Carassius auratus).

    PubMed

    Blanco, A M; Gómez-Boronat, M; Redondo, I; Valenciano, A I; Delgado, M J

    2016-08-01

    The periprandial profile and effects of short- (7 days) and long-term (30 days) fasting on the ghrelinergic system were studied in goldfish (Carassius auratus). Plasma levels of acyl-ghrelin, desacyl-ghrelin, and ghrelin O-acyl transferase (GOAT) were analyzed by enzymoimmunoassays, and expression of preproghrelin, goat and growth hormone secretagogue receptors (ghs-r) was quantified by real-time PCR. Circulating levels of acyl-ghrelin and GOAT rise preprandially, supporting the role of acyl-ghrelin as a meal initiator in this teleost. Consistently, preproghrelin and ghs-r1a1 expression increases 1 h before feeding time in intestinal bulb, suggesting that this receptor subtype might be involved in the preprandial action of ghrelin in this tissue. Significant postfeeding variations are detected for preproghrelin in telencephalon, goat in telencephalon and hypothalamus, ghs-r1a1 in vagal lobe, ghs-r1a2 and ghs-r2a1 in hypothalamus and ghs-r2a2 in telencephalon and vagal lobe, especially in unfed fish. Short- and long-term fasting significantly increase preproghrelin expression in telencephalon and gut. Goat expression is upregulated by short-term fasting in telencephalon and hypothalamus, and by both short- and long-term fasting in gut. Expression of ghs-r increases by fasting in telencephalon, while an upregulation of type 2, but not type 1, receptors is observed in vagal lobe. In intestinal bulb, ghs-r1a2 transcripts increase after both short- and long-term fasting. These results show a high dependence of the ghrelinergic system on feeding and nutritional status in fish, and demonstrate for the first time a differential implication of the various components of this system suggesting different roles for the four ghrelinergic receptor subtypes. PMID:27062032

  10. Ghrelin receptor (GHS-R1A) antagonism alters preference for ethanol and sucrose in a concentration-dependent manner in prairie voles.

    PubMed

    Stevenson, J R; Francomacaro, L M; Bohidar, A E; Young, K A; Pesarchick, B F; Buirkle, J M; McMahon, E K; O'Bryan, C M

    2016-03-01

    Ghrelin receptor (GHS-R1A) activity has been implicated in reward for preferred foods and drugs; however, a recent study in our laboratory indicated that GHS-R1A antagonism reduces early (after only four exposures) preference for 20% ethanol, but not 10% sucrose in prairie voles, a genetically diverse high alcohol-consuming species. The purpose of the present study was to determine if these effects of GHS-R1A antagonism depend on the concentration of the rewarding solution being consumed. We first characterized preference for varying concentrations of ethanol and sucrose. Two bottle tests of each ethanol concentration versus water indicated that 10% and 20% ethanol are less preferred than 3% ethanol, and a follow-up direct comparison of 10% vs. 20% showed that 10% was preferred over 20%. Direct two-bottle comparisons of 2% vs. 5%, 2% vs. 10%, and 5% vs. 10% sucrose showed that 10% sucrose was most preferred, and 2% sucrose was least preferred. The effects of JMV 2959, a GHS-R1A antagonist, on preference for each concentration of ethanol and sucrose were then tested. In a between groups design prairie voles were given four two-hour drinking sessions in which animals had access to ethanol (3, 10, or 20%) versus water, or sucrose (2, 5, or 10%) versus water every other day. Saline habituation injections were given 30 min before the third drinking session. JMV 2959 (i.p.; 9 mg/kg), a GHS-R1A antagonist, or saline was administered 30 min before the fourth drinking session. JMV 2959 reduced preference for 20% ethanol and 2% sucrose, but had no significant effect on preference for the other ethanol and sucrose concentrations. These data identify constraints on the role of GHS-R1A in early preference for ethanol and sucrose, and the concentration-dependent effects suggest strong preference for a reward may limit the importance of GHS-R1A activity.

  11. Ghrelin receptor (GHS-R1A) antagonism alters preference for ethanol and sucrose in a concentration-dependent manner in prairie voles.

    PubMed

    Stevenson, J R; Francomacaro, L M; Bohidar, A E; Young, K A; Pesarchick, B F; Buirkle, J M; McMahon, E K; O'Bryan, C M

    2016-03-01

    Ghrelin receptor (GHS-R1A) activity has been implicated in reward for preferred foods and drugs; however, a recent study in our laboratory indicated that GHS-R1A antagonism reduces early (after only four exposures) preference for 20% ethanol, but not 10% sucrose in prairie voles, a genetically diverse high alcohol-consuming species. The purpose of the present study was to determine if these effects of GHS-R1A antagonism depend on the concentration of the rewarding solution being consumed. We first characterized preference for varying concentrations of ethanol and sucrose. Two bottle tests of each ethanol concentration versus water indicated that 10% and 20% ethanol are less preferred than 3% ethanol, and a follow-up direct comparison of 10% vs. 20% showed that 10% was preferred over 20%. Direct two-bottle comparisons of 2% vs. 5%, 2% vs. 10%, and 5% vs. 10% sucrose showed that 10% sucrose was most preferred, and 2% sucrose was least preferred. The effects of JMV 2959, a GHS-R1A antagonist, on preference for each concentration of ethanol and sucrose were then tested. In a between groups design prairie voles were given four two-hour drinking sessions in which animals had access to ethanol (3, 10, or 20%) versus water, or sucrose (2, 5, or 10%) versus water every other day. Saline habituation injections were given 30 min before the third drinking session. JMV 2959 (i.p.; 9 mg/kg), a GHS-R1A antagonist, or saline was administered 30 min before the fourth drinking session. JMV 2959 reduced preference for 20% ethanol and 2% sucrose, but had no significant effect on preference for the other ethanol and sucrose concentrations. These data identify constraints on the role of GHS-R1A in early preference for ethanol and sucrose, and the concentration-dependent effects suggest strong preference for a reward may limit the importance of GHS-R1A activity. PMID:26723269

  12. Ghrelin promotes oral tumor cell proliferation by modifying GLUT1 expression.

    PubMed

    Kraus, Dominik; Reckenbeil, Jan; Wenghoefer, Matthias; Stark, Helmut; Frentzen, Matthias; Allam, Jean-Pierre; Novak, Natalija; Frede, Stilla; Götz, Werner; Probstmeier, Rainer; Meyer, Rainer; Winter, Jochen

    2016-03-01

    In our study, ghrelin was investigated with respect to its capacity on proliferative effects and molecular correlations on oral tumor cells. The presence of all molecular components of the ghrelin system, i.e., ghrelin and its receptors, was analyzed and could be detected using real-time PCR and immunohistochemistry. To examine cellular effects caused by ghrelin and to clarify downstream-regulatory mechanisms, two different oral tumor cell lines (BHY and HN) were used in cell culture experiments. Stimulation of either cell line with ghrelin led to a significantly increased proliferation. Signal transduction occurred through phosphorylation of GSK-3β and nuclear translocation of β-catenin. This effect could be inhibited by blocking protein kinase A. Glucose transporter1 (GLUT1), as an important factor for delivering sufficient amounts of glucose to tumor cells having high requirements for this carbohydrate (Warburg effect) was up-regulated by exogenous and endogenous ghrelin. Silencing intracellular ghrelin concentrations using siRNA led to a significant decreased expression of GLUT1 and proliferation. In conclusion, our study describes the role for the appetite-stimulating peptide hormone ghrelin in oral cancer proliferation under the particular aspect of glucose uptake: (1) tumor cells are a source of ghrelin. (2) Ghrelin affects tumor cell proliferation through autocrine and/or paracrine activity. (3) Ghrelin modulates GLUT1 expression and thus indirectly enhances tumor cell proliferation. These findings are of major relevance, because glucose uptake is assumed to be a promising target for cancer treatment.

  13. Insulin suppresses ghrelin-induced calcium signaling in neuropeptide Y neurons of the hypothalamic arcuate nucleus

    PubMed Central

    Maejima, Yuko; Kohno, Daisuke; Iwasaki, Yusaku; Yada, Toshihiko

    2011-01-01

    Neuropeptide Y (NPY) neurons in the hypothalamic arcuate nucleus (ARC) play an important role in feeding regulation. Plasma levels of ghrelin and insulin show reciprocal dynamics before and after meals. We hypothesized that ghrelin and insulin also exert reciprocal effects on ARC NPY neurons. Cytosolic Ca2+ concentration ([Ca2+]i) was measured by fura-2 microfluorometry in single neurons isolated from ARC of adult rats, followed by immunocytochemical identification of NPY neurons. Ghrelin at 10−10 M increased [Ca2+]i in isolated ARC neurons, and co-administration of insulin concentration-dependently suppressed the ghrelin-induced [Ca2+]i increases. Insulin at 10−16 M, 10−14 M, 10−12 M and 10−10 M counteracted ghrelin action in 26%, 41%, 61% and 53% of ghrelin-responsive neurons, respectively, showing a maximal effect at 10−12 M, the estimated postprandial concentration of insulin in the brain. The majority (>70%) of the ghrelin-activated insulin-inhibited neurons were shown to contain NPY. Double-immunohistochemistry revealed that 85% of NPY neurons in ARC express insulin receptors. These data demonstrate that insulin directly interacts with ARC NPY neurons and counteracts ghrelin action. Our results suggest that postprandial increase in plasma insulin/ghrelin ratio and insulin inhibition of ghrelin action on ARC NPY neurons cooperate to effectively inhibit the neuron activity and terminate feeding. PMID:22081645

  14. Serum Concentrations of Insulin, Ghrelin, Adiponectin, Leptin, Leptin Receptor and Lipocalin-2 in Children with Celiac Disease Who Do and Do Not Adhere to a Gluten-Free Diet

    PubMed Central

    Janas, Roman M.; Rybak, Anna; Wierzbicka-Rucińska, Aldona; Socha, Piotr; Śnitko, Rafał; Szaflarska-Popławska, Anna; Stolarczyk, Anna; Oralewska, Beata; Cytra-Jarocka, Elżbieta; Iwańczak, Barbara; Grzybowska-Chlebowczyk, Urszula; Cichy, Wojciech; Czaja-Bulsa, Grażyna; Socha, Jerzy

    2016-01-01

    Background/Aims The roles of the many bioactive peptides in the pathogenesis of celiac disease remain unclear. To evaluate the serum concentrations of insulin, ghrelin, adiponectin, leptin, leptin receptor, and lipocalin-2 in children with celiac disease who do and do not adhere to a gluten-free diet (GFD, intermittent adherence). Methods Prepubertal, pubertal, and adolescent celiac children were included in this study (74 girls and 53 boys on a GFD and 80 girls and 40 boys off of a GFD). Results Insulin levels in prepubertal (9.01±4.43 μIU/mL), pubertal (10.3±3.62 μIU/mL), and adolescent (10.8±4.73 μIU/mL) girls were higher than those in boys (5.88±2.02, 8.81±2.88, and 8.81±2.26 μIU/mL, respectively) and were neither age-dependent nor influenced by a GFD. Prepubertal children off of a GFD exhibited higher ghrelin levels than prepubertal children on a GFD. Adiponectin levels were not age-, sex- nor GFD-dependent. Adherence to a GFD had no effect on the expression of leptin, leptin receptor, and lipocalin-2. Conclusions Adherence to a GFD had no influence on the adiponectin, leptin, leptin receptor, and lipocalin-2 concentrations in celiac children, but a GFD decreased highly elevated ghrelin levels in prepubertal children. Further studies are required to determine whether increased insulin concentrations in girls with celiac disease is suggestive of an increased risk for hyperinsulinemia. PMID:27074817

  15. 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

  16. Anti-ghrelin Spiegelmer inhibits exogenous ghrelin-induced increases in food intake, hoarding, and neural activation, but not food deprivation-induced increases

    PubMed Central

    Teubner, Brett J. W.

    2013-01-01

    Circulating concentrations of the stomach-derived “hunger-peptide” ghrelin increase in direct proportion to the time since the last meal. Exogenous ghrelin also increases food intake in rodents and humans, suggesting ghrelin may increase post-fast ingestive behaviors. Food intake after food deprivation is increased by laboratory rats and mice, but not by humans (despite dogma to the contrary) or by Siberian hamsters; instead, humans and Siberian hamsters increase food hoarding, suggesting the latter as a model of fasting-induced changes in human ingestive behavior. Exogenous ghrelin markedly increases food hoarding by ad libitum-fed Siberian hamsters similarly to that after food deprivation, indicating sufficiency. Here, we tested the necessity of ghrelin to increase food foraging, food hoarding, and food intake, and neural activation [c-Fos immunoreactivity (c-Fos-ir)] using anti-ghrelin Spiegelmer NOX-B11–2 (SPM), an l-oligonucleotide that specifically binds active ghrelin, inhibiting peptide-receptor interaction. SPM blocked exogenous ghrelin-induced increases in food hoarding the first 2 days after injection, and foraging and food intake at 1–2 h and 2–4 h, respectively, and inhibited hypothalamic c-Fos-ir. SPM given every 24 h across 48-h food deprivation inconsistently inhibited food hoarding after refeeding and c-Fos-ir, similarly to inabilities to do so in laboratory rats and mice. These results suggest that ghrelin may not be necessary for food deprivation-induced foraging and hoarding and neural activation. A possible compensatory response, however, may underlie these findings because SPM treatment led to marked increases in circulating ghrelin concentrations. Collectively, these results show that SPM can block exogenous ghrelin-induced ingestive behaviors, but the necessity of ghrelin for food deprivation-induced ingestive behaviors remains unclear. PMID:23804279

  17. Anti-ghrelin Spiegelmer inhibits exogenous ghrelin-induced increases in food intake, hoarding, and neural activation, but not food deprivation-induced increases.

    PubMed

    Teubner, Brett J W; Bartness, Timothy J

    2013-08-15

    Circulating concentrations of the stomach-derived "hunger-peptide" ghrelin increase in direct proportion to the time since the last meal. Exogenous ghrelin also increases food intake in rodents and humans, suggesting ghrelin may increase post-fast ingestive behaviors. Food intake after food deprivation is increased by laboratory rats and mice, but not by humans (despite dogma to the contrary) or by Siberian hamsters; instead, humans and Siberian hamsters increase food hoarding, suggesting the latter as a model of fasting-induced changes in human ingestive behavior. Exogenous ghrelin markedly increases food hoarding by ad libitum-fed Siberian hamsters similarly to that after food deprivation, indicating sufficiency. Here, we tested the necessity of ghrelin to increase food foraging, food hoarding, and food intake, and neural activation [c-Fos immunoreactivity (c-Fos-ir)] using anti-ghrelin Spiegelmer NOX-B11-2 (SPM), an l-oligonucleotide that specifically binds active ghrelin, inhibiting peptide-receptor interaction. SPM blocked exogenous ghrelin-induced increases in food hoarding the first 2 days after injection, and foraging and food intake at 1-2 h and 2-4 h, respectively, and inhibited hypothalamic c-Fos-ir. SPM given every 24 h across 48-h food deprivation inconsistently inhibited food hoarding after refeeding and c-Fos-ir, similarly to inabilities to do so in laboratory rats and mice. These results suggest that ghrelin may not be necessary for food deprivation-induced foraging and hoarding and neural activation. A possible compensatory response, however, may underlie these findings because SPM treatment led to marked increases in circulating ghrelin concentrations. Collectively, these results show that SPM can block exogenous ghrelin-induced ingestive behaviors, but the necessity of ghrelin for food deprivation-induced ingestive behaviors remains unclear.

  18. Schizothorax davidi ghrelin: cDNA cloning, tissue distribution and indication for its stimulatory character in food intake.

    PubMed

    Zhou, Chaowei; Zhang, Xingdong; Liu, Tao; Wei, Rongbin; Yuan, Dengyue; Wang, Tao; Lin, Fangjun; Wu, Hongwei; Chen, Fu; Yang, Shiyong; Chen, Defang; Wang, Yan; Li, Zhiqiong

    2014-01-15

    Ghrelin is a gut/brain hormone with a unique acyl modification and various biological functions in fish and mammals. The objectives of this project were to identify ghrelin gene organization, study tissue specific ghrelin mRNA expression and investigate the short- (0, 0.5, 1.5, 3, 6, 9, 12h post-fasting) and long- (1, 3, 5, 7 days) term fasting as well as refeeding after a 7 day fasting induced changes in the expression of ghrelin mRNA in Schizothorax davidi. Our reverse transcription polymerase chain reaction analysis confirmed the predicted ghrelin sequence available in the GenBank and identified ghrelin mRNA expression in several tissues including the gut, liver, brain, heart, spleen, head kidney, gill and muscle. Quantitative PCR studies indicated that the expression level of ghrelin mRNA presented ascendant trend in short-term fasting group compared to the fed group, but it did not reach the significant level on statistics, while there is a significant increase in ghrelin mRNA expression in the gut of Schizothorax davidi fasted for 3, 5 and 7 days when compared to the expression in ad libitum fed fish. Refeeding after a 7 day fasting caused a significant and dramatic decrease in ghrelin mRNA expression in the gut of Schizothorax davidi. An increase in the expression of ghrelin mRNA during fasting, and its decrease following refeeding suggests an orexigenic role for ghrelin in Schizothorax davidi. Overall, our results provide evidence for a highly conserved structure and biological actions of ghrelin during evolution.

  19. Assessment of Serum Concentrations of Ghrelin, Obestatin, Omentin-1, and Apelin in Children with Type 1 Diabetes

    PubMed Central

    Polkowska, Agnieszka; Szczepaniak, Izabela; Bossowski, Artur

    2016-01-01

    The increasing knowledge on the functions of gastric peptides and adipokines in the body allows the assumption of their major role linking the process of food intake, nutritional status, and body growth, largely through the regulation of glucose metabolism and insulin resistance. The aim of the study was the assessment of serum levels of selected gastric peptides and adipocytokines in children with type 1 diabetes, with respect to the disease duration. The study involved 80 children aged 4–18 years (M/F -37/43). Children with type 1 diabetes (n = 46) were compared to the control group (n = 34). The study group was divided into 4 subgroups: (I) patients with newly diagnosed type 1 diabetes, after an episode of ketoacidosis (n = 10), (II) patients with type 1 diabetes of duration no longer than 5 years (n = 9), (III) patients with 5 to 10 years of DT1 (n = 20), and (IV) patients with type 1 diabetes of duration longer than 10 years (n = 7). The concentrations of gastric peptide and adipocytokines across all subgroups were lower than in the control group. The differences were statistically significant (p < 0.0001), which may be of importance in the development of the disease complications. PMID:26904686

  20. 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.

  1. Increased ghrelin signaling prolongs survival in mouse models of human aging through activation of sirtuin1

    PubMed Central

    Fujitsuka, N; Asakawa, A; Morinaga, A; Amitani, M S; Amitani, H; Katsuura, G; Sawada, Y; Sudo, Y; Uezono, Y; Mochiki, E; Sakata, I; Sakai, T; Hanazaki, K; Yada, T; Yakabi, K; Sakuma, E; Ueki, T; Niijima, A; Nakagawa, K; Okubo, N; Takeda, H; Asaka, M; Inui, A

    2016-01-01

    Caloric restriction (CR) is known to retard aging and delay functional decline as well as the onset of diseases in most organisms. Ghrelin is secreted from the stomach in response to CR and regulates energy metabolism. We hypothesized that in CR ghrelin has a role in protecting aging-related diseases. We examined the physiological mechanisms underlying the ghrelin system during the aging process in three mouse strains with different genetic and biochemical backgrounds as animal models of accelerated or normal human aging. The elevated plasma ghrelin concentration was observed in both klotho-deficient and senescence-accelerated mouse prone/8 (SAMP8) mice. Ghrelin treatment failed to stimulate appetite and prolong survival in klotho-deficient mice, suggesting the existence of ghrelin resistance in the process of aging. However, ghrelin antagonist hastened death and ghrelin signaling potentiators rikkunshito and atractylodin ameliorated several age-related diseases with decreased microglial activation in the brain and prolonged survival in klotho-deficient, SAMP8 and aged ICR mice. In vitro experiments, the elevated sirtuin1 (SIRT1) activity and protein expression through the cAMP–CREB pathway was observed after ghrelin and ghrelin potentiator treatment in ghrelin receptor 1a-expressing cells and human umbilical vein endothelial cells. Furthermore, rikkunshito increased hypothalamic SIRT1 activity and SIRT1 protein expression of the heart in the all three mouse models of aging. Pericarditis, myocardial calcification and atrophy of myocardial and muscle fiber were improved by treatment with rikkunshito. Ghrelin signaling may represent one of the mechanisms activated by CR, and potentiating ghrelin signaling may be useful to extend health and lifespan. PMID:26830139

  2. 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.

  3. 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.

  4. 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. PMID:23770219

  5. Serum ghrelin levels in acromegaly: effects of surgical and long-acting octreotide therapy.

    PubMed

    Freda, Pamela U; Reyes, Carlos M; Conwell, Irene M; Sundeen, Robert E; Wardlaw, Sharon L

    2003-05-01

    the postsurgery normalization of GH and IGF-I and improved insulin resistance. In contrast to surgical therapy, long-acting octreotide therapy persistently suppressed serum ghrelin levels. It remains to be determined whether altered circulating ghrelin concentrations could impact on body composition changes in acromegaly.

  6. 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. PMID:26172570

  7. 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.

  8. 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...

  9. Rhythms of ghrelin, leptin, and sleep in rats: effects of the normal diurnal cycle, restricted feeding, and sleep deprivation.

    PubMed

    Bodosi, B; Gardi, J; Hajdu, I; Szentirmai, E; Obal, F; Krueger, J M

    2004-11-01

    To determine the relationships among plasma ghrelin and leptin concentrations and hypothalamic ghrelin contents, and sleep, cortical brain temperature (Tcrt), and feeding, we determined these parameters in rats in three experimental conditions: in free-feeding rats with normal diurnal rhythms, in rats with feeding restricted to the 12-h light period (RF), and in rats subjected to 5-h of sleep deprivation (SD) at the beginning of the light cycle. Plasma ghrelin and leptin displayed diurnal rhythms with the ghrelin peak preceding and the leptin peak following the major daily feeding peak in hour 1 after dark onset. RF reversed the diurnal rhythm of these hormones and the rhythm of rapid-eye-movement sleep (REMS) and significantly altered the rhythm of Tcrt. In contrast, the duration and intensity of non-REMS (NREMS) were hardly responsive to RF. SD failed to change leptin concentrations, but it promptly stimulated plasma ghrelin and induced eating. SD elicited biphasic variations in the hypothalamic ghrelin contents. SD increased plasma corticosterone, but corticosterone did not seem to influence either leptin or ghrelin. The results suggest a strong relationship between feeding and the diurnal rhythm of leptin and that feeding also fundamentally modulates the diurnal rhythm of ghrelin. The variations in hypothalamic ghrelin contents might be associated with sleep-wake activity in rats, but, unlike the previous observations in humans, obvious links could not be detected between sleep and the diurnal rhythms of plasma concentrations of either ghrelin or leptin in the rat. PMID:15475503

  10. Ghrelin – A Pleiotropic Hormone Secreted from Endocrine X/A-Like Cells of the Stomach

    PubMed Central

    Stengel, Andreas; Taché, Yvette

    2012-01-01

    The gastric X/A-like endocrine cell receives growing attention due to its peptide products with ghrelin being the best characterized. This peptide hormone was identified a decade ago as a stimulator of food intake and to date remains the only known peripherally produced and centrally acting orexigenic hormone. In addition, subsequent studies identified numerous other functions of this peptide including the stimulation of gastrointestinal motility, the maintenance of energy homeostasis and an impact on reproduction. Moreover, ghrelin is also involved in the response to stress and assumed to play a role in coping functions and exert a modulatory action on immune pathways. Our knowledge on the regulation of ghrelin has markedly advanced during the past years by the identification of the ghrelin acylating enzyme, ghrelin-O-acyltransferase, and by the description of changes in expression, activation, and release under different metabolic as well as physically and psychically challenging conditions. However, our insight on regulatory processes of ghrelin at the cellular and subcellular levels is still very limited and warrants further investigation. PMID:22355282

  11. Effect of Acute Surgical Stress on Serum Ghrelin Levels

    PubMed Central

    Kontoravdis, Nikolaos; Vassilikostas, George; Lagoudianakis, Emmanuel; Pappas, Apostolos; Seretis, Charalampos; Panagiotopoulos, Nikolaos; Koronakis, Nikolaos; Chrysikos, John; Karanikas, George; Manouras, Ioannis; Legakis, Ioanis; Voros, Dionysios

    2012-01-01

    Background Ghrelin is an appetite hormone that influences the gastrointestinal function and regulates energy metabolism. Growing evidence also suggests that this hormone plays a central role in immune modulation. Each surgical operation is followed by a series of inflammatory and metabolic changes that constitute the stress response. The aim of our study is to evaluate the effect of stress during different types of abdominal surgery in ghrelin serum levels. Methods An overall of 25 patients were prospectively allocated in two groups based on the type of surgical operation. Group A (n = 10) patients were scheduled to undergo cholecystectomy, whereas Group B (n = 15) patients underwent colectomy. Serum ghrelin concentrations were evaluated in each patient preoperatively, after the induction of general anesthesia and tracheal intubation, one and five hours after the beginning of surgery and the morning of the first and second postoperative day. Results In both groups serum ghrelin concentrations reached their peak level at 24 hr (Group A: 8.4 ± 3.4 ng/mL; Group B: 7.4 ± 1.8 ng/mL) and these values were significantly higher than those in the preoperative period (Group A: 5.0 ±1.5 ng/mL; Group B: 4.8 ± 0.6 ng/mL) (P < 0.05). Forty eight hours after surgery the levels of ghrelin returned to their preoperative status. Patients’ gender, age, ASA score and type of surgical procedure did not influence the serum ghrelin levels. Conclusions Serum ghrelin concentration appears to elevate in response to surgical stress. Future studies are needed to improve comprehension of the mechanisms underlying responses of this hormone to acute surgical stress and to evaluate their possible clinical implications.

  12. Adipocytokine and ghrelin responses to acute exercise and sport training in children during growth and maturation.

    PubMed

    Jürimäe, Jaak

    2014-11-01

    Physical exercise is known to regulate energy balance. Important to this regulatory system is the existence of several peptides that communicate the status of body energy stores to the brain and are related to the body fatness including leptin, adiponectin and ghrelin. These hormones assist in regulating energy balance as well as somatic and pubertal growth in children. It appears that rather few studies have investigated the responses of leptin, adiponectin and ghrelin to acute exercise and these studies have demonstrated no changes in these peptides as a result of exercise. Leptin levels are decreased and may remain unchanged advancing from prepuberty to pubertal maturation in young male and female athletes. A limited number of studies indicate that adiponectin levels are not different between prepubertal and pubertal athletes and untrained controls. However, in certain circumstances circulating adiponectin could be increased in young athletes after onset of puberty as a result of heavily increased energy expenditure. Ghrelin levels are elevated in young sportsmen. However, pubertal onset decreases ghrelin levels in boys and girls even in the presence of chronically elevated energy expenditure as seen in young athletes. Ghrelin may also be used as an indicator of energy imbalance across the menstrual cycle in adolescent athletes. There are no studies with high-molecular-weight adiponectin and only very few studies with acylated ghrelin responses to acute exercise and chronic training have been performed in young athletes. Since these forms of adiponectin and ghrelin have been thought to be bioactive forms, further studies with these specific forms of adiponectin and ghrelin are needed. In conclusion, further studies should be conducted to investigate the response of these hormones to acute and chronic negative energy balance to better understand their role in regulating energy balance during growth and maturation in young athletes.

  13. Integrating solid-state NMR and computational modeling to investigate the structure and dynamics of membrane-associated ghrelin.

    PubMed

    Vortmeier, Gerrit; DeLuca, Stephanie H; Els-Heindl, Sylvia; Chollet, Constance; Scheidt, Holger A; Beck-Sickinger, Annette G; Meiler, Jens; Huster, Daniel

    2015-01-01

    The peptide hormone ghrelin activates the growth hormone secretagogue receptor 1a, also known as the ghrelin receptor. This 28-residue peptide is acylated at Ser3 and is the only peptide hormone in the human body that is lipid-modified by an octanoyl group. Little is known about the structure and dynamics of membrane-associated ghrelin. We carried out solid-state NMR studies of ghrelin in lipid vesicles, followed by computational modeling of the peptide using Rosetta. Isotropic chemical shift data of isotopically labeled ghrelin provide information about the peptide's secondary structure. Spin diffusion experiments indicate that ghrelin binds to membranes via its lipidated Ser3. Further, Phe4, as well as electrostatics involving the peptide's positively charged residues and lipid polar headgroups, contribute to the binding energy. Other than the lipid anchor, ghrelin is highly flexible and mobile at the membrane surface. This observation is supported by our predicted model ensemble, which is in good agreement with experimentally determined chemical shifts. In the final ensemble of models, residues 8-17 form an α-helix, while residues 21-23 and 26-27 often adopt a polyproline II helical conformation. These helices appear to assist the peptide in forming an amphipathic conformation so that it can bind to the membrane. PMID:25803439

  14. Calorie-restricted weight loss reverses high-fat diet-induced ghrelin resistance, which contributes to rebound weight gain in a ghrelin-dependent manner.

    PubMed

    Briggs, Dana I; Lockie, Sarah H; Wu, Qunli; Lemus, Moyra B; Stark, Romana; Andrews, Zane B

    2013-02-01

    Twelve weeks of high-fat diet feeding causes ghrelin resistance in arcuate neuropeptide Y (NPY)/agouti-related protein (AgRP) neurons. In the current study, we investigated whether diet-induced weight loss could restore NPY/AgRP neuronal responsiveness to ghrelin and whether ghrelin mediates rebound weight gain after calorie-restricted (CR) weight loss. Diet-induced obese (DIO) mice were allocated to one of two dietary interventions until they reached the weight of age-matched lean controls. DIO mice received chow diet ad libitum or chow diet with 40% CR. Chow-fed and high-fat-fed mice served as controls. Both dietary interventions normalized body weight, glucose tolerance, and plasma insulin. We show that diet-induced weight loss with CR increases total plasma ghrelin, restores ghrelin sensitivity, and increases hypothalamic NPY and AgRP mRNA expression. We propose that long-term DIO creates a higher body weight set-point and that weight loss induced by CR, as seen in the high-fat CR group, provokes the brain to protect the new higher set-point. This adaptation to weight loss likely contributes to rebound weight gain by increasing peripheral ghrelin concentrations and restoring the function of ghrelin-responsive neuronal populations in the hypothalamic arcuate nucleus. Indeed, we also show that DIO ghrelin-knockout mice exhibit reduced body weight regain after CR weight loss compared with ghrelin wild-type mice, suggesting ghrelin mediates rebound weight gain after CR weight loss.

  15. 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.

  16. Ghrelin acts as an interface between physiological state and phasic dopamine signaling.

    PubMed

    Cone, Jackson J; McCutcheon, James E; Roitman, Mitchell F

    2014-04-01

    Brief, high-concentration (phasic) spikes in nucleus accumbens dopamine critically participate in aspects of food reward. Although physiological state (e.g., hunger, satiety) and associated hormones are known to affect dopamine tone in general, whether they modulate food-evoked, phasic dopamine specifically is unknown. Here, we used fast-scan cyclic voltammetry in awake, behaving rats to record dopamine spikes evoked by delivery of sugar pellets while pharmacologically manipulating central receptors for the gut "hunger" hormone ghrelin. Lateral ventricular (LV) ghrelin increased, while LV ghrelin receptor antagonism suppressed the magnitude of dopamine spikes evoked by food. Ghrelin was effective when infused directly into the lateral hypothalamus (LH), but not the ventral tegmental area (VTA). LH infusions were made in close proximity to orexin neurons, which are regulated by ghrelin and project to the VTA. Thus, we also investigated and found potentiation of food-evoked dopamine spikes by intra-VTA orexin-A. Importantly, intra-VTA blockade of orexin receptors attenuated food intake induced by LV ghrelin, thus establishing a behaviorally relevant connection between central ghrelin and VTA orexin. Further analysis revealed that food restriction increased the magnitude of dopamine spikes evoked by food independent of any pharmacological manipulations. The results support the regulation of food-evoked dopamine spikes by physiological state with endogenous fluctuations in ghrelin as a key contributor. Our data highlight a novel mechanism by which signals relating physiological state could influence food reinforcement and food-directed behavior. PMID:24695709

  17. 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...

  18. 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

  19. 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.

  20. Low glucose-induced ghrelin secretion is mediated by an ATP-sensitive potassium channel.

    PubMed

    Oya, Manami; Kitaguchi, Tetsuya; Harada, Kazuki; Numano, Rika; Sato, Takahiro; Kojima, Masayasu; Tsuboi, Takashi

    2015-07-01

    Ghrelin is synthesized in X/A-like cells of the gastric mucosa, which plays an important role in the regulation of energy homeostasis. Although ghrelin secretion is known to be induced by neurotransmitters or hormones or by nutrient sensing in the ghrelin-secreting cells themselves, the mechanism of ghrelin secretion is not clearly understood. In the present study, we found that changing the extracellular glucose concentration from elevated (25  mM) to optimal (10 mM) caused an increase in the intracellular Ca2+ concentration ([Ca2+]i) in ghrelin-secreting mouse ghrelinoma 3-1 (MGN3-1) cells (n=32, P<0.01), whereas changing the glucose concentration from elevated to lowered (5 or 1 mM) had little effect on [Ca2+]i increase. Overexpression of a closed form of an ATP-sensitive K+ (KATP) channel mutant suppressed the 10  mM glucose-induced [Ca2+]i increase (n=8, P<0.01) and exocytotic events (n=6, P<0.01). We also found that a low concentration of a KATP channel opener, diazoxide, with 25  mM glucose induced [Ca2+]i increase (n=23, P<0.01) and ghrelin secretion (n≥3, P<0.05). In contrast, the application of a low concentration of a KATP channel blocker, tolbutamide, significantly induced [Ca2+]i increase (n=15, P<0.01) and ghrelin secretion (n≥3, P<0.05) under 5 mM glucose. Furthermore, the application of voltage-dependent Ca2+ channel inhibitors suppressed the 10 mM glucose-induced [Ca2+]i increase (n≥26, P<0.01) and ghrelin secretion (n≥5, P<0.05). These findings suggest that KATP and voltage-dependent Ca2+ channels are involved in glucose-dependent ghrelin secretion in MGN3-1 cells.

  1. Ghrelin and anterior pituitary function.

    PubMed

    Lanfranco, Fabio; Motta, Giovanna; Baldi, Matteo; Gasco, Valentina; Grottoli, Silvia; Benso, Andrea; Broglio, Fabio; Ghigo, Ezio

    2010-01-01

    Ghrelin, a 28-amino-acid octanoylated peptide predominantly produced by the stomach, was discovered to be the natural ligand of the type 1a GH secretagogue receptor. Thus, it was considered as a natural GH secretagogue (GHS) additional to GHRH, although later on ghrelin has mostly been considered a major orexigenic factor. The GH-releasing action of ghrelin takes place both directly on pituitary cells and through modulation of GHRH from the hypothalamus; some functional anti-somatostatin action has also been shown. However, even at the neuroendocrine level, ghrelin is much more than a natural GHS. In fact, it significantly stimulates prolactin secretion in humans, independent of both gender and age and probably involving a direct action on somatomammotroph cells. Above all, ghrelin and synthetic GHS possess an acute stimulatory effect on the activity of the hypothalamus-pituitary-adrenal axis in humans, which is, at least, similar to that of the opioid antagonist naloxone, arginine vasopressin and even corticotropin-releasing hormone. Also, ghrelin plays a relevant role in the modulation of the hypothalamic-pituitary-gonadal function, with a predominantly CNS-mediated inhibitory effect upon the gonadotropin pulsatility both in animals and in humans.

  2. 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.

  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. 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...

  5. INHIBITION OF GHRELIN O-ACYLTRANSFERASE ATTENUATES FOOD DEPRIVATION-INDUCED INCREASES IN INGESTIVE BEHAVIOR1

    PubMed Central

    Teubner, Brett J.W.; Garretson, John T.; Hwang, Yousang; Cole, Philip A.; Bartness, Timothy J.

    2013-01-01

    Ghrelin is an orexigenic hormone produced by the stomach in direct proportion to the time since the last meal and has therefore been called a ‘hunger signal’. The octanoylation of ghrelin is critical for its orexigenic functions and is dependent upon ghrelin O-acyltransferase (GOAT) catalyzation. The GOAT inhibitor, GO-CoA-Tat, decreases the circulating concentrations of octanoylated ghrelin and attenuates weight gain on a high fat diet in mice. Unlike rats and mice, Siberian hamsters and humans do not increase food intake after food deprivation, but increase food hoarding after food deprivation. In Siberian hamsters, exogenous ghrelin increases ingestive behaviors similarly to 48–56 h food deprivation. Therefore, we tested the necessity of increased ghrelin in food-deprived Siberian hamsters to stimulate ingestive behaviors. To do so we used our simulated natural housing system that allows hamsters to forage for and hoard food. Animals were given an injection of GO-CoA-Tat (i.p., 11 μmol/kg) every 6 h because that is the duration of its effective inhibition of octanoylated ghrelin concentrations during a 48 h food deprivation. We found that GO-CoA-Tat attenuated food foraging (0–1 h), food intake (0–1 and 2–4 h), and food hoarding (0–1 h and 2 and 3 d) post-refeeding compared with saline treated animals. This suggests that increased octanoylated ghrelin concentrations play a role in the food deprivation-induced increases in ingestive behavior. Therefore, ghrelin is a critical aspect of the multi-faceted mechanisms that stimulate ingestive behaviors, and might be a critical point for a successful clinical intervention scheme in humans. PMID:23399323

  6. Ghrelin and ghrelin receptor modulation of psychostimulant action

    PubMed Central

    Wellman, Paul J.; Clifford, P. Shane; Rodriguez, Juan A.

    2013-01-01

    Ghrelin (GHR) is an orexigenic gut peptide that modulates multiple homeostatic functions including gastric emptying, anxiety, stress, memory, feeding, and reinforcement. GHR is known to bind and activate growth-hormone secretagogue receptors (termed GHR-Rs). Of interest to our laboratory has been the assessment of the impact of GHR modulation of the locomotor activation and reward/reinforcement properties of psychostimulants such as cocaine and nicotine. Systemic GHR infusions augment cocaine stimulated locomotion and conditioned place preference (CPP) in rats, as does food restriction (FR) which elevates plasma ghrelin levels. Ghrelin enhancement of psychostimulant function may occur owing to a direct action on mesolimbic dopamine function or may reflect an indirect action of ghrelin on glucocorticoid pathways. Genomic or pharmacological ablation of GHR-Rs attenuates the acute locomotor-enhancing effects of nicotine, cocaine, amphetamine and alcohol and blunts the CPP induced by food, alcohol, amphetamine and cocaine in mice. The stimulant nicotine can induce CPP and like amphetamine and cocaine, repeated administration of nicotine induces locomotor sensitization in rats. Inactivation of ghrelin circuit function in rats by injection of a ghrelin receptor antagonist (e.g., JMV 2959) diminishes the development of nicotine-induced locomotor sensitization. These results suggest a key permissive role for GHR-R activity for the induction of locomotor sensitization to nicotine. Our finding that GHR-R null rats exhibit diminished patterns of responding for intracranial self-stimulation complements an emerging literature implicating central GHR circuits in drug reward/reinforcement. Finally, antagonism of GHR-Rs may represent a smoking cessation modality that not only blocks nicotine-induced reward but that also may limit weight gain after smoking cessation. PMID:24093007

  7. 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

  8. 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

    2016-01-01

    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

  9. Biochemical and histopathological evaluations of ghrelin effects following cadmium toxicity in the rat testis.

    PubMed

    Kheradmand, A; Alirezaei, M; Dezfoulian, O

    2015-08-01

    Numerous reports demonstrate that cadmium (Cd) induces oxidative stress by increasing lipid peroxidation and altering antioxidative enzymes status. Thirty male rats were subdivided into control-saline, Cd-saline and Cd-ghrelin groups. A single dose of Cd was injected to induce testicular injury and also ghrelin for 10 consecutive days to group 3. SOD activity decreased and lipid peroxidation increased by Cd administration. The mean activities of GPx and CAT as well as GSH content were lower in the Cd-saline rats; however, they did not statistically differ compared with the controls. Exposure to Cd resulted in complete degeneration of seminiferous tubules with severe depletion of germ cells and arrest in spermatogenesis. Notably, ghrelin treatment not only prevented reduction in SOD, GPx, CAT and GSH level, but also increased enzyme activities form their normal values. Moreover, TBARS concentration was significantly reduced by ghrelin administration. Furthermore, ghrelin pre-treatment resulted in partial but not significant prevention in testicular histopathological features damaged by Cd. In conclusion, the obtained results indicate for the first time the novel evidences of ghrelin ability in promotion of antioxidant enzyme activities and reduction of lipid peroxidation following Cd-induced oxidative stress in the rat testis. These observations also demonstrate that ghrelin may be considered as promising antioxidant agent in prevention and attenuation of testicular injury upon Cd toxicity. PMID:25059551

  10. Preprandial ghrelin is not affected by macronutrient intake, energy intake or energy expenditure

    PubMed Central

    Paul, David R; Kramer, Matthew; Rhodes, Donna G; Rumpler, William V

    2005-01-01

    Background Ghrelin, a peptide secreted by endocrine cells in the gastrointestinal tract, is a hormone purported to have a significant effect on food intake and energy balance in humans. The influence of factors related to energy balance on ghrelin, such as daily energy expenditure, energy intake, and macronutrient intake, have not been reported. Secondly, the effect of ghrelin on food intake has not been quantified under free-living conditions over a prolonged period of time. To investigate these effects, 12 men were provided with an ad libitum cafeteria-style diet for 16 weeks. The macronutrient composition of the diets were covertly modified with drinks containing 2.1 MJ of predominantly carbohydrate (Hi-CHO), protein (Hi-PRO), or fat (Hi-FAT). Total energy expenditure was measured for seven days on two separate occasions (doubly labeled water and physical activity logs). Results Preprandial ghrelin concentrations were not affected by macronutrient intake, energy expenditure or energy intake (all P > 0.05). In turn, daily energy intake was significantly influenced by energy expenditure, but not ghrelin. Conclusion Preprandial ghrelin does not appear to be influenced by macronutrient composition, energy intake, or energy expenditure. Similarly, ghrelin does not appear to affect acute or chronic energy intake under free-living conditions. PMID:15745452

  11. 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. PMID:24096007

  12. Expression and localization of ghrelin and its receptor in ovarian follicles during different stages of development and the modulatory effect of ghrelin on granulosa cells function in buffalo.

    PubMed

    Gupta, M; Dangi, S S; Singh, G; Sarkar, M

    2015-01-01

    Ghrelin, a hormone predominantly found in the stomach, was recently described as a factor that controls female reproductive function. The aim of our study was to investigate the expression and localization of ghrelin and its active receptor, growth hormone secretagogue receptor type 1a (GHS-R1a) in buffalo ovarian follicles of different follicular size and to investigate role of ghrelin on estradiol (E2) secretion, aromatase (CYP19A1), proliferating cell nuclear antigen (PCNA) and apoptosis regulator Bax gene expression on granulosa cell culture. Using real time PCR and western blot, we measured gene and protein expression of examined factors. Localization was done with immunofluorescence method. Expression of ghrelin increased with follicle size with significantly highest in dominant or pre-ovulatory follicle (P<0.05). Expression of GHS-R1a was comparable in medium and large follicle but was higher than small follicles (P<0.05). Both the factors were localized in granulosa and theca cells. Pattern of intensity of immunofluorescence was similar with mRNA and protein expression. In the in vitro study granulosa cells (GCs) were cultured and treated with ghrelin each at 1, 10 and 100ng/ml concentrations for two days after obtaining 75-80 per cent confluence. Ghrelin treatment significantly (P<0.05) inhibited E2 secretion, CYP19A1 expression, apoptosis and promoted cell proliferation. In conclusion, this study provides novel evidence for the presence of ghrelin and receptor GHS-R1a in ovarian follilcles and modulatory role of ghrelin on granulosa cell function in buffalo.

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

    PubMed

    Sever, Sakine; White, Donna L; Garcia, José M

    2016-09-01

    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

  15. Revisiting the metabolism and physiological functions of caprylic acid (C8:0) with special focus on ghrelin octanoylation.

    PubMed

    Lemarié, Fanny; Beauchamp, Erwan; Legrand, Philippe; Rioux, Vincent

    2016-01-01

    Caprylic acid (octanoic acid, C8:0) belongs to the class of medium-chain saturated fatty acids (MCFAs). Dairy products and specific oils like coconut oil are natural sources of dietary C8:0 but higher intakes of this fatty acid can be provided with MCT (Medium-Chain Triglycerides) oil that consists in 75% of C8:0. MCFAs have physical and metabolic properties that are distinct from those of long-chain saturated fatty acids (LCFAs ≥ 12 carbons). Beneficial physiological effects of dietary C8:0 have been studied for a long time and MCT oil has been used as a special energy source for patients suffering from pancreatic insufficiency, impaired lymphatic chylomicron transport and fat malabsorption. More recently, caprylic acid was also shown to acylate ghrelin, the only known peptide hormone with an orexigenic effect. Through its covalent binding to the ghrelin peptide, caprylic acid exhibits an emerging and specific role in modulating physiological functions themselves regulated by octanoylated ghrelin. Dietary caprylic acid is therefore now suspected to provide the ghrelin O-acyltransferase (GOAT) enzyme with octanoyl-CoA co-substrates necessary for the acyl modification of ghrelin. This review tries to highlight the discrepancy between the formerly described beneficial effects of dietary MCFAs on body weight loss and the C8:0 newly reported effect on appetite stimulation via ghrelin octanoylation. The subsequent aim of this review is to demonstrate the relevance of carrying out further studies to better understand the physiological functions of this particular fatty acid. PMID:26253695

  16. Revisiting the metabolism and physiological functions of caprylic acid (C8:0) with special focus on ghrelin octanoylation.

    PubMed

    Lemarié, Fanny; Beauchamp, Erwan; Legrand, Philippe; Rioux, Vincent

    2016-01-01

    Caprylic acid (octanoic acid, C8:0) belongs to the class of medium-chain saturated fatty acids (MCFAs). Dairy products and specific oils like coconut oil are natural sources of dietary C8:0 but higher intakes of this fatty acid can be provided with MCT (Medium-Chain Triglycerides) oil that consists in 75% of C8:0. MCFAs have physical and metabolic properties that are distinct from those of long-chain saturated fatty acids (LCFAs ≥ 12 carbons). Beneficial physiological effects of dietary C8:0 have been studied for a long time and MCT oil has been used as a special energy source for patients suffering from pancreatic insufficiency, impaired lymphatic chylomicron transport and fat malabsorption. More recently, caprylic acid was also shown to acylate ghrelin, the only known peptide hormone with an orexigenic effect. Through its covalent binding to the ghrelin peptide, caprylic acid exhibits an emerging and specific role in modulating physiological functions themselves regulated by octanoylated ghrelin. Dietary caprylic acid is therefore now suspected to provide the ghrelin O-acyltransferase (GOAT) enzyme with octanoyl-CoA co-substrates necessary for the acyl modification of ghrelin. This review tries to highlight the discrepancy between the formerly described beneficial effects of dietary MCFAs on body weight loss and the C8:0 newly reported effect on appetite stimulation via ghrelin octanoylation. The subsequent aim of this review is to demonstrate the relevance of carrying out further studies to better understand the physiological functions of this particular fatty acid.

  17. 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.

  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. PMID:26769837

  19. 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 ...

  20. Ghrelin inhibits sympathetic nervous activity in sepsis.

    PubMed

    Wu, Rongqian; Zhou, Mian; Das, Padmalaya; Dong, Weifeng; Ji, Youxin; Yang, Derek; Miksa, Michael; Zhang, Fangming; Ravikumar, Thanjavur S; Wang, Ping

    2007-12-01

    Our previous studies have shown that norepinephrine (NE) upregulates proinflammatory cytokines by activating alpha(2)-adrenoceptor. Therefore, modulation of the sympathetic nervous system represents a novel treatment for sepsis. We have also shown that a novel stomach-derived peptide, ghrelin, is downregulated in sepsis and that its intravenous administration decreases proinflammatory cytokines and mitigates organ injury. However, it remains unknown whether ghrelin inhibits sympathetic activity through central ghrelin receptors [i.e., growth hormone secretagogue receptor 1a (GHSR-la)] in sepsis. To study this, sepsis was induced in male rats by cecal ligation and puncture (CLP). Ghrelin was administered through intravenous or intracerebroventricular injection 30 min before CLP. Our results showed that intravenous administration of ghrelin significantly reduced the elevated NE and TNF-alpha levels at 2 h after CLP. NE administration partially blocked the inhibitory effect of ghrelin on TNF-alpha in sepsis. GHSR-la inhibition by the administration of a GHSR-la antagonist, [d-Arg(1),d-Phe(5), d-Trp(7,9),Leu(11)]substance P, significantly increased both NE and TNF-alpha levels even in normal animals. Markedly elevated circulating levels of NE 2 h after CLP were also significantly decreased by intracerebroventricular administration of ghrelin. Ghrelin's inhibitory effect on NE release was completely blocked by intracerebroventricular injection of the GHSR-1a antagonist or a neuropeptide Y (NPY)/Y(1) receptor antagonist. However, ghrelin's downregulatory effect on TNF-alpha release was only partially diminished by these agents. Thus ghrelin has sympathoinhibitory properties that are mediated by central ghrelin receptors involving a NPY/Y1 receptor-dependent pathway. Ghrelin's inhibitory effect on TNF-alpha production in sepsis is partially because of its modulation of the overstimulated sympathetic nerve activation.

  1. 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

  2. Methyl Donor Deficiency Affects Fetal Programming of Gastric Ghrelin Cell Organization and Function in the Rat

    PubMed Central

    Bossenmeyer-Pourié, Carine; Blaise, Sébastien; Pourié, Grégory; Tomasetto, Catherine; Audonnet, Sandra; Ortiou, Sandrine; Koziel, Violette; Rio, Marie-Christine; Daval, Jean-Luc; Guéant, Jean-Louis; Beck, Bernard

    2010-01-01

    Methyl donor deficiency (MDD) during pregnancy influences intrauterine development. Ghrelin is expressed in the stomach of fetuses and influences fetal growth, but MDD influence on gastric ghrelin is unknown. We examined the gastric ghrelin system in MDD-induced intrauterine growth retardation. By using specific markers and approaches (such as periodic acid–Schiff, bromodeoxyuridine, homocysteine, terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling, immunostaining, reverse transcription-polymerase chain reaction), we studied the gastric oxyntic mucosa cellular organization and ghrelin gene expression in the mucosa in 20-day-old fetuses and weanling pups, and plasma ghrelin concentration in weanling rat pups of dams either normally fed or deprived of choline, folate, vitamin B6, and vitamin B12 during gestation and suckling periods. MDD fetuses weighed less than controls; the weight deficit reached 57% at weaning (P < 0.001). Both at the end of gestation and at weaning, they presented with an aberrant gastric oxyntic mucosa formation with loss of cell polarity, anarchic cell migration, abnormal progenitor differentiation, apoptosis, and signs of surface layer erosion. Ghrelin cells were abnormally located in the pit region of oxyntic glands. At weaning, plasma ghrelin levels were decreased (−28%; P < 0.001) despite unchanged mRNA expression in the stomach. This decrease was associated with lower body weight. Taken together, these data indicate that one mechanism through which MDD influences fetal programming is the remodeling of gastric cellular organization, leading to dysfunction of the ghrelin system and dramatic effects on growth. PMID:19948829

  3. 1 Peripheral ghrelin stimulates feeding behavior and positive energy balance in a sciurid hibernator

    PubMed Central

    Healy, Jessica E.; Bateman, Jenna L.; Ostrom, Cara E.; Florant, Gregory L.

    2011-01-01

    Hibernators exhibit a robust circannual cycle of body mass gain and loss primarily mediated by food intake, but the pathways controlling food intake in these animals have not been fully elucidated. Ghrelin is an orexigenic hormone that increases feeding in all mammals studied so far, but has not until recently been studied in hibernators. In other mammals, ghrelin stimulates feeding through phosphorylation and activation of AMP-activated protein kinase (AMPK). Activation of AMPK phosphorylates and deactivates acetyl Co-A carboxylase (ACC), a committed step in fatty acid synthesis. In order to determine the effects of exogenous ghrelin on food intake and metabolic factors (i.e. non-esterified fatty acids (NEFAs), and hypothalamic AMPK and ACC) in hibernators, ghrelin was peripherally injected into ground squirrels in all four seasons. Changes in food intake and body mass were recorded over a 2–6 hour period post injections, and squirrels were euthanized. Brains and blood were removed, and Western blots were performed to determine changes in phosphorylation of hypothalamic AMPK and ACC. A colorimetric assay was used to determine changes in concentration of serum NEFAs. We found that food intake, body mass, and locomotor activity significantly increased with ghrelin injections versus saline-injected controls, even in animals injected during their aphagic winter season. Injected ghrelin was correlated with increased phosphorylation of AMPK, but didn’t have an effect on ACC in winter. Ghrelin-injected animals also had increased levels of serum NEFAs compared with saline controls. This study is the first to show an effect of injected ghrelin on a hibernator. PMID:21310157

  4. 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

  5. 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.

  6. 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...

  7. Carbohydrate-rich breakfast attenuates glycaemic, insulinaemic and ghrelin response to ad libitum lunch relative to morning fasting in lean adults.

    PubMed

    Chowdhury, Enhad A; Richardson, Judith D; Tsintzas, Kostas; Thompson, Dylan; Betts, James A

    2015-07-14

    Breakfast omission is associated with obesity and CVD/diabetes, but the acute effects of extended morning fasting upon subsequent energy intake and metabolic/hormonal responses have received less attention. In a randomised cross-over design, thirty-five lean men (n 14) and women (n 21) extended their overnight fast or ingested a typical carbohydrate-rich breakfast in quantities relative to RMR (i.e. 1963 (sd 238) kJ), before an ad libitum lunch 3 h later. Blood samples were obtained hourly throughout the day until 3 h post-lunch, with subjective appetite measures assessed. Lunch intake was greater following extended fasting (640 (sd 1042) kJ, P< 0.01) but incompletely compensated for the omitted breakfast, with total intake lower than the breakfast trial (3887 (sd 1326) v. 5213 (sd 1590) kJ, P< 0.001). Systemic concentrations of peptide tyrosine-tyrosine and leptin were greater during the afternoon following breakfast (both P< 0.05) but neither acylated/total ghrelin concentrations were suppressed by the ad libitum lunch in the breakfast trial, remaining greater than the morning fasting trial throughout the afternoon (all P< 0.05). Insulin concentrations were greater during the afternoon in the morning fasting trial (all P< 0.01). There were no differences between trials in subjective appetite during the afternoon. In conclusion, morning fasting caused incomplete energy compensation at an ad libitum lunch. Breakfast increased some anorectic hormones during the afternoon but paradoxically abolished ghrelin suppression by the second meal. Extending morning fasting until lunch altered subsequent metabolic and hormonal responses but without greater appetite during the afternoon. The present study clarifies the impact of acute breakfast omission and adds novel insights into second-meal metabolism. PMID:26004166

  8. Carbohydrate-rich breakfast attenuates glycaemic, insulinaemic and ghrelin response to ad libitum lunch relative to morning fasting in lean adults.

    PubMed

    Chowdhury, Enhad A; Richardson, Judith D; Tsintzas, Kostas; Thompson, Dylan; Betts, James A

    2015-07-14

    Breakfast omission is associated with obesity and CVD/diabetes, but the acute effects of extended morning fasting upon subsequent energy intake and metabolic/hormonal responses have received less attention. In a randomised cross-over design, thirty-five lean men (n 14) and women (n 21) extended their overnight fast or ingested a typical carbohydrate-rich breakfast in quantities relative to RMR (i.e. 1963 (sd 238) kJ), before an ad libitum lunch 3 h later. Blood samples were obtained hourly throughout the day until 3 h post-lunch, with subjective appetite measures assessed. Lunch intake was greater following extended fasting (640 (sd 1042) kJ, P< 0.01) but incompletely compensated for the omitted breakfast, with total intake lower than the breakfast trial (3887 (sd 1326) v. 5213 (sd 1590) kJ, P< 0.001). Systemic concentrations of peptide tyrosine-tyrosine and leptin were greater during the afternoon following breakfast (both P< 0.05) but neither acylated/total ghrelin concentrations were suppressed by the ad libitum lunch in the breakfast trial, remaining greater than the morning fasting trial throughout the afternoon (all P< 0.05). Insulin concentrations were greater during the afternoon in the morning fasting trial (all P< 0.01). There were no differences between trials in subjective appetite during the afternoon. In conclusion, morning fasting caused incomplete energy compensation at an ad libitum lunch. Breakfast increased some anorectic hormones during the afternoon but paradoxically abolished ghrelin suppression by the second meal. Extending morning fasting until lunch altered subsequent metabolic and hormonal responses but without greater appetite during the afternoon. The present study clarifies the impact of acute breakfast omission and adds novel insights into second-meal metabolism.

  9. Ghrelin in female and male reproduction.

    PubMed

    Dupont, Joëlle; Maillard, Virginie; Coyral-Castel, Stéphanie; Ramé, Christelle; Froment, Pascal

    2010-01-01

    Ghrelin and one of its functional receptors, GHS-R1a (Growth Hormone Secretagogue Receptor 1a), were firstly studied about 15 years. Ghrelin is a multifunctional peptide hormone that affects several biological functions including food intake, glucose release, cell proliferation... Ghrelin and GHS-R1a are expressed in key cells of both male and female reproductive organs in several species including fishes, birds, and mammals suggesting a well-conserved signal through the evolution and a role in the control of fertility. Ghrelin could be a component of the complex series of nutrient sensors such as adipokines, and nuclear receptors, which regulate reproduction in function of the energy stores. The objective of this paper was to report the available information about the ghrelin system and its role at the level of the hypothalamic-pituitary-gonadal axis in both sexes.

  10. Ghrelin--an indicator for fat oxidation in obese children and adolescents during a weight reduction program.

    PubMed

    Nitsche, Hildegard; Nitsche, Marianne; Sudi, Karl; Tschop, Matthias; Zotter, Heinz; Weinhand, Gudrun; Froehlich-Reiterer, Elke; Gallistl, Siegfried; Pirker, Martina; Borkenstein, Martin

    2007-06-01

    The aim of this study was to investigate the effect of short-term energy restriction combined with physical activity on changes in substrate oxidation and changes in plasma concentrations of ghrelin. We designed a longitudinal intervention study of 4.2 MJ (= 1,000 kcal) daily with exercise. Eighteen obese children and adolescents (age: 13.1 +/- 1.6 years, 13 girls, 5 boys, 17 White, 1 Black) participated. We measured body mass index (BMI), plasma ghrelin, resting energy expenditure (REE), VCO2, VO2 and respiratory quotient (RQ) at baseline and after 10 days. There was a significant decrease of BMI during the 10 day program (28.6 +/- 4.3 vs 27.5 +/- 4.2; p < 0.001). Ghrelin and RQ showed a tendency to increase, but the difference did not reach significance (ghrelin: 83.4 +/- 37.1 vs 99.5 +/- 41.2, p = 0067; RQ: 0.83 +/- 0.06 vs 0.85 +/- 0.08, p = 0.433). The changes in RQ were significantly and independently correlated with the changes in plasma ghrelin (p = 0.029). The increase in RQ suggests a shift from fat oxidation towards carbohydrate oxidation. Ghrelin reflects the same sensitivity as RQ to changes in energy balance. Therefore, ghrelin seems to be a sensitive indicator for changes in substrate oxidation.

  11. Relationship between Serum Leptin, Ghrelin and Dietary Macronutrients in Women with Polycystic Ovary Syndrome

    PubMed Central

    Pourghassem Gargari, Bahram; Houjeghani, Shiva; Farzadi, Laya; Houjeghani, Sheyda; Safaeiyan, Abdolrasoul

    2015-01-01

    Background Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women. It may involve an impairment in physiologic regulation of leptin and ghrelin. There is limited, controversial data on the relation of dietary components with leptin and ghrelin in PCOS, so the current study has been conducted to explore the effects of different macronutrients on serum levels of leptin and ghrelin in PCOS and healthy subjects. Materials and Methods In this case-control study, we randomly choose 30 PCOS pa- tients and 30 healthy age and body mass index (BMI) matched controls. Intake of macronutrients [protein, total fat, saturated, monounsaturated and polyunsaturated fatty acids (PUFA), carbohydrate, dietary fiber] and energy were assessed using 3-day, 24-hour food recall and food frequency questionnaires (FFQ). Fasting hormonal status was measured for each participant. Results PCOS women had higher levels of serum leptin, insulin, testosterone, and luteinizing hormone (LH), whereas sex hormone-binding globulin (SHBG) was lower compared to healthy women. There was no significant difference in mean ghrelin concentrations between the groups. Among PCOS women, independent of BMI and total energy intake, we observed an inverse association between leptin concentration and total dietary fat (β=-0.16, P<0.05) and saturated fatty acid (SFA) intake (β=-0.58, P<0.05). This relationship was not seen in the healthy subjects. There was no significant association between ghrelin and macronutrients in PCOS and healthy participants. Conclusion Certain habitual dietary components such as fat and SFA may decrease serum leptin, whereas ghrelin is not influenced by these in PCOS women. More studies are needed to better clarify the effects of dietary macronutrients on serum leptin and ghrelin. PMID:26644854

  12. Serum ghrelin is inversely associated with risk of subsequent oesophageal squamous cell carcinoma

    PubMed Central

    Murphy, Gwen; Kamangar, Farin; Albanes, Demetrius; Stanczyk, Frank Z.; Weinstein, Stephanie J.; Taylor, Philip R.; Virtamo, Jarmo; Abnet, Christian C.; Dawsey, Sanford M.; Freedman, Neal D.

    2012-01-01

    Background Oesophageal cancers rank as the eighth most common cancer and the sixth most common cause of cancer death, worldwide. Gastric atrophy, as determined by a low serum pepsinogen I/II ratio, may be associated with an increased risk of oesophageal squamous cell carcinoma (OSCC). Ghrelin, a hormone which, like pepsinogen, is produced in the fundic glands of the stomach, may be a sensitive and specific marker of gastric atrophy, but its association with OSCC is not known. Methods To examine the relationship between baseline serum ghrelin concentration and subsequent risk of OSCC, we conducted a nested case-control study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. 82 cases of OSCC were matched (1:1) by age and date of blood draw to controls from the ATBC study. Serum ghrelin was measured by radioimmunoassay. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using conditional logistic regression with adjustment for potential confounders. Results For those individuals in the lowest quartile of serum ghrelin, compared to those in the highest, the multivariate odds ratio of subsequent OSCC was 6.83 (95% CI: 1.46, 31.84). These associations were dose dependent (P for trend = 0.005 for both), and independent of the effects of low pepsinogen I/II ratio (a marker of gastric fundic atrophy) and Helicobacter pylori infection. The significance of these associations remained even for individuals developing OSCC up to 10 years after baseline ghrelin measurement, though they become attenuated after 10 years. Conclusion Lower baseline concentrations of serum ghrelin were associated with an increase in risk of OSCC. Further studies are needed to confirm this finding in other populations and to explore the role of ghrelin in the aetiology of OSCC. PMID:22180062

  13. Fatty acylation of proteins: The long and the short of it.

    PubMed

    Resh, Marilyn D

    2016-07-01

    Long, short and medium chain fatty acids are covalently attached to hundreds of proteins. Each fatty acid confers distinct biochemical properties, enabling fatty acylation to regulate intracellular trafficking, subcellular localization, protein-protein and protein-lipid interactions. Myristate and palmitate represent the most common fatty acid modifying groups. New insights into how fatty acylation reactions are catalyzed, and how fatty acylation regulates protein structure and function continue to emerge. Myristate is typically linked to an N-terminal glycine, but recent studies reveal that lysines can also be myristoylated. Enzymes that remove N-terminal myristoyl-glycine or myristate from lysines have now been identified. DHHC proteins catalyze S-palmitoylation, but the mechanisms that regulate substrate recognition by individual DHHC family members remain to be determined. New studies continue to reveal thioesterases that remove palmitate from S-acylated proteins. Another area of rapid expansion is fatty acylation of the secreted proteins hedgehog, Wnt and Ghrelin, by Hhat, Porcupine and GOAT, respectively. Understanding how these membrane bound O-acyl transferases recognize their protein and fatty acyl CoA substrates is an active area of investigation, and is punctuated by the finding that these enzymes are potential drug targets in human diseases. PMID:27233110

  14. Acyl glucuronides: the good, the bad and the ugly.

    PubMed

    Regan, Sophie L; Maggs, James L; Hammond, Thomas G; Lambert, Craig; Williams, Dominic P; Park, B Kevin

    2010-10-01

    Acyl glucuronidation is the major metabolic conjugation reaction of most carboxylic acid drugs in mammals. The physiological consequences of this biotransformation have been investigated incompletely but include effects on drug metabolism, protein binding, distribution and clearance that impact upon pharmacological and toxicological outcomes. In marked contrast, the exceptional but widely disparate chemical reactivity of acyl glucuronides has attracted far greater attention. Specifically, the complex transacylation and glycation reactions with proteins have provoked much inconclusive debate over the safety of drugs metabolised to acyl glucuronides. It has been hypothesised that these covalent modifications could initiate idiosyncratic adverse drug reactions. However, despite a large body of in vitro data on the reactions of acyl glucuronides with protein, evidence for adduct formation from acyl glucuronides in vivo is limited and potentially ambiguous. The causal connection of protein adduction to adverse drug reactions remains uncertain. This review has assessed the intrinsic reactivity, metabolic stability and pharmacokinetic properties of acyl glucuronides in the context of physiological, pharmacological and toxicological perspectives. Although numerous experiments have characterised the reactions of acyl glucuronides with proteins, these might be attenuated substantially in vivo by rapid clearance of the conjugates. Consequently, to delineate a relationship between acyl glucuronide formation and toxicological phenomena, detailed pharmacokinetic analysis of systemic exposure to the acyl glucuronide should be undertaken adjacent to determining protein adduct concentrations in vivo. Further investigation is required to ascertain whether acyl glucuronide clearance is sufficient to prevent covalent modification of endogenous proteins and consequentially a potential immunological response. PMID:20830700

  15. Head-group acylation of monogalactosyldiacylglycerol is a common stress response, and the acyl-galactose acyl composition varies with the plant species and applied stress.

    PubMed

    Vu, Hieu Sy; Roth, Mary R; Tamura, Pamela; Samarakoon, Thilani; Shiva, Sunitha; Honey, Samuel; Lowe, Kaleb; Schmelz, Eric A; Williams, Todd D; Welti, Ruth

    2014-04-01

    Formation of galactose-acylated monogalactosyldiacylglycerols has been shown to be induced by leaf homogenization, mechanical wounding, avirulent bacterial infection and thawing after snap-freezing. Here, lipidomic analysis using mass spectrometry showed that galactose-acylated monogalactosyldiacylglycerols, formed in wheat (Triticum aestivum) and tomato (Solanum lycopersicum) leaves upon wounding, have acyl-galactose profiles that differ from those of wounded Arabidopsis thaliana, indicating that different plant species accumulate different acyl-galactose components in response to the same stress. Additionally, the composition of the acyl-galactose component of Arabidopsis acMGDG (galactose-acylated monogalactosyldiacylglycerol) depends on the stress treatment. After sub-lethal freezing treatment, acMGDG contained mainly non-oxidized fatty acids esterified to galactose, whereas mostly oxidized fatty acids accumulated on galactose after wounding or bacterial infection. Compositional data are consistent with acMGDG being formed in vivo by transacylation with fatty acids from digalactosyldiacylglycerols. Oxophytodienoic acid, an oxidized fatty acid, was more concentrated on the galactosyl ring of acylated monogalactosyldiacylglycerols than in galactolipids in general. Also, oxidized fatty acid-containing acylated monogalactosyldiacylglycerols increased cumulatively when wounded Arabidopsis leaves were wounded again. These findings suggest that, in Arabidopsis, the pool of galactose-acylated monogalactosyldiacylglycerols may serve to sequester oxidized fatty acids during stress responses. PMID:24286212

  16. 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

  17. Hypotensive effects of ghrelin receptor agonists mediated through a novel receptor

    PubMed Central

    Callaghan, Brid; Kosari, Samin; Pustovit, Ruslan V; Sartor, Daniela M; Ferens, Dorota; Ban, Kung; Baell, Jonathan; Nguyen, Trung V; Rivera, Leni R; Brock, James A; Furness, John B

    2014-01-01

    BACKGROUND AND PURPOSE Some agonists of ghrelin receptors cause rapid decreases in BP. The mechanisms by which they cause hypotension and the pharmacology of the receptors are unknown. EXPERIMENTAL APPROACH The effects of ligands of ghrelin receptors were investigated in rats in vivo, on isolated blood vessels and on cells transfected with the only molecularly defined ghrelin receptor, growth hormone secretagogue receptor 1a (GHSR1a). KEY RESULTS Three agonists of GHSR1a receptors, ulimorelin, capromorelin and CP464709, caused a rapid decrease in BP in the anaesthetized rat. The effect was not reduced by either of two GHSR1a antagonists, JMV2959 or YIL781, at doses that blocked effects on colorectal motility, in vivo. The rapid hypotension was not mimicked by ghrelin, unacylated ghrelin or the unacylated ghrelin receptor agonist, AZP531. The early hypotension preceded a decrease in sympathetic nerve activity. Early hypotension was not reduced by hexamethonium or by baroreceptor (sino-aortic) denervation. Ulimorelin also relaxed isolated segments of rat mesenteric artery, and, less potently, relaxed aorta segments. The vascular relaxation was not reduced by JMV2959 or YIL781. Ulimorelin, capromorelin and CP464709 activated GHSR1a in transfected HEK293 cells at nanomolar concentrations. JMV2959 and YIL781 both antagonized effects in these cells, with their pA2 values at the GHSR1a receptor being 6.55 and 7.84. CONCLUSIONS AND IMPLICATIONS Our results indicate a novel vascular receptor or receptors whose activation by ulimorelin, capromorelin and CP464709 lowered BP. This receptor is activated by low MW GHSR1a agonists, but is not activated by ghrelin. PMID:24670149

  18. Ghrelin regulates phasic dopamine and nucleus accumbens signaling evoked by food-predictive stimuli

    PubMed Central

    Cone, Jackson J.; Roitman, Jamie D.; Roitman, Mitchell F.

    2015-01-01

    Environmental stimuli that signal food availability hold powerful sway over motivated behavior and promote feeding, in part, by activating the mesolimbic system. These food-predictive cues evoke brief (phasic) changes in nucleus accumbens (NAc) dopamine concentration and in the activity of individual NAc neurons. Phasic fluctuations in mesolimbic signaling have been directly linked to goal-directed behaviors, including behaviors elicited by food-predictive cues. Food-seeking behavior is also strongly influenced by physiological state (i.e. hunger vs. satiety). Ghrelin, a stomach hormone that crosses the blood-brain barrier, is linked to the perception of hunger and drives food intake, including intake potentiated by environmental cues. Notwithstanding, whether ghrelin regulates phasic mesolimbic signaling evoked by food-predictive stimuli is unknown. Here, rats underwent Pavlovian conditioning in which one cue predicted the delivery of rewarding food (CS+) and a second cue predicted nothing (CS−). After training, we measured the effect of ghrelin infused into the lateral ventricle (LV) on sub-second fluctuations in NAc dopamine using fast-scan cyclic voltammetry and individual NAc neuron activity using in vivo electrophysiology in separate groups of rats. LV ghrelin augmented both phasic dopamine and phasic increases in the activity of NAc neurons evoked by the CS+. Importantly, ghrelin did not affect the dopamine nor NAc neuron response to the CS−, suggesting that ghrelin selectively modulated mesolimbic signaling evoked by motivationally significant stimuli. These data demonstrate that ghrelin, a hunger signal linked to physiological state, can regulate cue-evoked mesolimbic signals that underlie food-directed behaviors. PMID:25708523

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

    PubMed

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

    2013-01-01

    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. 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

  1. Fetuin-A and Ghrelin Levels in Children with End Stage Renal Disease and the Effect of a Single Hemodialysis Session on Them

    PubMed Central

    Shouman, Mohamed Gamal; Ismail, Nagwa Abdallah; Badr, Ahmed; Abdelrahman, Safaa Mohamed; Ragab, Shadia; Farouk, Hebatallah

    2015-01-01

    BACKGROUND: Fetuin-A and ghrelin have been implicated in cardiovascular diseases and mortality among end stage renal disease patients. The exact mechanisms have not been fully elucidated. There is robust data supporting an association between ghrelin and various cardiovascular conditions, and some common processes such as inflammation, oxidative stress, and endoplasmic reticulum stress have been implicated. AIM: This study was conducted to assay serum fetuin-A and ghrelin in chronic renal failure pediatric patients and to study changes in their level that may occur after a single hemodialysis. MATERIAL AND METHODS: Forty nine pediatric patients suffering from ESRD on maintenance hemodialysis (HD), 20 patients with chronic renal failure (CRF) not on dialysis and 35 healthy subjects as control group were included. The mean age of the study population was 10.58 ± 3.94, 10.62 ± 3.24 and 10.61 ± 3.97 years respectively. Serum fetuin-A and plasma acyl ghrelin levels were measured by using ELISA method. RESULTS: The present study revealed that predialysis serum fetuin-A level was significantly increased in pediatric HD patients compared with the normal population, while ghrelin levels were significantly reduced. Furthermore, serum levels of fetuin-A decreased significantly after a single HD session. CONCLUSION: Our study concluded that fetuin-A and acyl ghrelin may play a role in inflammatory process among HD pediatric patients which may account for cardiovascular insults and mortality but their use as biochemical markers among ESRD pediatric patients have limitations due to wide fluctuations. PMID:27275256

  2. Little or no ability of obestatin to interact with ghrelin or modify motility in the rat gastrointestinal tract

    PubMed Central

    Bassil, A K; Häglund, Y; Brown, J; Rudholm, T; Hellström, P M; Näslund, E; Lee, K; Sanger, G J

    2006-01-01

    Background and purpose: Obestatin, encoded by the ghrelin gene may inhibit gastrointestinal (GI) motility. This activity was re-investigated. Experimental approach: Rat GI motility was studied in vitro (jejunum contractility and cholinergically-mediated contractions of forestomach evoked by electrical field stimulation; EFS) and in vivo (gastric emptying and intestinal myoelectrical activity). Ghrelin receptor function was studied using a GTPγS assay and transfected cells. Key results: Contractions of the jejunum or forestomach were unaffected by obestatin 100 nM or 0.01–1000 nM, respectively (P>0.05 each; n=4-18). Obestatin (0.1-1 nM) reduced the ability of ghrelin 1 μM to facilitate EFS-evoked contractions of the stomach (increases were 42.7±7.8% and 21.2±5.0 % in the absence and presence of obestatin 1 nM; P<0.05; n=12); higher concentrations (10–1000 nM) tended to reduce the response to ghrelin but changes were not statistically significant. Similar concentrations of obestatin did not significantly reduce a facilitation of contractions caused by the 5-HT4 receptor agonist prucalopride, although an inhibitory trend occurred at the higher concentrations (increases were 69.3±14.0% and 42.6±8.7% in the absence and presence of 1000 nM obestatin; n=10). Obestatin (up to 10 μM) did not modulate recombinant ghrelin receptor function. Ghrelin increased gastric emptying and reduced MMC cycle time; obestatin (1000 and 30,000 pmol kg−1 min−1) had no effects. Obestatin (2500 pmol kg−1 min−1, starting 10 min before ghrelin) did not prevent the ability of ghrelin (500 pmol kg−1 min−1) to shorten MMC cycle time. Conclusions and implications: Obestatin has little ability to modulate rat GI motility. PMID:17128285

  3. Head-group acylation of monogalactosyldiacylglycerol is a common stress response, and the acyl-galactose acyl composition varies with the plant species and applied stress

    PubMed Central

    Vu, Hieu Sy; Roth, Mary R.; Tamura, Pamela; Samarakoon, Thilani; Shiva, Sunitha; Honey, Samuel; Lowe, Kaleb; Schmelz, Eric A.; Williams, Todd D.; Welti, Ruth

    2014-01-01

    Formation of galactose-acylated monogalactosyldiacylglycerols has been shown to be induced by leaf homogenization, mechanical wounding, avirulent bacterial infection, and thawing after snap-freezing. Here, lipidomic analysis using mass spectrometry showed that galactose-acylated monogalactosyldiacylglycerols, formed in wheat (Triticum aestivum) and tomato (Solanum lycopersicum) leaves upon wounding, have acyl-galactose profiles that differ from those of wounded Arabidopsis thaliana, indicating that different plant species accumulate different acyl-galactose components in response to the same stress. Additionally, the composition of the acyl-galactose component of Arabidopsis acMGDG depends on the stress treatment. After sub-lethal freezing treatment, acMGDG contained mainly non-oxidized fatty acids esterified to galactose, whereas mostly oxidized fatty acids accumulated on galactose after wounding or bacterial infection. Compositional data are consistent with acMGDG being formed in vivo by transacylation with fatty acids from digalactosyldiacylglycerols. Oxophytodienoic acid, an oxidized fatty acid, was more concentrated on the galactosyl ring of acylated monogalactosyldiacylglycerols than in galactolipids in general. Also, oxidized fatty acid-containing acylated monogalactosyldiacylglycerols increased cumulatively when wounded Arabidopsis leaves were wounded again. These findings suggest that, in Arabidopsis, the pool of galactose-acylated monogalactosyldiacylglycerols may serve to sequester oxidized fatty acids during stress responses. PMID:24286212

  4. 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. PMID:27431015

  5. Comprehensive Profiling of GPCR Expression in Ghrelin-Producing Cells.

    PubMed

    Koyama, Hiroyuki; Iwakura, Hiroshi; Dote, Katsuko; Bando, Mika; Hosoda, Hiroshi; Ariyasu, Hiroyuki; Kusakabe, Toru; Son, Choel; Hosoda, Kiminori; Akamizu, Takashi; Kangawa, Kenji; Nakao, Kazuwa

    2016-02-01

    To determine the comprehensive G protein-coupled receptor (GPCR) expression profile in ghrelin-producing cells and to elucidate the role of GPCR-mediated signaling in the regulation of ghrelin secretion, we determined GPCR expression profiles by RNA sequencing in the ghrelin-producing cell line MGN3-1 and analyzed the effects of ligands for highly expressed receptors on intracellular signaling and ghrelin secretion. Expression of selected GPCRs was confirmed in fluorescence-activated cell-sorted fluorescently tagged ghrelin-producing cells from ghrelin-promoter CreERT2/Rosa-CAG-LSL-ZsGreen1 mice. Expression levels of GPCRs previously suggested to regulate ghrelin secretion including adrenergic-β1 receptor, GPR81, oxytocin receptor, GPR120, and somatostatin receptor 2 were high in MGN3-1 cells. Consistent with previous reports, isoproterenol and oxytocin stimulated the Gs and Gq pathways, respectively, whereas lactate, palmitate, and somatostatin stimulated the Gi pathway, confirming the reliability of current assays. Among other highly expressed GPCRs, prostaglandin E receptor 4 agonist prostaglandin E2 significantly stimulated the Gs pathway and ghrelin secretion. Muscarine, the canonical agonist of cholinergic receptor muscarinic 4, stimulated both the Gq and Gi pathways. Although muscarine treatment alone did not affect ghrelin secretion, it did suppress forskolin-induced ghrelin secretion, suggesting that the cholinergic pathway may play a role in counterbalancing the stimulation of ghrelin by Gs (eg, by adrenaline). In addition, GPR142 ligand tryptophan stimulated ghrelin secretion. In conclusion, we determined the comprehensive expression profile of GPCRs in ghrelin-producing cells and identified two novel ghrelin regulators, prostaglandin E2 and tryptophan. These results will lead to a greater understanding of the physiology of ghrelin and facilitate the development of ghrelin-modulating drugs.

  6. 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. PMID:26202202

  7. 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

  8. 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

  9. Acyl-lipid metabolism.

    PubMed

    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

  10. 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.

  11. 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.

  12. Neuropeptide Y in black seabream Acanthopagrus schlegelii: identification, distribution and mRNA expression responses to ghrelin.

    PubMed

    Ma, X L; Zheng, L W; Mao, L T; Zhou, L B; Wang, A L

    2013-04-01

    The coding region of neuropeptide Y (NPY) complementary (c)DNA was cloned from the hypothalamus RNA of black seabream Acanthopagrus schlegelii, including 297 bp coding for prepro-NPY of 98 amino acids. Real-time reverse transcriptase-polymerase chain reaction was performed to determine A. schlegelii npy gene expression; NPY messenger RNA (mRNA) was expressed highly in the brain and stomach. Treatment with acylated ghrelin significantly up-regulated NPY mRNA level in the hypothalamus, suggesting that NPY may be involved in regulating food intake of A. schlegelii.

  13. Adipokines and ghrelin in gastric cancer cachexia

    PubMed Central

    Kerem, Mustafa; Ferahkose, Zafer; Yilmaz, Utku Tonguc; Pasaoglu, Hatice; Ofluoglu, Ebru; Bedirli, Abdulkadir; Salman, Bulent; Sahin, Tevfik Tolga; Akin, Murat

    2008-01-01

    AIM: To investigate the roles of the adipocytokines, ghrelin and leptin in gastric cancer cachexia. METHODS: Resistin, ghrelin, leptin, adiponectin, insulin and insulin-like growth factor (IGF-I), were measured in 30 healthy subjects, and 60 gastric cancer patients of which 30 suffered from cancer-induced cachexia and 30 served as a control group. The relationships between hormones, body mass index (BMI) loss ratio, age, gender, and Glasgow Prognostic Score (GPS) were investigated. RESULTS: Cachexia patients had higher tumor stage and GPS when compared with non-cachexia patients (P < 0.05). Ghrelin, resistin, leptin, adiponectin and IGF-I, showed a significant correlation with BMI loss ratio and GPS (P < 0.05). A strong correlation was seen between GPS and BMI loss (R = -0.570, P < 0.0001). Multivariate analysis indicated that BMI loss was significantly independent as a predictor of ghrelin, resistin, leptin and IGF-I (P < 0.05). Existence of an important significant relationship between resistin and insulin resistance was also noted. CONCLUSION: These results showed that serum ghrelin, leptin, adiponectin, and IGF-I play important roles in cachexia-related gastric cancers. No relationship was found between resistin and cancer cachexia. Also, because of the correlation between these parameters and GPS, these parameters might be used as a predictor factor. PMID:18595130

  14. Ghrelin's second life: from appetite stimulator to glucose regulator.

    PubMed

    Verhulst, Pieter-Jan; Depoortere, Inge

    2012-07-01

    Ghrelin, a 28 amino acid peptide hormone produced by the stomach, was the first orexigenic hormone to be discovered from the periphery. The octanoyl modification at Ser³, mediated by ghrelin O-acyltransferase (GOAT), is essential for ghrelin's biological activity. Ghrelin stimulates food intake through binding to its receptor (GRLN-R) on neurons in the arcuate nucleus of the hypothalamus. Ghrelin is widely expressed throughout the body; accordingly, it is implicated in several other physiological functions, which include growth hormone release, gastric emptying, and body weight regulation. Ghrelin and GRLN-R expression are also found in the pancreas, suggesting a local physiological role. Accordingly, several recent studies now point towards an important role for ghrelin and its receptor in the regulation of blood glucose homeostasis, which is the main focus of this review. Several mechanisms of this regulation by ghrelin have been proposed, and one possibility is through the regulation of insulin secretion. Despite some controversy, most studies suggest that ghrelin exerts an inhibitory effect on insulin secretion, resulting in increased circulating glucose levels. Ghrelin may thus be a diabetogenic factor. Obesity-related type 2 diabetes has become an increasingly important health problem, almost reaching epidemic proportions in the world; therefore, antagonists of the ghrelin-GOAT signaling pathway, which will tackle both energy- and glucose homeostasis, may be considered as promising new therapies for this disease. PMID:22783041

  15. 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

  16. 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

  17. Obesity Impairs the Action of the Neuroendocrine Ghrelin System

    PubMed Central

    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. PMID:26542050

  18. Ghrelin Receptor Mutations and Human Obesity.

    PubMed

    Wang, W; Tao, Y-X

    2016-01-01

    Growth hormone secretagogue receptor (GHSR) was originally identified as an orphan receptor in porcine and rat anterior pituitary membranes. In 1999, GHSR was deorphanized and shown to be a receptor for ghrelin, a peptide hormone secreted from the stomach. Therefore, GHSR is also called ghrelin receptor. In addition to regulating growth hormone secretion, ghrelin receptor regulates various physiological processes, including food intake and energy expenditure, glucose metabolism, cardiovascular functions, gastric acid secretion and motility, and immune function. Several human genetic studies conducted in populations originated from Europe, Africa, South America, and East Asia identified rare mutations and single nucleotide polymorphisms that might be associated with human obesity and short stature. Functional analyses of mutant GHSRs reveal multiple defects, including cell surface expression, ligand binding, and basal and stimulated signaling. With growing understanding in the functionality of naturally occurring GHSR mutations, potential therapeutic strategies including pharmacological chaperones and novel ligands could be used to correct the GHSR mutants. PMID:27288828

  19. Acyl-acyl carrier protein: Lysomonogalactosyldiacylglycerol acyl transferase in Anabaena variabilis

    SciTech Connect

    Chen, H.H.

    1989-01-01

    Monogalactosyldiacylglycerol was produced when membranes isolated from the cyanobacterium, Anabaena variabilis, and washed free of soluble endogenous constituents, were incubated with ({sup 14}C)acyl-acyl carrier protein. This enzymatic synthesis of monogalactosyldiacylglycerol localized in the membranes was not dependent on any added cofactors, such as ATP, coenzyme A, and dithiothreitol. Palmitoyl-, stearoyl-, and oleoyl-acyl carrier proteins were approximately equally active as substrates with Km of 0.37, 0.36, and 0.23 {mu}M, respectively. The ({sup 14}C)acyl group was exclusively transferred to the sn-1 hydroxyl of the glycerol backbone of monogalactosyldiacylglycerol as demonstrated by hydrolysis of all incorporated acyl groups by the lipase from Rhizopus arrhizus delamar. Using a double labelled ({sup 14}C)acyl-({sup 14}C)acyl carrier protein, this enzyme catalyzed the direct transfer of the acyl group from acyl-acyl carrier protein to an endogenous lysomonogalactosyldiacylglycerol to form monogalactosyldiacylglycerol. The transfer reaction mechanism was also confirmed by the increased activity with the addition of the lysomonogalactosyldiacylglycerol suspension. A specific galactolipid acyl hydrolase activity was released into the soluble protein fraction when the membranes of Anabaena variabilis were treated with 2% Triton X-100. The positional specificity of this acyl hydrolase was demonstrated to be similar to that of Rhizopus lipase, i.e. only the acyl group at the sn-1 position was hydrolyzed. The acyl hydrolase which was also localized in the membrane fraction of Anabaena variabilis was presumably responsible for producing endogenous lysomonogalactosyldiacylglycerol used by the acyltransferase.

  20. The Stomach-Derived Hormone Ghrelin Increases Impulsive Behavior

    PubMed Central

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

    2016-01-01

    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. 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

  2. Food restriction, ghrelin, its antagonist and obestatin control expression of ghrelin and its receptor in chicken hypothalamus and ovary.

    PubMed

    Sirotkin, Alexander V; Pavlova, Silvia; Tena-Sempere, Manuel; Grossmann, Roland; Jiménez, Magdalena Romero; Rodriguez, Juan Manuel Castellano; Valenzuela, Francisco

    2013-01-01

    The purpose of the present study was to identify the role of age, nutritional state and some metabolic hormones in control of avian hypothalamic and ovarian ghrelin/ghrelin receptor system. We examined the effect of food restriction, administration of ghrelin 1-18, ghrelin antagonistic analogue (D-Lys-3)-GHRP-6, obestatin and combinations of them on the expression of ghrelin and ghrelin receptor (GHS-R1a) in hypothalamus and ovary of old (23months of age) and young (7months of age) chickens. Expression of mRNAs for ghrelin and GHS-R1a in both hypothalamus and largest ovarian follicle was measured by RT-PCR. It was observed that food restriction could promote the expression of ghrelin and GHS-R1a in hypothalamus and ovary of the old chickens, but in the young chickens it reduced expression of ghrelin and did not affect expression of GHS-R1a in the ovary. Administration of ghrelin 1-18 did not affect hypothalamic or ovarian ghrelin mRNA, but significantly increased the expression of GHS-R1a in hypothalamus, but not in ovary. (D-Lys-3)-GHRP-6, significantly stimulated accumulation of ghrelin, but not GHS-R1a mRNA in hypothalamus or ghrelin or GHS-R1a in the ovary. Ghrelin 1-18 and (D-Lys-3)-GHRP-6, when given together, were able either to prevent or to induce effect of these hormones. Obestatin administration increased expression of ghrelin gene in the hypothalamus, but not expression of hypothalamic GHS-R1a, ovarian ghrelin and GHS-R1a. Furthermore, obestatin was able to modify effect of both ghrelin and fasting on hypothalamic and ovarian mRNA for ghrelin GHS-R1a. Our results (1) confirm the existence of ghrelin and its functional receptors GHS-R1a in the chicken hypothalamus and ovary (2) confirm the age-dependent control of ovarian ghrelin by feeding, (3) demonstrate, that nutritional status can influence the expression of both ghrelin and GHS-R1a in hypothalamus and in the ovary (3) demonstrates for the first time, that ghrelin can promote generation of its

  3. Carbohydrate and fat digestion is necessary for maximal suppression of total plasma ghrelin in healthy adults.

    PubMed

    Tai, Kamilia; Hammond, Angela J; Wishart, Judith M; Horowitz, Michael; Chapman, Ian M

    2010-12-01

    It is uncertain whether the postprandial suppression of ghrelin is dependent on digestion and absorption of nutrients or whether the presence of nutrients in the small intestine is sufficient. Twenty-four healthy young adults with a mean age of 23 ± 0.6 years were examined on 3 separate days after an overnight fast. Twelve subjects participated in Part A, and the other 12 subjects in Part B. In Part A, subjects consumed, in random order, one of three study drinks: 300 mL water; 300 mL high-fat drink, with and without, 120 mg orlistat. In Part B, subjects received, in random order, one of three drinks: 300 mL water; 300 mL sucrose, with and without, 100mg acarbose. In both parts gastric emptying as measured by 2-D ultrasound. In Part A, plasma ghrelin concentrations decreased following ingestion of the high-fat drink, but did not change with the high-fat-orlistat drink or water. In Part B, the suppression of plasma ghrelin following the sucrose drink, was attenuated by acarbose. Orlistat accelerated gastric emptying of the high-fat drink, while acarbose delayed gastric emptying of the sucrose drink. In conclusion, fat and carbohydrate digestion is required for maximal suppression of ghrelin secretion.

  4. Postprandial ghrelin is elevated in black compared with white women.

    PubMed

    Brownley, Kimberly A; Light, Kathleen C; Grewen, Karen M; Bragdon, Edith E; Hinderliter, Alan L; West, Sheila G

    2004-09-01

    Ghrelin, a gut-brain peptide that signals hunger, is normally suppressed after meals. Subnormal suppression of postprandial ghrelin, previously noted in obese, insulin-resistant individuals, may contribute to increased food intake. Given the ethnic disparities in obesity and obesity-related cardiovascular morbidity in the United States, the present study compared a single postprandial ghrelin measure in 43 women (22 white, 21 black). Each completed a rigorously controlled 4-d dietary intervention designed to maintain weight and constant daily sodium and potassium intake (220 mEq Na, 40 mEq K). Two hours after consuming a test meal of identical content, blood samples were drawn to assess postprandial ghrelin, leptin, and norepinephrine; resting cardiovascular function was measured; and a 24-h urinary cortisol sample was obtained. Independent of body mass index, postprandial ghrelin was significantly higher in black vs. white women, and higher ghrelin was associated with higher cortisol in blacks, who failed to show the expected inverse relation between ghrelin and central obesity seen in whites. Higher ghrelin was correlated with higher blood pressure but lower norepinephrine in obese women. These findings suggest subnormal postprandial ghrelin suppression (or faster ghrelin rebound) in black women, especially the obese, that might play a role in their increased prevalence of obesity and cardiovascular disorders.

  5. The role of ghrelin in energy balance regulation in fish.

    PubMed

    Jönsson, Elisabeth

    2013-06-15

    Knowledge about the endocrine regulation of energy balance in fish is of interest for basic as well as aquaculture research. Ghrelin is a peptide hormone that was first identified in fish 10 years ago and has important roles in the control of food intake and metabolism. Both ghrelin and its receptor, the growth hormone secretagogue receptor (GHS-R), have been found in numerous fish species. Their tissue distributions support the idea that ghrelin has an integrative role in the regulation of energy balance at both the central nervous system level and systemic level. In tilapia and goldfish, ghrelin treatment appears to increase food intake and to stimulate lipogenesis and tissue fat deposition to promote a more positive energy status. In rainbow trout, on the other hand, ghrelin decreases food intake. Goldfish and rainbow trout are the fish species in which the mode of action of ghrelin on food intake has been most thoroughly investigated. The results from these studies indicate that ghrelin alters food intake by acting on well-known appetite signals, such as CRH, NPY and orexin, in the hypothalamus in a species-specific manner. In goldfish, sensory fibres of the vagus nerve convey the signal from gut-derived ghrelin to modulate appetite. The data also indicate that ghrelin may modulate foraging/swimming activity and the perception of food in fish. Results related to the effects of energy status, temperature, and stressors on plasma ghrelin/tissue ghrelin mRNA levels are occasionally inconsistent between short- and long-term studies, between the protein and mRNA, and between species. Recent data also imply a role of ghrelin in carbohydrate metabolism. More functional studies are required to understand the role of ghrelin and its mechanisms of action in the regulation of energy balance among fish.

  6. Ghrelin treatment prevents development of activity based anorexia in mice.

    PubMed

    Legrand, Romain; Lucas, Nicolas; Breton, Jonathan; Azhar, Saïda; do Rego, Jean-Claude; Déchelotte, Pierre; Coëffier, Moïse; Fetissov, Sergueï O

    2016-06-01

    Stimulation of feeding is necessary for treatment of pathological conditions of chronic malnutrition due to anorexia. Ghrelin, a hunger hormone, is one of the candidate for pharmacological treatments of anorexia, but because of its instability in plasma has limited efficacy. We previously showed that plasmatic IgG protect ghrelin from degradation and that IgG from obese subjects and mice may increase ghrelin׳s orexigenic effect. In this study we tested if ghrelin alone or combined with IgG may improve feeding in chronically food-restricted mice with or without physical activity-based anorexia (ABA) induced by free access to a running wheel. Mice received a single daily intraperitoneal injection of ghrelin (1nM) together or not with total IgG (1nM) from obese ob/ob or lean mice before access to food during 8 days of 3h/day feeding time. We found that both ghrelin and ghrelin combined with IgG from obese, but not lean mice, prevented ABA, however, they were not able to diminish body weight loss. Physical activity was lower during the feeding period and was increased shortly after feeding in mice receiving ghrelin together with IgG from obese mice. In food-restricted mice without ABA, ghrelin treatments did not have significant effects on food intake. Thus, this study supports pharmacological use of ghrelin or ghrelin combined with IgG from obese animals for treatment of anorexia accompanied by elevated physical activity. The utility of combining ghrelin with protective IgG should be further determined in animal models of anorexia with unrestricted access to food.

  7. Cisplatin-induced anorexia and ghrelin.

    PubMed

    Hattori, Tomohisa; Yakabi, Koji; Takeda, Hiroshi

    2013-01-01

    Cisplatin, a formidable anticancer treatment, is used for several varieties of cancer. There are, however, many cases in which treatment must be abandoned due to a decrease in the patient's quality of life from loss of appetite associated with vomiting and nausea. There is a moderate degree of improvement in prevention of cisplatin-induced nausea and vomiting when serotonin (5-HT) 3 receptor antagonists, neurokinin 1 receptor antagonists, and steroids-either alone or in combination-are administered. The mechanism of action for anorexia, which continues during or after treatment, is, however, still unclear. This anorexia is, similar to the onset of vomiting and nausea, caused by the action of large amounts of 5-HT released as a result of cisplatin administration on tissue 5-HT receptors. Among the 5-HT receptors, the activation of 5-HT2b and 5-HT2c receptors, in particular, seems to play a major role in cisplatin-induced anorexia. Following activation of these two receptors, there is reduced gastric and hypothalamic secretion of the appetite-stimulating hormone ghrelin. There is ample evidence of the usefulness of exogenous ghrelin, synthetic ghrelin agonists, and the endogenous ghrelin signal-enhancer rikkunshito, which are expected to play significant roles in the clinical treatment and prevention of anorexia in future.

  8. 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

  9. Novel approach in LC-MS/MS using MRM to generate a full profile of acyl-CoAs: discovery of acyl-dephospho-CoAs[S

    PubMed Central

    Li, Qingling; Zhang, Shenghui; Berthiaume, Jessica M.; Simons, Brigitte; Zhang, Guo-Fang

    2014-01-01

    A metabolomic approach to selectively profile all acyl-CoAs was developed using a programmed multiple reaction monitoring (MRM) method in LC-MS/MS and was employed in the analysis of various rat organs. The programmed MRM method possessed 300 mass ion transitions with the mass difference of 507 between precursor ion (Q1) and product ion (Q3), and the precursor ion started from m/z 768 and progressively increased one mass unit at each step. Acyl-dephospho-CoAs resulting from the dephosphorylation of acyl-CoAs were identified by accurate MS and fragmentation. Acyl-dephospho-CoAs were also quantitatively scanned by the MRM method with the mass difference of 427 between Q1 and Q3 mass ions. Acyl-CoAs and dephospho-CoAs were assayed with limits of detection ranging from 2 to 133 nM. The accuracy of the method was demonstrated by assaying a range of concentrations of spiked acyl-CoAs with the results of 80–114%. The distribution of acyl-CoAs reflects the metabolic status of each organ. The physiological role of dephosphorylation of acyl-CoAs remains to be further characterized. The methodology described herein provides a novel strategy in metabolomic studies to quantitatively and qualitatively profile all potential acyl-CoAs and acyl-dephospho-CoAs. PMID:24367045

  10. Multi-species sequence comparison reveals conservation of ghrelin gene-derived splice variants encoding a truncated ghrelin peptide.

    PubMed

    Seim, Inge; Jeffery, Penny L; Thomas, Patrick B; Walpole, Carina M; Maugham, Michelle; Fung, Jenny N T; Yap, Pei-Yi; O'Keeffe, Angela J; Lai, John; Whiteside, Eliza J; Herington, Adrian C; Chopin, Lisa K

    2016-06-01

    The peptide hormone ghrelin is a potent orexigen produced predominantly in the stomach. It has a number of other biological actions, including roles in appetite stimulation, energy balance, the stimulation of growth hormone release and the regulation of cell proliferation. Recently, several ghrelin gene splice variants have been described. Here, we attempted to identify conserved alternative splicing of the ghrelin gene by cross-species sequence comparisons. We identified a novel human exon 2-deleted variant and provide preliminary evidence that this splice variant and in1-ghrelin encode a C-terminally truncated form of the ghrelin peptide, termed minighrelin. These variants are expressed in humans and mice, demonstrating conservation of alternative splicing spanning 90 million years. Minighrelin appears to have similar actions to full-length ghrelin, as treatment with exogenous minighrelin peptide stimulates appetite and feeding in mice. Forced expression of the exon 2-deleted preproghrelin variant mirrors the effect of the canonical preproghrelin, stimulating cell proliferation and migration in the PC3 prostate cancer cell line. This is the first study to characterise an exon 2-deleted preproghrelin variant and to demonstrate sequence conservation of ghrelin gene-derived splice variants that encode a truncated ghrelin peptide. This adds further impetus for studies into the alternative splicing of the ghrelin gene and the function of novel ghrelin peptides in vertebrates.

  11. Ghrelin response to hedonic eating in underweight and short-term weight restored patients with anorexia nervosa.

    PubMed

    Maria Monteleone, Alessio; Monteleone, Palmiero; Dalle Grave, Riccardo; Nigro, Massimiliano; El Ghoch, Marwan; Calugi, Simona; Cimino, Monica; Maj, Mario

    2016-01-30

    Recently, anorexia nervosa (AN) has been conceptualized as a reward-related disorder, and alterations in brain reward processes have been documented in both acute and recovered AN patients. However, the role of endogenous biochemical mediators, such as ghrelin, in the modulation of reward processes has been poorly investigated in this eating disorder. Hedonic eating, that is the consumption of food exclusively for pleasure and not to maintain energy homeostasis, is a useful paradigm to investigate the physiology of food-related reward. Therefore, we assessed the response of peripheral ghrelin to hedonic eating in 7 underweight and 7 recently weight-restored AN patients and compared it to that of previously studied healthy controls. We found that in satiated underweight patients with AN plasma ghrelin levels progressively decreased after the exposure and the consumption of both the favorite and unfavorite food whereas in satiated weight-restored AN patients and satiated healthy controls plasma ghrelin concentrations significantly increased after the exposure to the favorite food and after eating it, but decreased after the unfavorite food. These results suggest a derangement in the ghrelin modulation of food-related pleasurable and rewarding feelings, which might sustain the reduced motivation toward food intake of acute AN patients. PMID:26674388

  12. Ghrelin response to hedonic eating in underweight and short-term weight restored patients with anorexia nervosa.

    PubMed

    Maria Monteleone, Alessio; Monteleone, Palmiero; Dalle Grave, Riccardo; Nigro, Massimiliano; El Ghoch, Marwan; Calugi, Simona; Cimino, Monica; Maj, Mario

    2016-01-30

    Recently, anorexia nervosa (AN) has been conceptualized as a reward-related disorder, and alterations in brain reward processes have been documented in both acute and recovered AN patients. However, the role of endogenous biochemical mediators, such as ghrelin, in the modulation of reward processes has been poorly investigated in this eating disorder. Hedonic eating, that is the consumption of food exclusively for pleasure and not to maintain energy homeostasis, is a useful paradigm to investigate the physiology of food-related reward. Therefore, we assessed the response of peripheral ghrelin to hedonic eating in 7 underweight and 7 recently weight-restored AN patients and compared it to that of previously studied healthy controls. We found that in satiated underweight patients with AN plasma ghrelin levels progressively decreased after the exposure and the consumption of both the favorite and unfavorite food whereas in satiated weight-restored AN patients and satiated healthy controls plasma ghrelin concentrations significantly increased after the exposure to the favorite food and after eating it, but decreased after the unfavorite food. These results suggest a derangement in the ghrelin modulation of food-related pleasurable and rewarding feelings, which might sustain the reduced motivation toward food intake of acute AN patients.

  13. 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

  14. Centrally Administered Ghrelin Acutely Influences Food Choice in Rodents

    PubMed Central

    Schéle, Erik; Bake, Tina; Rabasa, Cristina; Dickson, Suzanne L.

    2016-01-01

    We sought to determine whether the orexigenic hormone, ghrelin, is involved in the intrinsic regulation of food choice in rats. Ghrelin would seem suited to serve such a role given that it signals hunger information from the stomach to brain areas important for feeding control, including the hypothalamus and reward system (e.g. ventral tegmental area, VTA). Thus, in rats offered a choice of palatable foods (sucrose pellets and lard) superimposed on regular chow for 2 weeks, we explored whether acute central delivery of ghrelin (intracerebroventricular (ICV) or intra-VTA) is able to redirect their dietary choice. The major unexpected finding is that, in rats with high baseline lard intake, acute ICV ghrelin injection increased their chow intake over 3-fold, relative to vehicle-injected controls, measured at both 3 hr and 6 hr after injection. Similar effects were observed when ghrelin was delivered to the VTA, thereby identifying the VTA as a likely contributing neurobiological substrate for these effects. We also explored food choice after an overnight fast, when endogenous ghrelin levels are elevated, and found similar effects of dietary choice to those described for ghrelin. These effects of fasting on food choice were suppressed in models of suppressed ghrelin signaling (i.e. peripheral injection of a ghrelin receptor antagonist to rats and ghrelin receptor (GHSR) knock-out mice), implicating a role for endogenous ghrelin in the changes in food choice that occur after an overnight fast. Thus, in line with its role as a gut-brain hunger hormone, ghrelin appears to be able to acutely alter food choice, with notable effects to promote “healthy” chow intake, and identify the VTA as a likely contributing neurobiological substrate for these effects. PMID:26925974

  15. Estradiol and testosterone modulate the tissue-specific expression of ghrelin, ghs-r, goat and nucb2 in goldfish.

    PubMed

    Bertucci, Juan Ignacio; Blanco, Ayelén Melisa; Canosa, Luis Fabián; Unniappan, Suraj

    2016-03-01

    Ghrelin, and nesfatin-1 (encoded by nucleobindin2/nucb2) are two metabolic peptides with multiple biological effects in vertebrates. While sex steroids are known to regulate endogenous ghrelin and NUCB2 in mammals, such actions by steroids in fish remain unknown. This study aimed to determine whether estradiol (E2) and testosterone (T) affects the expression of preproghrelin, ghrelin/growth hormone secretagogue receptor (GHS-R), ghrelin O-acyl transferase (GOAT) and NUCB2 in goldfish (Carassius auratus). First, a dose-response assay was performed in which fish were intraperitoneally (ip) implanted with pellets containing 25, 50 or 100 μg/g body weight (BW) of E2 or T. It was found that sex steroids (100 μg/g BW) administered for 2.5 days achieved the highest E2 or T in circulation. In a second experiment, fish were ip implanted with pellets containing 100 μg/g BW of E2, T or without hormone (control). RT-qPCR analyses at 2.5 days post-administration show that gut preproghrelin and GOAT expression was upregulated by both E2 and T treatments, while the same effect was observed for GHS-R only in the pituitary. Both treatments also reduced hypothalamic preproghrelin mRNA expression. NUCB2 expression was increased in the forebrain of T treated group and reduced in the gut and pituitary under both treatments. These results show for the first time a modulation of preproghrelin and nucb2/nesfatin-1 by sex steroids in fish. The interaction between sex steroids and genes implicated in both metabolism and reproduction might help meeting the reproduction dependent energy demands in fish. PMID:26773340

  16. Brain Mapping of Ghrelin O-Acyltransferase in Goldfish (Carassius Auratus): Novel Roles for the Ghrelinergic System in Fish?

    PubMed

    Blanco, Ayelén M; Sánchez-Bretaño, Aída; Delgado, María J; Valenciano, Ana I

    2016-06-01

    Ghrelin O-acyltransferase (GOAT) is the enzyme responsible for acylation of ghrelin, a gut-brain hormone with important roles in many physiological functions in vertebrates. Many aspects of GOAT remain to be elucidated, especially in fish, and particularly its anatomical distribution within the different brain areas has never been reported to date. The present study aimed to characterize the brain mapping of GOAT using RT-qPCR and immunohistochemistry in a teleost, the goldfish (Carassius auratus). Results show that goat transcripts are expressed in different brain areas of the goldfish, with the highest levels in the vagal lobe. Using immunohistochemistry, we also report the presence of GOAT immunoreactive cells in different encephalic areas, including the telencephalon, some hypothalamic nuclei, pineal gland, optic tectum and cerebellum, although they are especially abundant in the hindbrain. Particularly, an important signal is observed in the vagal lobe and some fiber tracts of the brainstem, such as the medial longitudinal fasciculus, Mauthneri fasciculus, secondary gustatory tract and spinothalamic tract. Most of the forebrain areas where GOAT is detected, particularly the hypothalamic nuclei, also express the ghs-r1a ghrelin receptor and other appetite-regulating hormones (e.g., orexin and NPY), supporting the role of ghrelin as a modulator of food intake and energy balance in fish. Present results are the first report on the presence of GOAT in the brain using imaging techniques. The high presence of GOAT in the hindbrain is a novelty, and point to possible new functions for the ghrelinergic system in fish. Anat Rec, 299:748-758, 2016. © 2016 Wiley Periodicals, Inc. PMID:27064922

  17. 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.

  18. The atypical antipsychotic, olanzapine, potentiates ghrelin-induced receptor signaling: An in vitro study with cells expressing cloned human growth hormone secretagogue receptor.

    PubMed

    Tagami, Keita; Kashiwase, Yohei; Yokoyama, Akinobu; Nishimura, Hitomi; Miyano, Kanako; Suzuki, Masami; Shiraishi, Seiji; Matoba, Motohiro; Ohe, Yuichiro; Uezono, Yasuhito

    2016-08-01

    The growth hormone secretagogue receptor (GHS-R) belongs to Gαq-coupled G protein-coupled receptor (GPCR) that mediates growth hormone release, food intake, appetite, glucose metabolism and body composition. Ghrelin has been identified as an endogenous ligand for GHS-R, and it is the only orexigenic peptide found in the peripheral organs. Olanzapine, an atypical antipsychotic agent that binds to and inhibits the activation of GPCR for several neurotransmitters, has metabolic side effects such as excessive appetite and weight gain. Recently, studies have revealed that the orexigenic mechanism of olanzapine is mediated via GHS-R signaling, although the precise mechanisms have not been clarified. In this study, we investigated the effect of olanzapine on ghrelin-mediated GHS-R signaling by using an electrical impedance-based receptor biosensor assay system (CellKey™). Olanzapine at concentrations of 10(-7) and 10(-6)mol/L enhanced ghrelin-induced (10(-10)-10(-8)mol/L) GHS-R activation. A Ca(2+) imaging assay revealed that olanzapine (10(-7) and 10(-6)mol/L) enhanced ghrelin (10(-7) M)-induced GHS-R activity. In contrast, haloperidol (an antipsychotic agent) failed to enhance this ghrelin-mediated GHS-R activation, as demonstrated by both the CellKey™ and Ca(2+) imaging assays. Together, these results suggest that olanzapine, but not haloperidol, promotes appetite by enhancing ghrelin-mediated GHS-R signaling. PMID:26775231

  19. Identification, tissue distribution and functional characterization of the ghrelin receptor in West African lungfish, Protopterus annectens.

    PubMed

    Kaiya, Hiroyuki; Konno, Norifumi; Kangawa, Kenji; Uchiyama, Minoru; Miyazato, Mikiya

    2014-12-01

    We identified two ghrelin receptor isoforms, the ghrelin receptor type-1a (GHS-R1a) and its alternative splice form (GHS-R1b) for West African lungfish, Protopterus annectens. Lungfish GHS-R1a and 1b comprised 361 and 281 amino acids, respectively. Lungfish GHS-R1a showed the highest identity to coelacanth GHS-R1a (80.4%). The highest expression of GHS-R1a mRNAs was seen in the brain, liver, ovary, heart, intestine, and gills. GHS-R1b mRNAs were also detected in the same tissues with GHS-R1a, but their expression level was 1/20 that of GHS-R1a. In human embryonic kidney 293 cells transiently expressing lungfish GHS-R1a, rat and bullfrog ghrelin, and two GHS-R1a agonists, GHRP-6 and hexarelin, increased intracellular Ca(2+) concentrations. The intensity of the Ca(2+) increases induced by GHS-R1a agonists was twice when compared to that induced by ghrelin, although the median effective doses (ED50) were similar, suggesting a long-lasting effect of GHS-R1a agonists with similar affinity. We also examined changes in the GHS-R gene expression during an eight-week estivation. Body weight was slightly lowered, but plasma sodium and glucose concentrations decreased; plasma urea concentration increased significantly 4weeks after the start of estivation. Overall, expression of GHS-R1a mRNA decreased, but changes in GHS-R1b mRNA expression were inconsistent with those of GHS-R1a during estivation, suggesting an involvement of GHS-R in energy homeostasis, as seen in mammals. Our results suggest that the ghrelin-GHS-R1a system is present in this lungfish although ghrelin has not yet been found. The structure of GHS-R1a is closer to that of tetrapods than Actinopterygian fish, indicating a process of evolution that follows the Crossopterygii such as coelacanth.

  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. 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.

  2. Acylation of Streptomyces type II polyketide synthase acyl carrier proteins.

    PubMed

    Crosby, J; Byrom, K J; Hitchman, T S; Cox, R J; Crump, M P; Findlow, I S; Bibb, M J; Simpson, T J

    1998-08-14

    Acyl derivatives of type II PKS ACPs are required for in vitro studies of polyketide biosynthesis. The presence of an exposed cysteine residue prevented specific chemical acylation of the phosphopantetheine thiol of the actinorhodin PKS holo ACP. Acylation studies were further complicated by intramolecular disulphide formation between cysteine 17 and the phosphopantetheine. The presence of this intramolecular disulphide was confirmed by tryptic digestion of the ACP followed by ESMS analysis of the fragments. An act Cys17Ser ACP was engineered by site-directed mutagenesis. S-Acyl adducts of act C17S, oxytetracycline and griseusin holo ACPs were rapidly formed by reaction with hexanoyl, 5-ketohexanoyl and protected acetoacetyl imidazolides. Comparisons with type 11 FAS ACPs were made.

  3. Reaction of Acylated Homoserine Lactone Bacterial Signaling Molecules with Oxidized Halogen Antimicrobials

    PubMed Central

    Borchardt, S. A.; Allain, E. J.; Michels, J. J.; Stearns, G. W.; Kelly, R. F.; McCoy, W. F.

    2001-01-01

    Oxidized halogen antimicrobials, such as hypochlorous and hypobromous acids, have been used extensively for microbial control in industrial systems. Recent discoveries have shown that acylated homoserine lactone cell-to-cell signaling molecules are important for biofilm formation in Pseudomonas aeruginosa, suggesting that biofouling can be controlled by interfering with bacterial cell-to-cell communication. This study was conducted to investigate the potential for oxidized halogens to react with acylated homoserine lactone-based signaling molecules. Acylated homoserine lactones containing a 3-oxo group were found to rapidly react with oxidized halogens, while acylated homoserine lactones lacking the 3-oxo functionality did not react. The Chromobacterium violaceum CV026 bioassay was used to determine the effects of such reactions on acylated homoserine lactone activity. The results demonstrated that 3-oxo acyl homoserine lactone activity was rapidly lost upon exposure to oxidized halogens; however, acylated homoserine lactones lacking the 3-oxo group retained activity. Experiments with the marine alga Laminaria digitata demonstrated that natural haloperoxidase systems are capable of mediating the deactivation of acylated homoserine lactones. This may illustrate a natural defense mechanism to prevent biofouling on the surface of this marine alga. The Chromobacterium violaceum activity assay illustrates that reactions between 3-oxo acylated homoserine lactone molecules and oxidized halogens do occur despite the presence of biofilm components at much greater concentrations. This work suggests that oxidized halogens may control biofilm not only via a cidal mechanism, but also by possibly interfering with 3-oxo acylated homoserine lactone-based cell signaling. PMID:11425738

  4. Ghrelin stimulates gastric emptying but is without effect on acid secretion and gastric endocrine cells.

    PubMed

    Dornonville de la Cour, Charlotta; Lindström, Erik; Norlén, Per; Håkanson, Rolf

    2004-08-15

    Ghrelin, a recently discovered peptide hormone, is produced by endocrine cells in the stomach, the so-called A-like cells. Ghrelin binds to the growth hormone (GH) secretagogue receptor and releases GH. It is claimed to be orexigenic and to control gastric acid secretion and gastric motility. In this study, we examined the effects of ghrelin, des-Gln14-ghrelin, des-octanoyl ghrelin, ghrelin-18, -10 and -5 (and motilin) on gastric emptying in mice and on gastric acid secretion in chronic fistula rats and pylorus-ligated rats. We also examined whether ghrelin affected the activity of the predominant gastric endocrine cell populations, G cells, ECL cells and D cells. Ghrelin and des-Gln14-ghrelin stimulated gastric emptying in a dose-dependent manner while des-octanoyl ghrelin and motilin were without effect. The C-terminally truncated ghrelin fragments were effective but much less potent than ghrelin itself. Ghrelin, des-Gln14-ghrelin and des-octanoyl ghrelin neither stimulated nor inhibited gastric acid secretion, and ghrelin, finally, did not affect secretion from either G cells, ECL cells or D cells.

  5. Integrating GHS into the Ghrelin System

    PubMed Central

    Veldhuis, Johannes D.; Bowers, Cyril Y.

    2010-01-01

    Oligopeptide derivatives of metenkephalin were found to stimulate growth-hormone (GH) release directly by pituitary somatotrope cells in vitro in 1977. Members of this class of peptides and nonpeptidyl mimetics are referred to as GH secretagogues (GHSs). A specific guanosine triphosphatate-binding protein-associated heptahelical transmembrane receptor for GHS was cloned in 1996. An endogenous ligand for the GHS receptor, acylghrelin, was identified in 1999. Expression of ghrelin and homonymous receptor occurs in the brain, pituitary gland, stomach, endothelium/vascular smooth muscle, pancreas, placenta, intestine, heart, bone, and other tissues. Principal actions of this peptidergic system include stimulation of GH release via combined hypothalamopituitary mechanisms, orexigenesis (appetitive enhancement), insulinostasis (inhibition of insulin secretion), cardiovascular effects (decreased mean arterial pressure and vasodilation), stimulation of gastric motility and acid secretion, adipogenesis with repression of fat oxidation, and antiapoptosis (antagonism of endothelial, neuronal, and cardiomyocyte death). The array of known and proposed interactions of ghrelin with key metabolic signals makes ghrelin and its receptor prime targets for drug development. PMID:20798846

  6. Anorexia in rats caused by a valine-deficient diet is not ameliorated by systemic ghrelin treatment.

    PubMed

    Goto, S; Nagao, K; Bannai, M; Takahashi, M; Nakahara, K; Kangawa, K; Murakami, N

    2010-03-10

    Rodents exhibit aversive behavior toward a diet that lacks at least one of the essential amino acids. We sought to determine whether the particular form of anorexia caused by such diets could be ameliorated by the administration of orexigenic peptides while simultaneously analyzing the neural mechanisms underlying anorexia. Rats were fed a valine-deficient diet, which induced severe anorexia (reducing food consumption by 80%). The severe anorexia was associated with a significant decrease in the cerebrospinal fluid valine concentration and hyper-ghrelinemia. Between 6 and 12 days after initiation of the valine-deficient diet, we injected rats twice daily with valine and/or an orexigenic peptide (ghrelin, neuropeptide Y, or agouti-related protein) either i.p. or i.c.v.. We then measured dietary intake. An i.c.v. valine injection allowed earlier food intake compared with an i.p valine injection and increased the density of c-Fos-positive ependymal cells lining the third ventricle. Whereas an i.c.v. injection of ghrelin or neuropeptide Y increased consumption of the valine-deficient diet, i.p injection of ghrelin or i.c.v. injection of agouti-related protein did not. Following i.c.v. administration of either valine or ghrelin, we did not observe complete recovery of consumption of the valine-deficient diet. This may be due to the ineffectiveness of peripheral ghrelin and central agouti-related protein and/or to conditioned aversion to the valine-deficient diet. Since ghrelin is known to be involved in food anticipatory activities, whether the hyper-ghrelinemia observed in valine-deficient rats play role in foraging behavior other than food intake is the future study to be investigated.

  7. 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

  8. 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. PMID:24637892

  9. Ghrelin role in hypothalamus-pituitary-ovarian axis.

    PubMed

    Rak-Mardyla, A

    2013-12-01

    Based on the available data, it was shown that ghrelin is involved in a series of physiological processes such as regulation of food intake, body weight, and cardiovascular or immune function. Recent studies have shown that ghrelin also plays an important role in the regulation of female reproduction. Information exists that its functional receptor, GHSR type 1a (GHS-R1a), is expressed in the hypothalamic-pituitary-ovarian axis. Ghrelin is synthesized locally in the hypothalamus, pituitary and ovaries of many species and has autocrine and/or paracrine effects. Most research indicates that ghrelin has inhibitory effect on gonadotropin secretion. Ghrelin also participates in the direct regulation of different ovarian functions such as steroid secretion, cell proliferation and apoptosis; these functions appear to be species-specific. Moreover, the importance of GHS-R1a or MAPK/IP3 pathway activation in ghrelin action in the ovary has been described. The article summarizes results of a series of recent studies on the effect of ghrelin on the hypothalamic-pituitary-ovarian axis, as well as on ovarian physiology with an indication that ghrelin via its biological functions such as energy metabolism and food intake could also be a key signal between animal energy status and control of ovarian function.

  10. Ghrelin reduces hepatic mitochondrial fatty acid beta oxidation.

    PubMed

    Rigault, C; Le Borgne, F; Georges, B; Demarquoy, J

    2007-04-01

    Ghrelin is a 28-amino-acid peptide secreted during starvation by gastric cells. Ghrelin physiologically induces food intake and seems to alter lipid and glucid metabolism in several tissues such as adipose tissue and liver. Liver has a key position in lipid metabolism as it allows the metabolic orientation of fatty acids between oxidation and esterification. We investigated the effects of peripheral ghrelin administration on 2 crucial parameters of fatty acid oxidation: the levocarnitine (L-carnitine)-dependent entry of the fatty acids in the mitochondria and the mitochondrial fatty acid oxidation. Ghrelin was either given to rats prior to the hepatocyte preparation and culture or used to treat hepatocytes prepared from control animals. Direct incubation of ghrelin to raw hepatocytes did not induce any change in the studied parameters. In hepatocytes prepared from 3 nmol ghrelin-treated rats, a 44% reduction of the mitochondrial fatty acid oxidation while no alteration of the L-carnitine-related parameters were observed. These results suggested (a) that ghrelin has no direct effect on liver, and (b) that when administrated to a whole organism, ghrelin may alter the lipid metabolism and the energy balance through a marked decrease in liver fatty acid oxidation. PMID:17556859

  11. Ghrelin receptor regulates adipose tissue inflammation in aging

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Aging is commonly associated with low-grade adipose inflammation, which is closely linked to insulin resistance. Ghrelin is the only circulating orexigenic hormone which is known to increase obesity and insulin resistance. We previously reported that the expression of the ghrelin receptor, growth ho...

  12. The effect of ghrelin on water intake during dipsogenic conditions.

    PubMed

    Mietlicki, Elizabeth G; Nowak, Erica L; Daniels, Derek

    2009-01-01

    Ghrelin has been studied extensively in the context of food intake and energy homeostasis, but less is known about its role in other ingestive behaviors. The present studies investigated the effects of this orexigenic peptide on both food and water intake during dipsogenic conditions. Specifically, animals were exposed to one of five dipsetic stimuli: (1) 24-h water deprivation, (2) replacement of drinking water with 2.5% NaCl, (3) peripheral administration of hypertonic saline, (4) ICV injection of angiotensin II (AngII), or (5) the combination of peripheral hypertonic saline and central AngII. Animals then were given an ICV injection of ghrelin (0.5 microg) or vehicle, and subsequent food and water intakes were measured. Ghrelin reliably increased food intake under each stimulus condition. Ghrelin also affected water intake, but with less consistency across the conditions. Specifically, ghrelin attenuated water intake stimulated by acute injection of AngII or hypertonic saline, but failed to affect drinking in the other three stimulus conditions. Investigation of the temporal pattern of food and water intakes in three of these dipsogenic conditions failed to support a role of different intake patterns in the observed differences in water intake by ghrelin-treated rats. Although the effect of ghrelin on water intake was not present in every dipsogenic condition, these data provide evidence that the actions of ghrelin are not limited to food intake, but can also include alterations in water intake.

  13. Evolution of Acyl-Substrate Recognition by a Family of Acyl-Homoserine Lactone Synthases

    PubMed Central

    Christensen, Quin H.; Brecht, Ryan M.; Dudekula, Dastagiri; Greenberg, E. Peter; Nagarajan, Rajesh

    2014-01-01

    Members of the LuxI protein family catalyze synthesis of acyl-homoserine lactone (acyl-HSL) quorum sensing signals from S-adenosyl-L-methionine and an acyl thioester. Some LuxI family members prefer acyl-CoA, and others prefer acyl-acyl carrier protein (ACP) as the acyl-thioester substrate. We sought to understand the evolutionary history and mechanisms mediating this substrate preference. Our phylogenetic and motif analysis of the LuxI acyl-HSL synthase family indicates that the acyl-CoA-utilizing enzymes evolved from an acyl-ACP-utilizing ancestor. To further understand how acyl-ACPs and acyl-CoAs are recognized by acyl-HSL synthases we studied BmaI1, an octanoyl-ACP-dependent LuxI family member from Burkholderia mallei, and BjaI, an isovaleryl-CoA-dependent LuxI family member from Bradyrhizobium japonicum. We synthesized thioether analogs of their thioester acyl-substrates to probe recognition of the acyl-phosphopantetheine moiety common to both acyl-ACP and acyl-CoA substrates. The kinetics of catalysis and inhibition of these enzymes indicate that they recognize the acyl-phosphopantetheine moiety and they recognize non-preferred substrates with this moiety. We find that CoA substrate utilization arose through exaptation of acyl-phosphopantetheine recognition in this enzyme family. PMID:25401334

  14. Hyperosmolarity in the small intestine contributes to postprandial ghrelin suppression

    PubMed Central

    Overduin, Joost; Tylee, Tracy S.; Frayo, R. Scott

    2014-01-01

    Plasma levels of the orexigenic hormone ghrelin are suppressed by meals with an efficacy dependent on their macronutrient composition. We hypothesized that heterogeneity in osmolarity among macronutrient classes contributes to these differences. In three studies, the impact of small intestinal hyperosmolarity was examined in Sprague-Dawley rats. In study 1, isotonic, 2.5×, and 5× hypertonic solutions of several agents with diverse absorption and metabolism properties were infused duodenally at a physiological rate (3 ml/10 min). Jugular vein blood was sampled before and at 30, 60, 90, 120, 180, 240, and 300 min after infusion. Plasma ghrelin was suppressed dose dependently and most strongly by glucose. Hyperosmolar infusions of lactulose, which transits the small intestine unabsorbed, and 3-O-methylglucose (3-O-MG), which is absorbed like glucose but remains unmetabolized, also suppressed ghrelin. Glucose, but not lactulose or 3-O-MG, infusions increased plasma insulin. In study 2, intestinal infusions of hyperosmolar NaCl suppressed ghrelin, a response that was not attenuated by coinfusion with the neural blocker lidocaine. In study 3, we reconfirmed that the low-osmolar lipid emulsion Intralipid suppresses ghrelin more weakly than isocaloric (but hypertonic) glucose. Importantly, raising Intralipid's osmolarity to that of the glucose solution by nonabsorbable lactulose supplementation enhanced ghrelin suppression to that seen after glucose. Hyperosmolar ghrelin occurred particularly during the initial 3 postinfusion hours. We conclude that small intestinal hyperosmolarity 1) is sufficient to suppress ghrelin, 2) may combine with other postprandial mechanisms to suppress ghrelin, 3) might contribute to altered ghrelin regulation after gastric bypass surgery, and 4) may inform dietary modifications for metabolic health. PMID:24789208

  15. Menstrual irregularities and energy deficiency in physically active women: the role of ghrelin, PYY and adipocytokines.

    PubMed

    Scheid, Jennifer L; De Souza, Mary Jane

    2010-01-01

    Menstrual cycle irregularities are often observed among physically active women and athletes who participate in physical activity ranging from recreational to competitive exercise training. Further, such irregularities have been casually linked to an energy deficiency where caloric intake is inadequate for exercise energy expenditure resulting in a suppressive effect on growth and reproduction. Adaptations consistent with chronic energy deficiency, including reductions in resting energy expenditure and total triiodothyronine, have been observed in exercising women with functional hypothalamic amenorrhea (FHA). Gut peptides and adipocytokines also appear to be altered in exercising women with FHA and have been hypothesized to be involved in the etiology of FHA. Ghrelin concentrations are elevated in exercising women with FHA. Interestingly, while fasting ghrelin, an orexigenic peptide, is elevated in women with FHA, PYY, an orexigenic peptide, is paradoxically also elevated in women with anorexia nervosa and exercising women with FHA. Leptin, an adipocytokine, is also suppressed in FHA associated with exercise and anorexia. A critical leptin concentration threshold is suggested to be necessary for regular menses to occur. Ghrelin, PYY, and leptin all have the ability to cross the blood brain barrier and, in the hypothalamus, can modulate appetite and food intake, and are hypothesized to affect the hypothalamic-pituitary-ovarian axis. Future studies are needed to determine if ghrelin, PYY, or leptin play a direct role in the regulation of the hypothalamic-pituitary-ovarian axis, and if these signals can be altered by improving energy status secondary to increasing caloric intake and initiate the reversal of amenorrhea. PMID:20956862

  16. Ablations of ghrelin and ghrelin receptor exhibit differential metabolic phenotypes and thermogenic capacity during aging

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Obesity is a hallmark of aging in many Western societies, and is a precursor to numerous serious age-related diseases. Ghrelin ("Ghrl"), via its receptor (growth hormone secretagogue receptor, GHS-R), is shown to stimulate GH secretion and appetite. Surprisingly, our previous studies showed that "Gh...

  17. Dietary intake and ghrelin and leptin changes after sleeve gastrectomy

    PubMed Central

    Zavadilová, Vladislava; Holéczy, Pavol; Švagera, Zdeněk; Švorc, Pavol; Foltys, Aleš; Zonča, Pavel

    2014-01-01

    Introduction Surgical intervention in obesity is today the most effective treatment method in high level obesity management. Bariatric interventions not only ensure body weight reduction, but may influence dietary habits. Aim To assess changes in adipose hormones and dietary habits in obese patients after sleeve gastrectomy. Material and methods The study set comprised 37 subjects (29 females and 8 males) 24 to 68 years old with body mass index 43.0 ±4.9 kg/m2. Pre-operative examination included baseline measurements of body composition. Dietary habits and intake frequency were monitored by a questionnaire method. Follow-up examinations were carried out in a scope identical to the pre-operative examination, 6 and 12 months after surgery, respectively. Results The average patient weight loss 12 months after surgery was 31.7 kg. Excess weight loss was 55.2 ±20.6%. Patients reported reduced appetite (p < 0.001), increasingly regular food intake (p < 0.001), intake of more meal portions per day (p = 0.003) and a decrease in consuming the largest portions during the afternoon and evening (p = 0.030). Plasma levels of fasting glucose, leptin and ghrelin significantly decreased (p = 0.006; p = 0.0.043); in contrast, the level of adiponectin significantly increased (p < 0.001). Conclusions Sleeve gastrectomy and follow-up nutritional therapy resulted in a significant body weight reduction within 1 year after surgery. An improvement of certain dietary habits in patients was registered. At 12 months after surgery, there were no statistically significant differences in decreases in ghrelin and leptin concentrations between patients without changed appetite and those reporting decreased appetite. PMID:25561993

  18. The ɛ-Amino Group of Protein Lysine Residues Is Highly Susceptible to Nonenzymatic Acylation by Several Physiological Acyl-CoA Thioesters.

    PubMed

    Simic, Zeljko; Weiwad, Matthias; Schierhorn, Angelika; Steegborn, Clemens; Schutkowski, Mike

    2015-11-01

    Mitochondrial enzymes implicated in the pathophysiology of diabetes, cancer, and metabolic syndrome are highly regulated by acetylation. However, mitochondrial acetyltransferases have not been identified. Here, we show that acetylation and also other acylations are spontaneous processes that depend on pH value, acyl-CoA concentration and the chemical nature of the acyl residue. In the case of a peptide derived from carbamoyl phosphate synthetase 1, the rates of succinylation and glutarylation were up to 150 times than for acetylation. These results were confirmed by using the protein substrate cyclophilin A (CypA). Deacylation experiments revealed that SIRT3 exhibits deacetylase activity but is not able to remove any of the succinyl groups from CypA, whereas SIRT5 is an effective protein desuccinylase. Thus, the acylation landscape on lysine residues might largely depend on the enzymatic activity of specific sirtuins, and the availability and reactivity of acyl-CoA compounds. PMID:26382620

  19. Meal-related ghrelin suppression requires postgastric feedback.

    PubMed

    Williams, Diana L; Cummings, David E; Grill, Harvey J; Kaplan, Joel M

    2003-07-01

    Plasma ghrelin levels are rapidly suppressed by ingestion or gastric delivery of nutrients. Given that the majority of circulating ghrelin appears to be of gastric origin, we addressed the contribution of gastric distention or nutrient sensitivity to this response. Awake, unrestrained rats received intragastric infusions of glucose or water (1 ml/min for 12 min) with gastric emptying either proceeding normally or prevented by inflation of a pyloric cuff. When emptying was permitted, glucose infusion reduced ghrelin level by approximately 50%, and, in agreement with previous data, water infusions were without effect. Ghrelin level was not affected by either infusate when gastric emptying was prevented, thereby discounting a role for gastric distention in the meal-related ghrelin response. That glucose and water infusions were similarly ineffective when the pylorus was occluded shows, further, that gastric chemosensation is not a sufficient trigger for the ghrelin response. We conclude that the meal-related suppression of plasma ghrelin requires postgastric (pre- or postabsorptive) stimulation. PMID:12810528

  20. Higher postprandial serum ghrelin among African American females before puberty

    PubMed Central

    Ellis, Amy C.; Casazza, Krista; Chandler-Laney, Paula; Gower, Barbara A.

    2013-01-01

    Objective Recent reports suggest that ghrelin regulation may differ by ethnicity and age. This study was designed to examine circulating ghrelin among overweight African American females across different age groups. Methods Eleven overweight peri-pubertal girls, 17 overweight pubertal girls, and a control group of 18 overweight AA premenopausal women ingested a standard liquid meal following an overnight fast. Blood samples were obtained before the meal and for 4 hours post-challenge. Participants rated appetite by a visual analog scale. Results Peri-pubertal girls demonstrated higher postprandial ghrelin and lesser ghrelin suppression compared to adults (p<0.05), corresponding with greater desire to eat across the test period (p=0.017). Fasting ghrelin tended to be inversely related to fasting estradiol (r=−0.264, p=0.076). Conclusion Compared to overweight African American women, peri-pubertal girls had higher ghrelin as well as greater appetite after a standard meal. These results may suggest a dysregulation in ghrelin reflective of demands of growth. PMID:23155695

  1. Potential ghrelin-mediated benefits and risks of hydrogen water.

    PubMed

    McCarty, Mark F

    2015-04-01

    Molecular hydrogen (H2) can scavenge hydroxyl radical and diminish the toxicity of peroxynitrite; hence, it has interesting potential for antioxidant protection. Recently, a number of studies have explored the utility of inhaled hydrogen gas, or of hydrogen-saturated water, administered parenterally or orally, in rodent models of pathology and in clinical trials, oftentimes with very positive outcomes. The efficacy of orally ingested hydrogen-rich water (HW) has been particularly surprising, given that only transient and rather small increments in plasma hydrogen can be achieved by this method. A recent study in mice has discovered that orally administered HW provokes increased gastric production of the orexic hormone ghrelin, and that this ghrelin mediates the favorable impact of HW on a mouse model of Parkinson's disease. The possibility that most of the benefits observed with HW in experimental studies are mediated by ghrelin merits consideration. Ghrelin is well known to function as an appetite stimulant and secretagogue for growth hormone, but it influences physiological function throughout the body via interaction with the widely express GHS-R1a receptor. Rodent and, to a more limited extent, clinical studies establish that ghrelin has versatile neuroprotective and cognitive enhancing activity, favorably impacts vascular health, exerts anti-inflammatory activity useful in autoimmune disorders, and is markedly hepatoprotective. The stimulatory impact of ghrelin on GH-IGF-I activity, while potentially beneficial in sarcopenia or cachectic disorders, does raise concerns regarding the long-term impact of ghrelin up-regulation on cancer risk. The impact of ingesting HW water on ghrelin production in humans needs to be evaluated; if HW does up-regulate ghrelin in humans, it may have versatile potential for prevention and control of a number of health disorders.

  2. Spontaneous sleep and homeostatic sleep regulation in ghrelin knockout mice.

    PubMed

    Szentirmai, Eva; Kapás, Levente; Sun, Yuxiang; Smith, Roy G; Krueger, James M

    2007-07-01

    Ghrelin is well known for its feeding and growth hormone-releasing actions. It may also be involved in sleep regulation; intracerebroventricular administration and hypothalamic microinjections of ghrelin stimulate wakefulness in rats. Hypothalamic ghrelin, together with neuropeptide Y and orexin form a food intake-regulatory circuit. We hypothesized that this circuit also promotes arousal. To further investigate the role of ghrelin in the regulation of sleep-wakefulness, we characterized spontaneous and homeostatic sleep regulation in ghrelin knockout (KO) and wild-type (WT) mice. Both groups of mice exhibited similar diurnal rhythms with more sleep and less wakefulness during the light period. In ghrelin KO mice, spontaneous wakefulness and rapid-eye-movement sleep (REMS) were slightly elevated, and non-rapid-eye-movement sleep (NREMS) was reduced. KO mice had more fragmented NREMS than WT mice, as indicated by the shorter and greater number of NREMS episodes. Six hours of sleep deprivation induced rebound increases in NREMS and REMS and biphasic changes in electroencephalographic slow-wave activity (EEG SWA) in both genotypes. Ghrelin KO mice recovered from NREMS and REMS loss faster, and the delayed reduction in EEG SWA, occurring after sleep loss-enhanced increases in EEG SWA, was shorter-lasting compared with WT mice. These findings suggest that the basic sleep-wake regulatory mechanisms in ghrelin KO mice are not impaired and they are able to mount adequate rebound sleep in response to a homeostatic challenge. It is possible that redundancy in the arousal systems of the brain or activation of compensatory mechanisms during development allow for normal sleep-wake regulation in ghrelin KO mice. PMID:17409264

  3. Potential ghrelin-mediated benefits and risks of hydrogen water.

    PubMed

    McCarty, Mark F

    2015-04-01

    Molecular hydrogen (H2) can scavenge hydroxyl radical and diminish the toxicity of peroxynitrite; hence, it has interesting potential for antioxidant protection. Recently, a number of studies have explored the utility of inhaled hydrogen gas, or of hydrogen-saturated water, administered parenterally or orally, in rodent models of pathology and in clinical trials, oftentimes with very positive outcomes. The efficacy of orally ingested hydrogen-rich water (HW) has been particularly surprising, given that only transient and rather small increments in plasma hydrogen can be achieved by this method. A recent study in mice has discovered that orally administered HW provokes increased gastric production of the orexic hormone ghrelin, and that this ghrelin mediates the favorable impact of HW on a mouse model of Parkinson's disease. The possibility that most of the benefits observed with HW in experimental studies are mediated by ghrelin merits consideration. Ghrelin is well known to function as an appetite stimulant and secretagogue for growth hormone, but it influences physiological function throughout the body via interaction with the widely express GHS-R1a receptor. Rodent and, to a more limited extent, clinical studies establish that ghrelin has versatile neuroprotective and cognitive enhancing activity, favorably impacts vascular health, exerts anti-inflammatory activity useful in autoimmune disorders, and is markedly hepatoprotective. The stimulatory impact of ghrelin on GH-IGF-I activity, while potentially beneficial in sarcopenia or cachectic disorders, does raise concerns regarding the long-term impact of ghrelin up-regulation on cancer risk. The impact of ingesting HW water on ghrelin production in humans needs to be evaluated; if HW does up-regulate ghrelin in humans, it may have versatile potential for prevention and control of a number of health disorders. PMID:25649854

  4. Ghrelin Inhibits Oligodendrocyte Cell Death by Attenuating Microglial Activation

    PubMed Central

    Lee, Jee Youn

    2014-01-01

    Background Recently, we reported the antiapoptotic effect of ghrelin in spinal cord injury-induced apoptotic cell death of oligodendrocytes. However, how ghrelin inhibits oligodendrocytes apoptosis, is still unknown. Therefore, in the present study, we examined whether ghrelin inhibits microglia activation and thereby inhibits oligodendrocyte apoptosis. Methods Using total cell extracts prepared from BV-2 cells activated by lipopolysaccharide (LPS) with or without ghrelin, the levels of p-p38 phosphor-p38 mitogen-activated protein kinase (p-p38MAPK), phospho-c-Jun N-terminal kinase (pJNK), p-c-Jun, and pro-nerve growth factor (proNGF) were examined by Western blot analysis. Reactive oxygen species (ROS) production was investigated by using dichlorodihydrofluorescein diacetate. To examine the effect of ghrelin on oligodendrocyte cell death, oligodendrocytes were cocultured in transwell chambers of 24-well plates with LPS-stimulated BV-2 cells. After 48 hours incubation, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and terminal deoxynucleotidyl transferase 2'-deoxyuridine, 5'-triphosphate nick end labeling staining were assessed. Results Ghrelin treatment significantly decreased levels of p-p38MAPK, p-JNK, p-c-Jun, and proNGF in LPS-stimulated BV-2 cells. ROS production increased in LPS-stimulated BV-2 cells was also significantly inhibited by ghrelin treatment. In addition, ghrelin significantly inhibited oligodendrocyte cell death when cocultured with LPS-stimulated BV-2 cells. Conclusion Ghrelin inhibits oligodendrocyte cell death by decreasing proNGF and ROS production as well as p38MAPK and JNK activation in activated microglia as an anti-inflammatory hormone. PMID:25309797

  5. Influence of Aging and Gender Differences on Feeding Behavior and Ghrelin-Related Factors during Social Isolation in Mice

    PubMed Central

    Yamada, Chihiro; Saegusa, Yayoi; Nahata, Miwa; Sadakane, Chiharu; Hattori, Tomohisa; Takeda, Hiroshi

    2015-01-01

    Psychological stress due to social isolation is known to cause abnormal feeding behaviors, but the influences of gender and aging on subchronic stress-induced changes in feeding behaviors are unknown. Thus, we examined the changes in body weight, food intake, and orexigenic ghrelin-related factors during 2 weeks of isolation stress in young and aged mice. Food intake increased significantly in young mice in the isolation group compared with the group-housed control throughout the experimental period. This isolation-induced increase in food intake was not observed in aged mice. In young mice, there were no significant differences in body weight between the isolated group and group-housed control up to 2 weeks. However, aged male mice exhibited significant weight loss at 2 weeks and a similar tendency was observed in aged female mice. Young male mice, but not female mice, had significantly increased (2.2-fold) plasma acylated ghrelin levels after 1 week of isolation compared with the group-housed control. A significant but lower increase (1.3-fold) was also observed in aged male mice. Hypothalamic preproghrelin gene expression decreased significantly with isolation in young male mice, whereas it increased significantly in female mice. The expression levels of NPY and AGRP in the hypothalamus, which are transmitted by elevated peripheral ghrelin signals, increased significantly in isolated young male mice, whereas the AGRP expression levels decreased significantly in young female mice. Isolation caused no significant differences in the expression levels of these genes in aged mice. In isolation, young female mice exhibited markedly increased dark- and light-phase locomotor activities compared with male mice, whereas male and female aged mice exhibited no obvious increases in activity immediately after the dark phase started. We conclude that the gender-specific homeostatic regulatory mechanisms required to maintain body weight operated during subchronic psychological

  6. Turnover of the 4'-phosphopantetheine prosthetic group of acyl carrier protein.

    PubMed

    Jackowski, S; Rock, C O

    1984-02-10

    Acyl carrier protein is an essential cofactor in fatty acid biosynthesis, and in contrast to the stability of the protein moiety during growth, its 4'-phosphopantetheine prosthetic group is metabolically active. The biosynthetic incorporation of deuterium into nonexchangeable positions of acyl carrier protein was found to enhance the sensitivity of the protein to pH-induced hydrodynamic expansion. This constitutional isotope effect was exploited to separate deuterated from normal acyl carrier protein by conformationally sensitive gel electrophoresis, thus providing the analytical framework for separating pre-existing (deuterated) from newly synthesized acyl carrier protein in pulse-chase experiments. The rate of acyl carrier protein prosthetic group turnover was found to depend on the intracellular concentration of coenzyme A. At low coenzyme A levels, prosthetic group turnover was four times faster than the rate of new acyl carrier protein biosynthesis but at the higher coenzyme A concentrations characteristic of logarithmic growth, turnover was an order of magnitude slower, amounting to approximately 25% of the acyl carrier protein pool per generation. These observations suggest that the acyl carrier protein prosthetic group turnover cycle may be related to coenzyme A metabolism rather than to lipid biosynthesis.

  7. Ghrelin suppression is associated with weight loss and insulin action following gastric bypass surgery at 12 months in obese adults with type 2 diabetes.

    PubMed

    Samat, A; Malin, S K; Huang, H; Schauer, P R; Kirwan, J P; Kashyap, S R

    2013-10-01

    Roux-en-Y gastric bypass (RYGB) surgery reverses type 2 diabetes mellitus (T2DM) in approximately 80% of patients. Ghrelin regulates glucose homeostasis, but its role in T2DM remission after RYGB surgery is unclear. Nine obese T2DM subjects underwent a mixed meal tolerance test before and at 1 and 12 months after RYGB surgery. Changes in ghrelin, body weight, glucagon-like polypeptide-1 (GLP-1, glucose tolerance and insulin sensitivity (IS) were measured. At 1 month, body weight, glycaemia and IS were improved, while ghrelin concentrations were reduced (p < 0.05). After 12 months, body weight and fasting glucose were reduced (30 and 16%, respectively; p < 0.05) and IS was enhanced (threefold; p < 0.05). Ghrelin suppression improved by 32% at 12 months (p < 0.05), and this was associated with weight loss (r = 0.72, p = 0.03), enhanced IS (r = -0.78, p = 0.01) and peak postprandial GLP-1 (r = -0.73, p = 0.03). These data suggest that postprandial ghrelin suppression may be part of the mechanism that contributes to diabetes remission after RYGB surgery.

  8. Developments in ghrelin biology and potential clinical relevance.

    PubMed

    Smith, Roy G; Jiang, Hong; Sun, Yuxiang

    2005-11-01

    The spiropiperidine, MK0677, has been exploited to characterize and expression clone the growth hormone secretagogue receptor (GHS-R). Cloning of this receptor led to identification of its natural ligands, ghrelin and adenosine. Targeted disruption of the Ghsr gene demonstrated unambiguously that the GH-releasing and orexigenic properties of ghrelin are dependent on Ghsr expression and that the orexigenic signal is mediated through neuropeptide Y and agouti-related peptide neurons. This review summarizes new developments in our understanding of the physiological roles of ghrelin and its receptor (GHS-R). Recent discoveries of the effects of ghrelin on the thymus and proinflammatory and chemotactic cytokine pathways stimulate renewed interest in potential clinical applications, which include age-associated disorders, such as metabolic disease, sarcopenia, congestive heart failure, atherosclerosis and anorexia. PMID:16213742

  9. Ghrelin as a target for gastrointestinal motility disorders.

    PubMed

    Greenwood-Van Meerveld, Beverley; Kriegsman, Michael; Nelson, Richard

    2011-11-01

    The therapeutic potential of ghrelin and synthetic ghrelin receptor (GRLN-R) agonists for the treatment of gastrointestinal (GI) motility disorders is based on their ability to stimulate coordinated patterns of propulsive GI motility. This review focuses on the latest findings that support the therapeutic potential of GRLN-R agonists for the treatment of GI motility disorders. The review highlights the preclinical and clinical prokinetic effects of ghrelin and a series of novel ghrelin mimetics to exert prokinetic effects on the GI tract. We build upon a series of excellent reviews to critically discuss the evidence that supports the potential of GRLN-R agonists to normalize GI motility in patients with GI hypomotility disorders such as gastroparesis, post-operative ileus (POI), idiopathic chronic constipation and functional bowel disorders. PMID:21453735

  10. Influence of puberty on ghrelin and BMD in athletes.

    PubMed

    Jürimäe, J; Lätt, E; Haljaste, K; Purge, P; Cicchella, A; Jürimäe, T

    2009-06-01

    The aim of our study was to examine the influence of elevated energy expenditure on ghrelin and BMD in young male competitive swimmers advancing from prepubertal to pubertal maturation levels. The study included 19 healthy swimmers (pubertal stage 1) aged between 10 and 12 years. The participants were at the pubertal stages 2 and 3, and 3 and 4 at the second and third year, respectively. Ghrelin was decreased only after the first year. No changes were observed in leptin during the study period. Testosterone increased according to the pubertal development at each measurements. IGF-I was increased at the third measurement compared to the first two measurements. Total and lumbar spine BMDs increased according to the pubertal development in all boys at each measurements, while no changes in femoral neck BMD were observed. Ghrelin was not related to BMD after adjusting for pubertal status. We conclude that ghrelin was decreased at onset of puberty, while no further changes in ghrelin were seen with advancing pubertal stage. Total and lumbar spine BMD increased, while no changes in femoral neck BMD occurred. Ghrelin did not appear to have a direct influence on BMD in young male competitive swimmers. PMID:19199214

  11. Elevated ghrelin predicts food intake during experimental sleep restriction

    PubMed Central

    Broussard, Josiane L.; Kilkus, Jennifer M.; Delebecque, Fanny; Abraham, Varghese; Day, Andrew; Whitmore, Harry R.; Tasali, Esra

    2015-01-01

    Objective Sleep curtailment has been linked to obesity, but underlying mechanisms remain to be elucidated. We assessed whether sleep restriction alters 24-hour profiles of appetite-regulating hormones ghrelin, leptin and pancreatic polypeptide during a standardized diet, and whether these hormonal alterations predict food intake during ad libitum feeding. Methods Nineteen healthy, lean men were studied under normal sleep and sleep restriction in a randomized crossover design. Blood samples were collected for 24-hours during standardized meals. Subsequently, participants had an ad libitum feeding opportunity (buffet meals and snacks) and caloric intake was measured. Results Ghrelin levels were increased after sleep restriction as compared to normal sleep (p<0.01). Overall, sleep restriction did not alter leptin or pancreatic polypeptide profiles. Sleep restriction was associated with an increase in total calories from snacks by 328 ± 140 Kcal (p=0.03), primarily from carbohydrates (p=0.02). The increase in evening ghrelin during sleep restriction was correlated with higher consumption of calories from sweets (r=0.48, p=0.04). Conclusions Sleep restriction as compared to normal sleep significantly increases ghrelin levels. The increase in ghrelin is associated with more consumption of calories. Elevated ghrelin may be a mechanism by which sleep loss leads to increased food intake and the development of obesity. PMID:26467988

  12. Ablation of ghrelin receptor in leptin-deficient ob/ob mice has paradoxical effects on glucose homeostasis when compared with ablation of ghrelin in ob/ob mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The orexigenic hormone ghrelin is important in diabetes because it has an inhibitory effect on insulin secretion. Ghrelin ablation in leptin-deficient ob/ob (Ghrelin(-/-):ob/ob) mice increases insulin secretion and improves hyperglycemia. The physiologically relevant ghrelin receptor is the growth ...

  13. Neuronal deletion of ghrelin receptor almost completely prevents diet-induced obesity

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Ghrelin signaling has major effects on energy- and glucose-homeostasis, but it is unknown whether ghrelin's functions are centrally and/or peripherally mediated. The ghrelin receptor, Growth Hormone Secretagogue Receptor (GHS-R), is highly expressed in brain and detectable in some peripheral tissues...

  14. Rise of plasma ghrelin with weight loss is not sustained during weight maintenance

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Ghrelin is postulated to be an orexigenic signal that promotes weight regain after weight loss (WL). However, it is not known whether this putative effect of ghrelin is sustained after weight stabilization. The objective of this study was to investigate the relationship of plasma ghrelin concentrati...

  15. Divergent neuronal circuitries underlying acute orexigenic effects of peripheral or central ghrelin: critical role of brain accessibility.

    PubMed

    Cabral, A; Valdivia, S; Fernandez, G; Reynaldo, M; Perello, M

    2014-08-01

    Ghrelin is an octanoylated peptide hormone that potently and rapidly increases food intake. The orexigenic action of ghrelin involves the hypothalamic arcuate nucleus (ARC), which is accessible to plasma ghrelin and expresses high levels of the ghrelin receptor. Local administration of ghrelin in a variety of other brain nuclei also increases food intake. It is currently unclear, however, whether these non-ARC ghrelin brain targets are impacted by physiological increases of plasma ghrelin. Thus, the present study aimed to clarify which ghrelin brain targets participate in the short-term orexigenic actions of ghrelin. First, c-Fos induction into mouse brains centrally or peripherally treated with ghrelin was analysed. It was confirmed that peripherally administered ghrelin dose-dependently increases food intake and mainly activates c-Fos in ARC neurones. By contrast, centrally administered ghrelin activates c-Fos in a larger number of brain nuclei. To determine which nuclei are directly accessible to ghrelin, mice were centrally or peripherally injected with a fluorescent ghrelin tracer. It was found that peripherally injected tracer mainly accesses the ARC, whereas centrally injected tracer reaches most brain areas known to express ghrelin receptors. Subsequently, the effects of ghrelin were tested in ARC-ablated mice and it was found that these mice failed to increase food intake in response to peripherally administered ghrelin but fully responded to centrally administered ghrelin. ARC-ablated mice showed patterns of ghrelin-induced c-Fos expression similar to those seen in control mice with the exception of the ARC, where no c-Fos was found. Thus, peripheral ghrelin mainly accesses the ARC, which is required for the orexigenic effects of the hormone. Central ghrelin accesses a variety of nuclei, which can mediate the orexigenic effects of the hormone, even in the absence of an intact ARC.

  16. Modified acyl-ACP desaturase

    DOEpatents

    Cahoon, Edgar B.; Shanklin, John; Lindgvist, Ylva; Schneider, Gunter

    1998-01-06

    Disclosed is a methods for modifying the chain length and double bond positional specificities of a soluble plant fatty acid desaturase. More specifically, the method involves modifying amino acid contact residues in the substrate binding channel of the soluble fatty acid desaturase which contact the fatty acid. Specifically disclosed is the modification of an acyl-ACP desaturase. Amino acid contact residues which lie within the substrate binding channel are identified, and subsequently replaced with different residues to effect the modification of activity.

  17. Modified Acyl-ACP desaturase

    DOEpatents

    Cahoon, Edgar B.; Shanklin, John; Lindqvist, Ylva; Schneider, Gunter

    1999-03-30

    Disclosed is a method for modifying the chain length and double bond positional specificities of a soluble plant fatty acid desaturase. More specifically, the method involves modifying amino acid contact residues in the substrate binding channel of the soluble fatty acid desaturase which contact the fatty acid. Specifically disclosed is the modification of an acyl-ACP desaturase. Amino acid contact residues which lie within the substrate binding channel are identified, and subsequently replaced with different residues to effect the modification of activity.

  18. The presence of acyl-CoA hydrolase in rat brown-adipose-tissue peroxisomes.

    PubMed

    Alexson, S E; Osmundsen, H; Berge, R K

    1989-08-15

    The subcellular distribution of acyl-CoA hydrolase was studied in rat brown adipose tissue, with special emphasis on possible peroxisomal localization. Subcellular fractionation by sucrose-density-gradient centrifugation, followed by measurement of short-chain (propionyl-CoA) acyl-CoA hydrolase in the presence of NADH, resulted in two peaks of activity in the gradient: one peak corresponded to the distribution of cytochrome oxidase (mitochondrial marker enzyme), and another peak of activity coincided with the peroxisomal marker enzyme catalase. The distribution of the NADH-inhibited short-chain hydrolase activity fully resembled that of cytochrome oxidase. The substrate-specificity curve of the peroxisomal acyl-CoA hydrolase activity indicated the presence of a single enzyme exhibiting a broad substrate specificity, with maximal activity towards fatty acids with chain lengths of 3-12 carbon atoms. The mitochondrial acyl-CoA hydrolase substrate specificity, in contrast, indicated the presence of at least two acyl-CoA hydrolases (of short- and medium-chain-length specificity). The peroxisomal acyl-CoA hydrolase activity was inhibited by CoA at low (microM) concentrations and by ATP at high concentrations (greater than 0.8 mM). In contrast with the mitochondrial short-chain hydrolase, the peroxisomal acyl-CoA hydrolase activity was not inhibited by NADH. PMID:2573347

  19. Stearoyl-Acyl Carrier Protein and Unusual Acyl-Acyl Carrier Protein Desaturase Activities Are Differentially Influenced by Ferredoxin1

    PubMed Central

    Schultz, David J.; Suh, Mi Chung; Ohlrogge, John B.

    2000-01-01

    Acyl-acyl carrier protein (ACP) desaturases function to position a single double bond into an acyl-ACP substrate and are best represented by the ubiquitous Δ9 18:0-ACP desaturase. Several variant acyl-ACP desaturases have also been identified from species that produce unusual monoenoic fatty acids. All known acyl-ACP desaturase enzymes use ferredoxin as the electron-donating cofactor, and in almost all previous studies the photosynthetic form of ferredoxin rather than the non-photosynthetic form has been used to assess activity. We have examined the influence of different forms of ferredoxin on acyl-ACP desaturases. Using combinations of in vitro acyl-ACP desaturase assays and [14C]malonyl-coenzyme A labeling studies, we have determined that heterotrophic ferredoxin isoforms support up to 20-fold higher unusual acyl-ACP desaturase activity in coriander (Coriandrum sativum), Thunbergia alata, and garden geranium (Pelargonium × hortorum) when compared with photosynthetic ferredoxin isoforms. Heterotrophic ferredoxin also increases activity of the ubiquitous Δ9 18:0-ACP desaturase 1.5- to 3.0-fold in both seed and leaf extracts. These results suggest that ferredoxin isoforms may specifically interact with acyl-ACP desaturases to achieve optimal enzyme activity and that heterotrophic isoforms of ferredoxin may be the in vivo electron donor for this reaction. PMID:11027717

  20. Hippocampus ghrelin signaling mediates appetite through lateral hypothalamic orexin pathways

    PubMed Central

    Hsu, Ted M; Hahn, Joel D; Konanur, Vaibhav R; Noble, Emily E; Suarez, Andrea N; Thai, Jessica; Nakamoto, Emily M; Kanoski, Scott E

    2015-01-01

    Feeding behavior rarely occurs in direct response to metabolic deficit, yet the overwhelming majority of research on the biology of food intake control has focused on basic metabolic and homeostatic neurobiological substrates. Most animals, including humans, have habitual feeding patterns in which meals are consumed based on learned and/or environmental factors. Here we illuminate a novel neural system regulating higher-order aspects of feeding through which the gut-derived hormone ghrelin communicates with ventral hippocampus (vHP) neurons to stimulate meal-entrained conditioned appetite. Additional results show that the lateral hypothalamus (LHA) is a critical downstream substrate for vHP ghrelin-mediated hyperphagia and that vHP ghrelin activated neurons communicate directly with neurons in the LHA that express the neuropeptide, orexin. Furthermore, activation of downstream orexin-1 receptors is required for vHP ghrelin-mediated hyperphagia. These findings reveal novel neurobiological circuitry regulating appetite through which ghrelin signaling in hippocampal neurons engages LHA orexin signaling. DOI: http://dx.doi.org/10.7554/eLife.11190.001 PMID:26745307

  1. Hippocampus ghrelin signaling mediates appetite through lateral hypothalamic orexin pathways.

    PubMed

    Hsu, Ted M; Hahn, Joel D; Konanur, Vaibhav R; Noble, Emily E; Suarez, Andrea N; Thai, Jessica; Nakamoto, Emily M; Kanoski, Scott E

    2015-12-15

    Feeding behavior rarely occurs in direct response to metabolic deficit, yet the overwhelming majority of research on the biology of food intake control has focused on basic metabolic and homeostatic neurobiological substrates. Most animals, including humans, have habitual feeding patterns in which meals are consumed based on learned and/or environmental factors. Here we illuminate a novel neural system regulating higher-order aspects of feeding through which the gut-derived hormone ghrelin communicates with ventral hippocampus (vHP) neurons to stimulate meal-entrained conditioned appetite. Additional results show that the lateral hypothalamus (LHA) is a critical downstream substrate for vHP ghrelin-mediated hyperphagia and that vHP ghrelin activated neurons communicate directly with neurons in the LHA that express the neuropeptide, orexin. Furthermore, activation of downstream orexin-1 receptors is required for vHP ghrelin-mediated hyperphagia. These findings reveal novel neurobiological circuitry regulating appetite through which ghrelin signaling in hippocampal neurons engages LHA orexin signaling.

  2. Loneliness predicts postprandial ghrelin and hunger in women.

    PubMed

    Jaremka, Lisa M; Fagundes, Christopher P; Peng, Juan; Belury, Martha A; Andridge, Rebecca R; Malarkey, William B; Kiecolt-Glaser, Janice K

    2015-04-01

    Loneliness is strongly linked to poor health. Recent research suggests that appetite dysregulation provides one potential pathway through which loneliness and other forms of social disconnection influence health. Obesity may alter the link between loneliness and appetite-relevant hormones, one unexplored possibility. We examined the relationships between loneliness and both postmeal ghrelin and hunger, and tested whether these links differed for people with a higher versus lower body mass index (BMI; kg/m(2)). During this double-blind randomized crossover study, women (N=42) ate a high saturated fat meal at the beginning of one full-day visit and a high oleic sunflower oil meal at the beginning of the other. Loneliness was assessed once with a commonly used loneliness questionnaire. Ghrelin was sampled before the meal and postmeal at 2 and 7h. Self-reported hunger was measured before the meal, immediately postmeal, and then 2, 4, and 7h later. Lonelier women had larger postprandial ghrelin and hunger increases compared with less lonely women, but only among participants with a lower BMI. Loneliness and postprandial ghrelin and hunger were unrelated among participants with a higher BMI. These effects were consistent across both meals. These data suggest that ghrelin, an important appetite-regulation hormone, and hunger may link loneliness to weight gain and its corresponding negative health effects among non-obese people.

  3. The Physiology of Protein S-acylation

    PubMed Central

    Chamberlain, Luke H.; Shipston, Michael J.

    2015-01-01

    Protein S-acylation, the only fully reversible posttranslational lipid modification of proteins, is emerging as a ubiquitous mechanism to control the properties and function of a diverse array of proteins and consequently physiological processes. S-acylation results from the enzymatic addition of long-chain lipids, most typically palmitate, onto intracellular cysteine residues of soluble and transmembrane proteins via a labile thioester linkage. Addition of lipid results in increases in protein hydrophobicity that can impact on protein structure, assembly, maturation, trafficking, and function. The recent explosion in global S-acylation (palmitoyl) proteomic profiling as a result of improved biochemical tools to assay S-acylation, in conjunction with the recent identification of enzymes that control protein S-acylation and de-acylation, has opened a new vista into the physiological function of S-acylation. This review introduces key features of S-acylation and tools to interrogate this process, and highlights the eclectic array of proteins regulated including membrane receptors, ion channels and transporters, enzymes and kinases, signaling adapters and chaperones, cell adhesion, and structural proteins. We highlight recent findings correlating disruption of S-acylation to pathophysiology and disease and discuss some of the major challenges and opportunities in this rapidly expanding field. PMID:25834228

  4. The ghrelin axis--does it have an appetite for cancer progression?

    PubMed

    Chopin, Lisa K; Seim, Inge; Walpole, Carina M; Herington, Adrian C

    2012-12-01

    Ghrelin, the endogenous ligand for the GH secretagogue receptor (GHSR), is a peptide hormone with diverse physiological roles. Ghrelin regulates GH release, appetite and feeding, gut motility, and energy balance and also has roles in the cardiovascular, immune, and reproductive systems. Ghrelin and the GHSR are expressed in a wide range of normal and tumor tissues, and a fluorescein-labeled, truncated form of ghrelin is showing promise as a biomarker for prostate cancer. Plasma ghrelin levels are generally inversely related to body mass index and are unlikely to be useful as a biomarker for cancer, but may be useful as a marker for cancer cachexia. Some single nucleotide polymorphisms in the ghrelin and GHSR genes have shown associations with cancer risk; however, larger studies are required. Ghrelin regulates processes associated with cancer, including cell proliferation, apoptosis, cell migration, cell invasion, inflammation, and angiogenesis; however, the role of ghrelin in cancer is currently unclear. Ghrelin has predominantly antiinflammatory effects and may play a role in protecting against cancer-related inflammation. Ghrelin and its analogs show promise as treatments for cancer-related cachexia. Further studies using in vivo models are required to determine whether ghrelin has a role in cancer progression.

  5. Ghrelin axis genes, peptides and receptors: recent findings and future challenges.

    PubMed

    Seim, Inge; Josh, Peter; Cunningham, Peter; Herington, Adrian; Chopin, Lisa

    2011-06-20

    The ghrelin axis consists of the gene products of the ghrelin gene (GHRL), and their receptors, including the classical ghrelin receptor GHSR. While it is well-known that the ghrelin gene encodes the 28 amino acid ghrelin peptide hormone, it is now also clear that the locus encodes a range of other bioactive molecules, including novel peptides and non-coding RNAs. For many of these molecules, the physiological functions and cognate receptor(s) remain to be determined. Emerging research techniques, including proteogenomics, are likely to reveal further ghrelin axis-derived molecules. Studies of the role of ghrelin axis genes, peptides and receptors, therefore, promises to be a fruitful area of basic and clinical research in years to come.

  6. 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. PMID:19082715

  7. IMPLICATIONS OF GHRELIN AXIS IN BREAST CANCER--REVIEW.

    PubMed

    Armasu, Ioana; Volovăt, C; Drug, V L; Crumpei, Iulia; Vasiliu, Ioana; Tofan, Mariana; Preda, Cristina; Serban, Ionela Lacrămioara; Vulpoi, Carmen

    2015-01-01

    Breast cancer is, by far, the most frequent cancer among women and many factors influence the physiological and pathological growth and development of the mammary gland. There is developing evidence that the hormone ghrelin, known for the growth hormone releasing effect and food intake modulator, could also play a role in the pathogenesis of breast cancer and may represent a new diagnostic marker and a potential therapeutic target. We performed a PubMed Database search of relevant studies and ten papers were included in our systematic review. Ghrelin axis seems to be definitely involved in the pathogenesis of breast cancer, although a precise role has not been yet established. In order to verify the precise role of ghrelin axis in breast cancer further studies with larger populations are necessary that should include the analysis of metabolic, genetic and environmental factors which are expected to influence the results. PMID:26204629

  8. Topology and acylation of spiralin.

    PubMed Central

    Wróblewski, H; Nyström, S; Blanchard, A; Wieslander, A

    1989-01-01

    Of the 51 polypeptides detected by sodium dodecyl sulfate-polyacrylamide gel electrophoresis in the plasma membrane of the helical mollicute Spiroplasma melliferum, 21 are acylated, predominantly with myristic (14:0) and palmitic (16:0) chains. This is notably the case for spiralin, the major membrane protein of this bacterium, which contains an average of 0.7 acyl chains per polypeptide, attached very probably by ester bonds to alcohol amino acids. The amphiphilicity of spiralin was demonstrated by the behavior of the protein in charge-shift electrophoresis, its incorporation into liposomes, and its ability to form in the absence of lipids and detergents, globular protein micelles (diameter, approximately 15 nm). The presence of epitopes on the two faces of the cell membrane, as probed by antibody adsorption and crossed immunoelectrophoresis, and the strong interaction between spiralin and the intracytoplasmic fibrils show that spiralin is a transmembrane protein. The mean hydropathy of the amino acid composition of spiralin (-0.30) is on the hydrophilic side of the scale. Surprisingly, the water-insoluble core of spiralin micelles, which is the putative membrane anchor, has a still more hydrophilic amino acid composition (mean hydropathy, -0.70) and is enriched in glycine and serine residues. Taking into account all these properties, we propose a topological model for spiralin featuring a transbilayer localization with hydrophilic domains protruding on the two faces of the membrane and connected by a small domain embedded within the apolar region of the lipid bilayer. In this model, the membrane anchoring of the protein is strengthened by a covalently bound acyl chain. Images PMID:2768198

  9. Versatility of acyl-acyl carrier protein synthetases.

    PubMed

    Beld, Joris; Finzel, Kara; Burkart, Michael D

    2014-10-23

    The acyl carrier protein (ACP) requires posttranslational modification with a 4'-phosphopantetheine arm for activity, and this thiol-terminated modification carries cargo between enzymes in ACP-dependent metabolic pathways. We show that acyl-ACP synthetases (AasSs) from different organisms are able to load even, odd, and unnatural fatty acids onto E. coli ACP in vitro. Vibrio harveyi AasS not only shows promiscuity for the acid substrate, but also is active upon various alternate carrier proteins. AasS activity also extends to functional activation in living organisms. We show that exogenously supplied carboxylic acids are loaded onto ACP and extended by the E. coli fatty acid synthase, including unnatural fatty acid analogs. These analogs are further integrated into cellular lipids. In vitro characterization of four different adenylate-forming enzymes allowed us to disambiguate CoA-ligases and AasSs, and further in vivo studies show the potential for functional application in other organisms. PMID:25308274

  10. Effects of development and delayed feed access on ghrelin expression in neonatal broiler chickens.

    PubMed

    Yu, Y; Zhang, Y H; Zhang, H H; Tao, H; Ou, C B; Wang, Q X; Guo, F; Ma, J Y

    2016-10-01

    Two experiments were conducted to study the effects of development and delayed feed access on ghrelin expression in neonatal chickens. In experiment 1, ghrelin levels in ad libitum-fed chickens were assessed from hatching (0 h) to 120 h. Ghrelin mRNA expression increased after hatching and reached peak levels at 24 h; levels were 1.8-fold higher compared to those at 0 h. Afterward, ghrelin expression decreased consistently throughout the later experimental period, and at 120 h, it was only 16.0% of 0 h levels. The density of ghrelin immunopositive cells in the proventriculus and plasma ghrelin levels decreased slightly from hatching to 48 h and later increased slowly until the end of the experimental period. In a follow-up study, chickens were assigned randomly into 2 groups after hatching, a control group ( C: , fed ad libitum) and a delayed feeding group ( F+SF: , 72-h fast period, subsequently fed ad libitum). Delayed feed access for 72 h up-regulated ghrelin mRNA expression significantly in the proventriculus (P < 0.05) to 2.1-fold higher levels compared to the control, while the density of ghrelin immunopositive cells and the plasma ghrelin level decreased (P < 0.05) to 28.4% and 64.8% of the control, respectively. After the onset of feeding, the ghrelin mRNA expression in the delayed feeding group was decreased but still higher than that of the control (P < 0.05). The density of ghrelin immunopositive cells and the plasma ghrelin level climbed quickly and all returned to the control level with a supply of food for 48 h. These results suggest that the onset of feeding in neonatal chickens stimulated an increase in ghrelin peptide levels and that ghrelin peptide levels increased with age. Neonatal chickens respond to food deprivation in a different way than do young and adult chickens. PMID:27194732

  11. Ghrelin knockout mice show decreased voluntary alcohol consumption and reduced ethanol-induced conditioned place preference.

    PubMed

    Bahi, Amine; Tolle, Virginie; Fehrentz, Jean-Alain; Brunel, Luc; Martinez, Jean; Tomasetto, Catherine-Laure; Karam, Sherif M

    2013-05-01

    Recent work suggests that stomach-derived hormone ghrelin receptor (GHS-R1A) antagonism may reduce motivational aspects of ethanol intake. In the current study we hypothesized that the endogenous GHS-R1A agonist ghrelin modulates alcohol reward mechanisms. For this purpose ethanol-induced conditioned place preference (CPP), ethanol-induced locomotor stimulation and voluntary ethanol consumption in a two-bottle choice drinking paradigm were examined under conditions where ghrelin and its receptor were blocked, either using ghrelin knockout (KO) mice or the specific ghrelin receptor (GHS-R1A) antagonist "JMV2959". We showed that ghrelin KO mice displayed lower ethanol-induced CPP than their wild-type (WT) littermates. Consistently, when injected during CPP-acquisition, JMV2959 reduced CPP-expression in C57BL/6 mice. In addition, ethanol-induced locomotor stimulation was lower in ghrelin KO mice. Moreover, GHS-R1A blockade, using JMV2959, reduced alcohol-stimulated locomotion only in WT but not in ghrelin KO mice. When alcohol consumption and preference were assessed using the two-bottle choice test, both genetic deletion of ghrelin and pharmacological antagonism of the GHS-R1A (JMV2959) reduced voluntary alcohol consumption and preference. Finally, JMV2959-induced reduction of alcohol intake was only observed in WT but not in ghrelin KO mice. Taken together, these results suggest that ghrelin neurotransmission is necessary for the stimulatory effect of ethanol to occur, whereas lack of ghrelin leads to changes that reduce the voluntary intake as well as conditioned reward by ethanol. Our findings reveal a major, novel role for ghrelin in mediating ethanol behavior, and add to growing evidence that ghrelin is a key mediator of the effects of multiple abused drugs. PMID:23428971

  12. Ghrelin knockout mice show decreased voluntary alcohol consumption and reduced ethanol-induced conditioned place preference.

    PubMed

    Bahi, Amine; Tolle, Virginie; Fehrentz, Jean-Alain; Brunel, Luc; Martinez, Jean; Tomasetto, Catherine-Laure; Karam, Sherif M

    2013-05-01

    Recent work suggests that stomach-derived hormone ghrelin receptor (GHS-R1A) antagonism may reduce motivational aspects of ethanol intake. In the current study we hypothesized that the endogenous GHS-R1A agonist ghrelin modulates alcohol reward mechanisms. For this purpose ethanol-induced conditioned place preference (CPP), ethanol-induced locomotor stimulation and voluntary ethanol consumption in a two-bottle choice drinking paradigm were examined under conditions where ghrelin and its receptor were blocked, either using ghrelin knockout (KO) mice or the specific ghrelin receptor (GHS-R1A) antagonist "JMV2959". We showed that ghrelin KO mice displayed lower ethanol-induced CPP than their wild-type (WT) littermates. Consistently, when injected during CPP-acquisition, JMV2959 reduced CPP-expression in C57BL/6 mice. In addition, ethanol-induced locomotor stimulation was lower in ghrelin KO mice. Moreover, GHS-R1A blockade, using JMV2959, reduced alcohol-stimulated locomotion only in WT but not in ghrelin KO mice. When alcohol consumption and preference were assessed using the two-bottle choice test, both genetic deletion of ghrelin and pharmacological antagonism of the GHS-R1A (JMV2959) reduced voluntary alcohol consumption and preference. Finally, JMV2959-induced reduction of alcohol intake was only observed in WT but not in ghrelin KO mice. Taken together, these results suggest that ghrelin neurotransmission is necessary for the stimulatory effect of ethanol to occur, whereas lack of ghrelin leads to changes that reduce the voluntary intake as well as conditioned reward by ethanol. Our findings reveal a major, novel role for ghrelin in mediating ethanol behavior, and add to growing evidence that ghrelin is a key mediator of the effects of multiple abused drugs.

  13. Sickness behaviour after lipopolysaccharide treatment in ghrelin deficient mice.

    PubMed

    Szentirmai, Éva; Krueger, James M

    2014-02-01

    Ghrelin is an orexigenic hormone produced mainly by the gastrointestinal system and the brain. Much evidence also indicates a role for ghrelin in sleep and thermoregulation. Further, ghrelin was recently implicated in immune system modulation. Administration of bacterial lipopolysaccharide (LPS) induces fever, anorexia, and increased non-rapid-eye movement sleep (NREMS) and these actions are mediated primarily by proinflammatory cytokines. Ghrelin reduces LPS-induced fever, suppresses circulating levels of proinflammatory cytokines and reduces the severity and mortality of various models of experimental endotoxemia. In the present study, we determined the role of intact ghrelin signaling in LPS-induced sleep, feeding, and thermoregulatory responses in mice. Sleep-wake activity was determined after intraperitoneal, dark onset administration of 0.4, 2 and 10 μg LPS in preproghrelin knockout (KO) and wild-type (WT) mice. In addition, body temperature, motor activity and changes in 24-h food intake and body weight were measured. LPS induced dose-dependent increases in NREMS, and suppressed rapid-eye movement sleep, electroencephalographic slow-wave activity, motor activity, food intake and body weight in both Ppg KO and WT mice. Body temperature changes showed a biphasic pattern with a decrease during the dark period followed by an increase in the light phase. The effects of the low and middle doses of LPS were indistinguishable between the two genotypes. Administration of 10 μg LPS, however, induced significantly larger changes in NREMS and wakefulness amounts, body temperature, food intake and body weight in the Ppg KO mice. These findings support a role for ghrelin as an endogenous modulator of inflammatory responses and a central component of arousal and feeding circuits.

  14. Sickness behaviour after lipopolysaccharide treatment in ghrelin deficient mice.

    PubMed

    Szentirmai, Éva; Krueger, James M

    2014-02-01

    Ghrelin is an orexigenic hormone produced mainly by the gastrointestinal system and the brain. Much evidence also indicates a role for ghrelin in sleep and thermoregulation. Further, ghrelin was recently implicated in immune system modulation. Administration of bacterial lipopolysaccharide (LPS) induces fever, anorexia, and increased non-rapid-eye movement sleep (NREMS) and these actions are mediated primarily by proinflammatory cytokines. Ghrelin reduces LPS-induced fever, suppresses circulating levels of proinflammatory cytokines and reduces the severity and mortality of various models of experimental endotoxemia. In the present study, we determined the role of intact ghrelin signaling in LPS-induced sleep, feeding, and thermoregulatory responses in mice. Sleep-wake activity was determined after intraperitoneal, dark onset administration of 0.4, 2 and 10 μg LPS in preproghrelin knockout (KO) and wild-type (WT) mice. In addition, body temperature, motor activity and changes in 24-h food intake and body weight were measured. LPS induced dose-dependent increases in NREMS, and suppressed rapid-eye movement sleep, electroencephalographic slow-wave activity, motor activity, food intake and body weight in both Ppg KO and WT mice. Body temperature changes showed a biphasic pattern with a decrease during the dark period followed by an increase in the light phase. The effects of the low and middle doses of LPS were indistinguishable between the two genotypes. Administration of 10 μg LPS, however, induced significantly larger changes in NREMS and wakefulness amounts, body temperature, food intake and body weight in the Ppg KO mice. These findings support a role for ghrelin as an endogenous modulator of inflammatory responses and a central component of arousal and feeding circuits. PMID:24309634

  15. Modified Acyl-ACP desaturase

    DOEpatents

    Cahoon, E.B.; Shanklin, J.; Lindqvist, Y.; Schneider, G.

    1999-03-30

    Disclosed is a method for modifying the chain length and double bond positional specificities of a soluble plant fatty acid desaturase. More specifically, the method involves modifying amino acid contact residues in the substrate binding channel of the soluble fatty acid desaturase which contact the fatty acid. Specifically disclosed is the modification of an acyl-ACP desaturase. Amino acid contact residues which lie within the substrate binding channel are identified, and subsequently replaced with different residues to effect the modification of activity. 2 figs.

  16. Modified acyl-ACP desaturase

    DOEpatents

    Cahoon, E.B.; Shanklin, J.; Lindgvist, Y.; Schneider, G.

    1998-01-06

    Disclosed is a method for modifying the chain length and double bond positional specificities of a soluble plant fatty acid desaturase. More specifically, the method involves modifying amino acid contact residues in the substrate binding channel of the soluble fatty acid desaturase which contact the fatty acid. Specifically disclosed is the modification of an acyl-ACP desaturase. Amino acid contact residues which lie within the substrate binding channel are identified, and subsequently replaced with different residues to effect the modification of activity. 1 fig.

  17. Fatty acyl donor selectivity in membrane bound O-acyltransferases and communal cell fate decision-making

    PubMed Central

    Tuladhar, Rubina; Lum, Lawrence

    2015-01-01

    The post-translational modification of proteins with lipid moieties confers spatial and temporal control of protein function by restricting their subcellular distribution or movement in the extracellular milieu. Yet, little is known about the significance of lipid selectivity to the activity of proteins targeted for such modifications. Membrane bound O-acyl transferases (MBOATs) are a superfamily of multipass enzymes that transfer fatty acids on to lipid or protein substrates. Three MBOATs constitute a subfamily with secreted signalling molecules for substrates, the Wnt, Hedgehog (Hh) and Ghrelin proteins. Given their important roles in adult tissue homoeostasis, all three molecules and their respective associated acyltransferases provide a framework for interrogating the role of extracellular acylation events in cell-to-cell communication. Here, we discuss how the preference for a fatty acyl donor in the Wnt acyltransferase porcupine (Porcn) and possibly in other protein lipidation enzymes may provide a means for coupling metabolic health at the single cell level to communal cell fate decision-making in complex multicellular organisms. PMID:25849923

  18. Lipid Acyl Chain Remodeling in Yeast

    PubMed Central

    Renne, Mike F.; Bao, Xue; De Smet, Cedric H.; de Kroon, Anton I. P. M.

    2015-01-01

    Membrane lipid homeostasis is maintained by de novo synthesis, intracellular transport, remodeling, and degradation of lipid molecules. Glycerophospholipids, the most abundant structural component of eukaryotic membranes, are subject to acyl chain remodeling, which is defined as the post-synthetic process in which one or both acyl chains are exchanged. Here, we review studies addressing acyl chain remodeling of membrane glycerophospholipids in Saccharomyces cerevisiae, a model organism that has been successfully used to investigate lipid synthesis and its regulation. Experimental evidence for the occurrence of phospholipid acyl chain exchange in cardiolipin, phosphatidylcholine, phosphatidylinositol, and phosphatidylethanolamine is summarized, including methods and tools that have been used for detecting remodeling. Progress in the identification of the enzymes involved is reported, and putative functions of acyl chain remodeling in yeast are discussed. PMID:26819558

  19. Photoaffinity Labeling of Developing Jojoba Seed Microsomal Membranes with a Photoreactive Analog of Acyl-Coenzyme A (Acyl-CoA) (Identification of a Putative Acyl-CoA:Fatty Alcohol Acyltransferase.

    PubMed Central

    Shockey, J. M.; Rajasekharan, R.; Kemp, J. D.

    1995-01-01

    Jojoba (Simmondsia chinensis, Link) is the only plant known that synthesizes liquid wax. The final step in liquid wax biosynthesis is catalyzed by an integral membrane enzyme, fatty acyl-coenzyme A (CoA):fatty alcohol acyltransferase, which transfers an acyl chain from acyl-CoA to a fatty alcohol to form the wax ester. To purify the acyltransferase, we have labeled the enzyme with a radioiodinated, photoreactive analog of acyl-CoA, 12-[N-(4-azidosalicyl)amino] dodecanoyl-CoA (ASD-CoA). This molecule acts as an inhibitor of acyltransferase activity in the dark and as an irreversible inhibitor upon exposure to ultraviolet light. Oleoyl-CoA protects enzymatic activity in a concentration-dependent manner. Photolysis of microsomal membranes with labeled ASD-CoA resulted in strong labeling of two polypeptides of 57 and 52 kD. Increasing concentrations of oleoyl-CoA reduced the labeling of the 57-kD polypeptide dramatically, whereas the labeling of the 52-kD polypeptide was much less responsive to oleoyl-CoA. Also, unlike the other polypeptide, the labeling of the 57-kD polypeptide was enhanced considerably when photolyzed in the presence of dodecanol. These results suggest that a 57-kD polypeptide from jojoba microsomes may be the acyl-CoA:fatty alcohol acyltransferase. PMID:12228351

  20. Photoaffinity Labeling of Developing Jojoba Seed Microsomal Membranes with a Photoreactive Analog of Acyl-Coenzyme A (Acyl-CoA) (Identification of a Putative Acyl-CoA:Fatty Alcohol Acyltransferase.

    PubMed

    Shockey, J. M.; Rajasekharan, R.; Kemp, J. D.

    1995-01-01

    Jojoba (Simmondsia chinensis, Link) is the only plant known that synthesizes liquid wax. The final step in liquid wax biosynthesis is catalyzed by an integral membrane enzyme, fatty acyl-coenzyme A (CoA):fatty alcohol acyltransferase, which transfers an acyl chain from acyl-CoA to a fatty alcohol to form the wax ester. To purify the acyltransferase, we have labeled the enzyme with a radioiodinated, photoreactive analog of acyl-CoA, 12-[N-(4-azidosalicyl)amino] dodecanoyl-CoA (ASD-CoA). This molecule acts as an inhibitor of acyltransferase activity in the dark and as an irreversible inhibitor upon exposure to ultraviolet light. Oleoyl-CoA protects enzymatic activity in a concentration-dependent manner. Photolysis of microsomal membranes with labeled ASD-CoA resulted in strong labeling of two polypeptides of 57 and 52 kD. Increasing concentrations of oleoyl-CoA reduced the labeling of the 57-kD polypeptide dramatically, whereas the labeling of the 52-kD polypeptide was much less responsive to oleoyl-CoA. Also, unlike the other polypeptide, the labeling of the 57-kD polypeptide was enhanced considerably when photolyzed in the presence of dodecanol. These results suggest that a 57-kD polypeptide from jojoba microsomes may be the acyl-CoA:fatty alcohol acyltransferase.

  1. Stability-increasing effects of anthocyanin glycosyl acylation.

    PubMed

    Zhao, Chang-Ling; Yu, Yu-Qi; Chen, Zhong-Jian; Wen, Guo-Song; Wei, Fu-Gang; Zheng, Quan; Wang, Chong-De; Xiao, Xing-Lei

    2017-01-01

    This review comprehensively summarizes the existing knowledge regarding the chemical implications of anthocyanin glycosyl acylation, the effects of acylation on the stability of acylated anthocyanins and the corresponding mechanisms. Anthocyanin glycosyl acylation commonly refers to the phenomenon in which the hydroxyl groups of anthocyanin glycosyls are esterified by aliphatic or aromatic acids, which is synthetically represented by the acylation sites as well as the types and numbers of acyl groups. Generally, glycosyl acylation increases the in vitro and in vivo chemical stability of acylated anthocyanins, and the mechanisms primarily involve physicochemical, stereochemical, photochemical, biochemical or environmental aspects under specific conditions. Additionally, the acylation sites as well as the types and numbers of acyl groups influence the stability of acylated anthocyanins to different degrees. This review could provide insight into the optimization of the stability of anthocyanins as well as the application of suitable anthocyanins in food, pharmaceutical and cosmetic industries. PMID:27507456

  2. Ghrelin and the brain-gut axis as a pharmacological target for appetite control.

    PubMed

    Seim, Inge; El-Salhy, Magdy; Hausken, Trygve; Gundersen, Doris; Chopin, Lisa

    2012-01-01

    Appetite regulation is highly complex and involves a large number of orexigenic and anorexigenic peptide hormones. These are small, processed, secreted peptides derived from larger prepropeptide precursors. These peptides are important targets for the development of therapeutics for obesity, a global health epidemic. As a case study, we consider the ghrelin axis. The ghrelin axis is likely to be a particularly useful drug target, as it also plays a role in energy homeostasis, adipogenesis, insulin regulation and reward associated with food intake. Ghrelin is the only known circulating gut orexigenic peptide hormone. As it appears to play a role in diet-induced obesity, blocking the action of ghrelin is likely to be effective for treating and preventing obesity. The ghrelin peptide has been targeted using a number of approaches, with ghrelin mirror-image oligonucleotides (Spiegelmers) and immunotherapy showing some promise. The ghrelin receptor, the growth hormone secretagogue receptor, may also provide a useful target and a number of antagonists and inverse agonists have been developed. A particularly promising new target is the enzyme which octanoylates ghrelin, ghrelin O-acyltransferase (GOAT), and drugs that inhibit GOAT are likely to circumvent pharmacological issues associated with approaches that directly target ghrelin or its receptor.

  3. Clinical application of ghrelin administration for gastric cancer patients undergoing gastrectomy.

    PubMed

    Takiguchi, Shuji; Takata, Akihiro; Murakami, Kohei; Miyazaki, Yasuhiro; Yanagimoto, Yoshitomo; Kurokawa, Yukinori; Takahashi, Tsuyoshi; Mori, Masaki; Doki, Yuichiro

    2014-04-01

    Loss of body weight is a common (and the most serious) sequela after gastrectomy. It impairs quality of life, increases various diseases including infection, and may affect long-term survival. Ghrelin, an intrinsic ligand of the growth hormone secretagogue receptor, was discovered in the stomach in 1999. In addition to growth hormone secretion, ghrelin has pleiotropic functions including appetite stimulation, increasing bowel movement and absorption, and anti-inflammatory reactions. In consequence, ghrelin comprehensively leads positive energy balance and weight gain. The fundic gland of the stomach produces the majority of ghrelin, and plasma ghrelin declines to 10-30 % of the preoperative level after total gastrectomy and 50-70 % after distal gastrectomy. Although plasma ghrelin is never restored after total gastrectomy, it gradually recovers to the preoperative level within a few years after distal gastrectomy. Chronic gastritis due to Helicobacter pylori infection and vagotomy are additional factors that perturb the ghrelin secretion of gastric cancer patients after gastrectomy. A randomized clinical trial that revealed that recombinant ghrelin administration successfully increased both food intake and appetite, and ameliorated weight loss after total gastrectomy. Ghrelin administration could thus be a promising strategy to transiently improve the nutritional status of patients who who have undergone gastrectomy, but its effect in the long term remains unclear. Further studies are warranted to elucidate the mechanism of ghrelin and to create and evaluate the analogs that could be administered orally or subcutaneously.

  4. Endocrine Modulation of Olfactory Responsiveness: Effects of the Orexigenic Hormone Ghrelin.

    PubMed

    Loch, Diana; Breer, Heinz; Strotmann, Jörg

    2015-09-01

    Finding food sources is a prerequisite for an acute food intake. This process is initiated by ghrelin released from X/A-like cells of the gastrointestinal tract. Because food finding often depends on olfaction, the question arises whether ghrelin may affect the responsiveness of the olfactory system. Monitoring odor-induced activation of the mouse olfactory epithelium via Egr1 expression revealed that after a nasal application of ghrelin, more sensory neurons responded upon odor exposure indicating an increased responsiveness. The higher reactivity of olfactory neurons was accompanied with an increased activity of receptor-specific glomeruli. In search for mechanisms underlying the ghrelin-mediated sensitization of olfactory neurons, it was shown that Ghsr1a, the ghrelin receptor gene, but not the hormone itself was expressed in the olfactory epithelium. Further analysis of isolated cells revealed that the receptor was in fact expressed in mature olfactory sensory neurons. Treatment with a ghrelin receptor antagonist abolished the ghrelin effect, strengthening the notion that ghrelin and its receptor are responsible for the enhanced neuronal responsiveness. In contrast to the effects of the "hunger" hormone ghrelin, the short-term "satiety" hormone PYY3-36 did not affect olfactory responsiveness. The results demonstrate that ghrelin, which signals acute hunger, renders the olfactory system more responsive to odors.

  5. Ghrelin stimulates angiogenesis in human microvascular endothelial cells: Implications beyond GH release

    SciTech Connect

    Li Aihua; Cheng Guangli; Zhu Genghui; Tarnawski, Andrzej S. . E-mail: atarnawski@yahoo.com

    2007-02-09

    Ghrelin, a peptide hormone isolated from the stomach, releases growth hormone and stimulates appetite. Ghrelin is also expressed in pancreas, kidneys, cardiovascular system and in endothelial cells. The precise role of ghrelin in endothelial cell functions remains unknown. We examined the expression of ghrelin and its receptor (GHSR1) mRNAs and proteins in human microvascular endothelial cells (HMVEC) and determined whether ghrelin affects in these cells proliferation, migration and in vitro angiogenesis; and whether MAPK/ERK2 signaling is important for the latter action. We found that ghrelin and GHSR1 are constitutively expressed in HMVEC. Treatment of HMVEC with exogenous ghrelin significantly increased in these cells proliferation, migration, in vitro angiogenesis and ERK2 phosphorylation. MEK/ERK2 inhibitor, PD 98059 abolished ghrelin-induced in vitro angiogenesis. This is First demonstration that ghrelin and its receptor are expressed in human microvascular endothelial cells and that ghrelin stimulates HMVEC proliferation, migration, and angiogenesis through activation of ERK2 signaling.

  6. Effects of ghrelin on Cx43 regulation and electrical remodeling after myocardial infarction in rats.

    PubMed

    Yuan, Ming-Jie; Huang, He; Tang, Yan-Hong; Wu, Gang; Gu, Yong-Wei; Chen, Yong-Jun; Huang, Cong-Xin

    2011-11-01

    Ghrelin is a novel growth hormone-releasing peptide, which has been shown to exert beneficial effects on ventricular remodeling. In this study, we investigated whether ghrelin could decrease vulnerability to ventricular arrhythmias in rats with myocardial infarction and the possible mechanism. Twenty-four hours after ligation of the anterior descending artery, adult male Sprague-Dawley rats were randomized to ghrelin (100 μg/kg) and saline (control group) for 4 weeks. Sham animals underwent thoracotomy and pericardiotomy, but not LAD ligation. Myocardial endothelin-1 (ET-1) levels were significantly elevated in saline-treated rats at the border zone compared with sham-operated rats. Myocardial connexin43 (Cx43) expression at the border zone was significantly decreased in saline-treated infarcted rats compared with sham-operated rats. Ghrelin significantly decreased the inducibility of ventricular tachyarrhythmias compared with control group. Arrhythmias sores during programmed stimulation in saline-treated rats were significantly higher than scores in those treated with ghrelin. The electrophysiological improvement of fatal ventricular tachyarrhythmias was accompanied with increased immunofluorescence-stained Cx43, myocardial Cx43 protein and mRNA levels in ghrelin treated rats. We also shown that ghrelin significantly decreased tissue ET-1 levels at the infarcted border zone. Thus, ghrelin showed the protective effect on ventricular arrhythmias after myocardial infarction. Although the precise mechanism by which ghrelin modulates the dephosphorylation of Cx43 remains unknown, it is most likely that the ghrelin increased expression of Cx43 through the inhibition of ET-1.

  7. 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

  8. Central but not systemic administration of ghrelin induces wakefulness in mice.

    PubMed

    Szentirmai, Éva

    2012-01-01

    Ghrelin is a brain-gut peptide hormone widely known for its orexigenic and growth hormone-releasing activities. Findings from our and other laboratories indicate a role of ghrelin in sleep regulation. The effects of exogenous ghrelin on sleep-wake activity in mice are, however, unknown. The aim of the present study was to determine the sleep-modulating effects of ghrelin after central and systemic administrations in mice. Sleep-wake activity after intracerebroventricular (i.c.v.) administration of 0.2, 1 and 5 µg ghrelin and intraperitoneal injections of 40, 100, and 400 µg/kg ghrelin prior to light onset were determined in C57BL/6 mice. In addition, body temperature, motor activity and 1-hour food intake was measured after the systemic injections. Sleep effects of systemic ghrelin (40 and 400 µg/kg) injected before dark onset were also determined. I.c.v. injection of ghrelin increased wakefulness and suppressed non-rapid-eye-movement sleep and electroencephalographic slow-wave activity in the first hour after injections. Rapid-eye-movement sleep was decreased for 2-4 hours after each dose of ghrelin. Sytemic administration of ghrelin did not induce changes in sleep-wake activity in mice at dark or light onset. Motor activity and body temperature remained unaltered and food intake was significantly increased after systemic injections of ghrelin given prior the light period. These findings indicate that the activation of central, but not peripheral, ghrelin-sensitive mechanisms elicits arousal in mice. The results are consistent with the hypothesis that the activation of the hypothalamic neuronal circuit formed by ghrelin, orexin, and neuropeptide Y neurons triggers behavioral sequence characterized by increased wakefulness, motor activity and feeding in nocturnal rodents.

  9. Reduced ghrelin production induced anorexia after rat gastric ischemia and reperfusion.

    PubMed

    Mogami, Sachiko; Suzuki, Hidekazu; Fukuhara, Seiichiro; Matsuzaki, Juntaro; Kangawa, Kenji; Hibi, Toshifumi

    2012-02-01

    The gastrointestinal (GI) tract is one of the most susceptible organs to ischemia. We previously reported altered gastric motility after gastric ischemia and reperfusion (I/R). However, there have also been few reports of alterations in the eating behavior after gastric I/R. Ghrelin is a GI peptide that stimulates food intake and GI motility. Although ghrelin itself has been demonstrated to attenuate the mucosal injuries induced by gastric I/R, the endogenous ghrelin dynamics after I/R has not yet been elucidated. The present study was designed to investigate the relationship between food intake and the ghrelin dynamics after gastric I/R. Wistar rats were exposed to 80-min gastric ischemia, followed by 12-h or 48-h reperfusion. The food intake, plasma ghrelin levels, gastric preproghrelin mRNA expression levels, and the histological localization of ghrelin-immunoreactive cells were evaluated. The effect of exogenous ghrelin on the food intake after I/R was also examined. Food intake, the plasma ghrelin levels, the count of ghrelin-immunoreactive cells corrected by the percentage areas of the remaining mucosa, and the expression levels of preproghrelin mRNA in the stomach were significantly reduced at 12 h and 48 h after I/R compared with the levels in the sham-operated rats. Intraperitoneal administration of ghrelin significantly reversed the decrease of food intake after I/R. These data show that gastric I/R evoked anorexia with decreased plasma ghrelin levels and ghrelin production, which appears to be attributable to the I/R-induced gastric mucosal injuries. The decrease in the plasma ghrelin levels may have been responsible for the decreased food intake after gastric I/R. PMID:22114115

  10. Gastrointestinal uptake of nasunin, acylated anthocyanin in eggplant.

    PubMed

    Ichiyanagi, Takashi; Terahara, Norihiko; Rahman, M Mamunur; Konishi, Tetsuya

    2006-07-26

    We previously showed that nasunin, acylated anthocyanins in eggplant peel, comprises two isomers, cis-nasunin and trans-nasunin. In this study, gastrointestinal absorption of cis- and trans-nasunins was studied in rats. Orally administered nasunins were quickly absorbed in their original acylated forms and maximally appeared in blood plasma after 15 min. When the maximum plasma concentration and area under the plasma concentration curve were normalized by orally administered dose (micromoles per kilogram), there was no significant difference in the uptake efficiency between two isomers and both exhibited a plasma level almost identical to that of delphinidin 3-O-beta-D-glucopyranoside. However, metabolites such as 4'-O-methyl analogues and extended glucuronides which were observed for delphinidin 3-O-beta-D-glucopyranoside and cyanidin 3-O-beta-D-glucopyranoside metabolisms were not detected in urine or blood plasma. Moreover, deacylated and glycolytic products of nasunins such as delphinidin 3-O-beta-D-glucopyranoside or delphinidin (aglycone) were also not detected in blood plasma even after oral administration for 8 h. These results indicated that nasunins were absorbed in their original acylated forms and exhibit a bioavailability almost identical to that of nonacylated anthocyanins. PMID:16848510

  11. Acyl-acyl-carrier protein: lysomonogalactosyldiacylglycerol acyltransferase from the cyanobacterium Anabaena variabilis.

    PubMed

    Chen, H H; Wickrema, A; Jaworski, J G

    1988-12-16

    Membranes isolated from the cyanobacterium, Anabaena variabilis, and washed free of soluble endogenous constituents, were capable of catalyzing the direct transfer of the acyl group from acyl-acyl-carrier protein to an endogenous lysomonogalactosyldiacylglycerol to form monogalactosyldiacylglycerol. Other glycolipids including monoglucosyldiacylglycerol and digalactosyldiacylglycerol were not products of this reaction. The transfer was not dependent on any added cofactors. Palmitoyl-, stearoyl- and oleoyl-acyl-carrier protein were approximately equally active as substrates. Transfer was exclusively to the C-1 of the glycerol, as demonstrated by hydrolysis of all incorporated acyl groups by the lipase from Rhizopus arrhizus delamar. In addition to the single galactolipid, a second minor reaction product was free fatty acid, presumably due to hydrolysis of the acyl-acyl-carrier protein. Using a double-labelled [14C]acyl-[14C]acyl-carrier protein, the reaction was demonstrated to be a transfer reaction, rather than a simple exchange of acyl groups with endogenous monogalactosyldiacylglycerol. The transfer reaction mechanism was also confirmed by increasing activity with the addition of liposomes of lysomonogalactosyldiacylglycerol.

  12. Abalation of Ghrelin receptor in leptin-deficient mice has paradoxical effects on glucose homeostasis compared to Ghrelin-abalated Leptin-deficient mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Ghrelin is produced predominantly in stomach and is known to be the endogenous ligand of the growth hormone secretagogue receptor (GHSR). Ghrelin is a GH stimulator and an orexigenic hormone. In contrast, leptin is an anorexic hormone, and leptin-deficient ob/ob mice are obese and diabetic. To study...

  13. Relation of Leptin, Ghrelin and Inflammatory Cytokines with Body Mass Index in Pulmonary Tuberculosis Patients with and without Type 2 Diabetes Mellitus

    PubMed Central

    Zheng, Ying; Ma, Aiguo; Wang, Qiuzhen; Han, Xiuxia; Cai, Jing; Schouten, Evert G.; Kok, Frans J.; Li, Yunchun

    2013-01-01

    Background Pulmonary tuberculosis (TB) patients often suffer from anorexia and poor nutrition, causing weight loss. The peptide hormones leptin and its counterpart ghrelin, acting in the regulation of food intake and fat utilization, play an important role in nutritional balance. This study aimed to investigate the association of blood concentrations of leptin, ghrelin and inflammatory cytokines with body mass index (BMI) in TB patients with and without type 2 diabetes mellitus (T2DM). Methods BMI, biochemical parameters and plasma levels of leptin, ghrelin and inflammatory cytokines were measured before the start of treatment in 27 incident TB patients with T2DM, 21 TB patients and 23 healthy subjects enrolled in this study. Results The levels of leptin were significantly higher in TB patients (35.2±19.1 ng/ml) than TB+T2DM (12.6±6.1 ng/ml) and control (16.1±11.1 ng/ml) groups. The level of ghrelin was significantly lower in TB (119.9±46.1 pg/ml) and non-significantly lower in TB+T2DM (127.7±38.6 pg/ml) groups than control (191.6±86.5 pg/ml) group. The levels of TNF-α were higher, while IFN-γ and IL-6 levels were lower in patients than in the control group. Leptin showed a negative correlation with BMI in TB (r=-0.622, p<0.05) and TB+T2DM (r= -0.654, p<0.05) groups, but a positive correlation with BMI in the control group (r=0.521, p<0.05). Contrary ghrelin showed a positive correlation with BMI in TB (r=0.695, p<0.05) and TB+T2DM (r= 0.199, p>0.05) groups, but negative correlation with BMI in the control (r=-0.693, p<0.05) group. Inflammatory cytokines were poorly correlated with BMI in this study. Only IFN-γ showed a significant negative correlation with BMI in the control group (r=-0.545, p<0.05). Conclusions This study may suggest that possible abnormalities in ghrelin and leptin regulation (high levels of leptin and low levels of ghrelin) may be associated with low BMI and may account for the poor nutrition associated with TB and TB+T2DM. PMID

  14. Effects of sugar-sweetened beverages on plasma acylation stimulating protein, leptin, and adiponectin: Relationships with metabolic outcomes

    Technology Transfer Automated Retrieval System (TEKTRAN)

    OBJECTIVE: The effects of fructose and glucose consumption on plasma acylation stimulating protein (ASP), adiponectin, and leptin concentrations relative to energy intake, body weight, adiposity, circulating triglycerides, and insulin sensitivity were determined. DESIGN AND METHODS: Thirty two over...

  15. 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.

  16. Plasma ghrelin levels in association with left ventricular function and nutritional status in dialysis patients

    PubMed Central

    XU, LIBIN; YU, LEI; CHI, NING; WANG, WENHAO; LIU, GUOPING; SHI, WEI

    2016-01-01

    The present study investigated the association between ghrelin levels and the cardiac function and malnutrition of dialysis patients. The aim was to examine the conducive use of exogenous ghrelin to improve the malnutrition, protect the cardiovascular function with dialysis patients in the future. The study included 30 continuous ambulatory peritoneal dialysis (CAPD) patients and 30 hemodialysis (HD) patients undertaking treatment between March 2013 and March 2014. The control group included a total of 30 healthy physical examinees. The plasma ghrelin levels were measured by the enzyme-linked immunosorbent assay to collect the clinical materials and biochemical parameters. The plasma ghrelin levels were 4.28±1.07, 4.63±1.08 and 2.00±0.48 ng/ml in the CAPD, HD and control groups, respectively, and statistical significance was identified between the three groups; F=75.106, P<0.0001. The plasma ghrelin levels in the CAPD group were positively correlated with left ventricular ejection fraction (LVEF) (r=0.506, P=0.004) and were negatively correlated with body mass index (BMI) (r=−0.556, P=0.001). The plasma ghrelin levels in the CAPD and HD groups were positively correlated with serum creatinine (Scr) and blood urea nitrogen (BUN). In conclusion, the plasma ghrelin levels of patients in the CAPD and HD groups were higher compared to those of the control group, which demonstrated that dialysis patients could not effectively remove the plasma ghrelin. The present study found that the plasma ghrelin levels were positively correlated with LVEF, and high levels of ghrelin will exhibit protective effects on the cardiovascular function of CAPD patients. Plasma ghrelin levels were positively correlated with Scr and BUN levels in CAPD and HD patients, and were negatively correlated with BMI in CAPD patients, which showed that ghrelin was correlated with malnutrition of dialysis patients. PMID:27347404

  17. Expression of ghrelin in human fetal adrenal glands and paraadrenal nerve ganglions.

    PubMed

    Obara-Moszyńska, Monika; Kedzia, Andrzej; Chmielnicka-Kopaczyk, Maria

    2009-01-01

    The aim of this paper was assessment of location, expression and role of ghrelin in the development and maturation of human fetal adrenal glands and paraadrenal nerve ganglions. Immunohistochemistry was used. The strongest expression of ghrelin was detected in the fetal zone of the adrenal glands, in the neuroepithelial cells of the medullar portion of the adrenals and in few nerve ganglion cells. Ghrelin takes part in molecular processes of proliferation and maturation, and does not influence on steroidogenesis.

  18. Diversification and coevolution of the ghrelin/growth hormone secretagogue receptor system in vertebrates.

    PubMed

    Tine, Mbaye; Kuhl, Heiner; Teske, Peter R; Tschöp, Matthias H; Jastroch, Martin

    2016-04-01

    The gut hormone ghrelin is involved in numerous metabolic functions, such as the stimulation of growth hormone secretion, gastric motility, and food intake. Ghrelin is modified by ghrelin O-acyltransferase (GOAT) or membrane-bound O-acyltransferase domain-containing 4 (MBOAT4) enabling action through the growth hormone secretagogue receptors (GHS-R). During the course of evolution, initially strong ligand/receptor specificities can be disrupted by genomic changes, potentially modifying physiological roles of the ligand/receptor system. Here, we investigated the coevolution of ghrelin, GOAT, and GHS-R in vertebrates. We combined similarity search, conserved synteny analyses, phylogenetic reconstructions, and protein structure comparisons to reconstruct the evolutionary history of the ghrelin system. Ghrelin remained a single-gene locus in all vertebrate species, and accordingly, a single GHS-R isoform was identified in all tetrapods. Similar patterns of the nonsynonymous (dN) and synonymous (dS) ratio (dN/dS) in the vertebrate lineage strongly suggest coevolution of the ghrelin and GHS-R genes, supporting specific functional interactions and common physiological pathways. The selection profiles do not allow confirmation as to whether ghrelin binds specifically to GOAT, but the ghrelin dN/dS patterns are more similar to those of GOAT compared to MBOAT1 and MBOAT2 isoforms. Four GHS-R isoforms were identified in teleost genomes. This diversification of GHS-R resulted from successive rounds of duplications, some of which remained specific to the teleost lineage. Coevolution signals are lost in teleosts, presumably due to the diversification of GHS-R but not the ghrelin gene. The identification of the GHS-R diversity in teleosts provides a molecular basis for comparative studies on ghrelin's physiological roles and regulation, while the comparative sequence and structure analyses will assist translational medicine to determine structure-function relationships of the

  19. Regulation of fatty acid elongation and initiation by acyl-acyl carrier protein in Escherichia coli.

    PubMed

    Heath, R J; Rock, C O

    1996-01-26

    Long chain acyl-acyl carrier protein (acyl-ACP) has been implicated as a physiological inhibitor of fatty acid biosynthesis since acyl-ACP degradation by thioesterase overexpression leads to constitutive, unregulated fatty acid production. The biochemical targets for acyl-ACP inhibition were unknown, and this work identified two biosynthetic enzymes that were sensitive to acyl-ACP feedback inhibition. Palmitoyl-ACP inhibited the incorporation of [14C]malonyl-CoA into long chain fatty acids in cell-free extracts of Escherichia coli. A short chain acyl-ACP species with the electrophoretic properties of beta-hydroxybutyryl-ACP accumulated concomitant with the overall decrease in the amount of [14C]malonyl-CoA incorporation, indicating that the first elongation cycle was targeted by acyl-ACP. All of the proteins required to catalyze the first round of fatty acid synthesis from acetyl-CoA plus malonyl-CoA in vitro were isolated, and the first fatty acid elongation cycle was reconstituted with these purified components. Analysis of the individual enzymes and the pattern of intermediate accumulation in the reconstituted system identified initiation of fatty acid synthesis by beta-ketoacyl-ACP synthase III (fabH) and enoyl-ACP reductase (fabI) in the elongation cycle as two steps attenuated by long chain acyl-ACP.

  20. Immunolocalisation of ghrelin and obestatin in human testis, seminal vesicles, prostate and spermatozoa.

    PubMed

    Moretti, E; Vindigni, C; Tripodi, S A; Mazzi, L; Nuti, R; Figura, N; Collodel, G

    2014-01-01

    The role of ghrelin and obestatin in male reproduction has not completely been clarified. We explored ghrelin and obestatin localisation in the male reproductive system. Polyclonal antibodies anti-ghrelin and anti-obestatin were used to detect the expression of these hormones in human testis, prostate and seminal vesicles by immunocytochemistry, while in ejaculated and swim up selected spermatozoa by immunofluorescence. Sertoli cells were positive for both peptides and Leydig cells for ghrelin; germ cells were negative for both hormones. Mild signals for ghrelin and obestatin were observed in rete testis; efferent ductules were the most immune reactive region for both peptides. Epididymis was moderately positive for ghrelin; vas deferens and seminal vesicles showed intense obestatin and moderate ghrelin labelling; prostate tissue expressed obestatin alone. Ejaculated and selected spermatozoa were positive for both peptides in different head and tail regions. This study confirms ghrelin localisation in Leydig and Sertoli cells; the finding that ghrelin is expressed in rete testis, epididymis, vas deferens and seminal vesicles is novel, as well as the localisation of obestatin in almost all tracts of the male reproductive system. This research could offer insights for stimulating other studies, particularly on the role of obestatin in sperm physiology, which is still obscure.

  1. Gender differences in ghrelin response to chronic immobilization stress in rats: possible role of estrogen.

    PubMed

    Elbassuoni, Eman A

    2014-01-01

    Ghrelin is a peptidergic hormone known to be one of the main hormones involved in the regulation of energy balance. Here we evaluated ghrelin response to stress in rats after ovariectomy and during estradiol benzoate (EB) therapy and compared results of males and females, to know whether ghrelin is involved in disordered eating behaviors in response to stress, and for understanding differences between males and females in food intake and weight gain especially during stress. 96 adult rats were classified into; male, female, ovariectomized (Ovx), Ovx with EB. Half animals of each group were exposed to immobilization stress 20 min/day for 21 days. We found that chronic stress significantly augments serum ghrelin levels in both males and females, which is correlated with an increase in food intake and body weight. Females displayed significant higher ghrelin than males especially in response to stress, ovariectomy suppresses serum ghrelin in both unstressed and stressed females which is rescued by replacement with EB. EB replacement augments ghrelin response to stress in Ovx female, and reduces food intake and body weight. In conclusion, there is a clear sex difference in ghrelin secretion in response to stress caused by EB, since it amplifies ghrelin response to stress in females.

  2. Centrally and peripherally administered ghrelin potently inhibits water intake in rats.

    PubMed

    Hashimoto, Hirofumi; Fujihara, Hiroaki; Kawasaki, Makoto; Saito, Takeshi; Shibata, Minori; Otsubo, Hiroki; Takei, Yoshio; Ueta, Yoichi

    2007-04-01

    Ghrelin is known as a potent orexigenic hormone through its action on the brain. In this study, we examined the effects of intracerebroventricular (icv) and iv injection of ghrelin on water intake, food intake, and urine volume in rats deprived of water for 24 h. Water intake that occurred after water deprivation was significantly inhibited by icv injection of ghrelin (0.1, 1, and 10 nmol/rat) in a dose-related manner, although food intake was stimulated by the hormone. The antidipsogenic effect was as potent as the orexigenic effect. Similarly, water intake was inhibited, whereas food intake was stimulated dose dependently after iv injection of ghrelin (0.1, 1, and 10 nmol/kg). The inhibition of drinking was comparable with, or even more potent than, atrial natriuretic peptide (ANP), an established antidipsogenic hormone, when administered icv, although the antidipsogenic effect lasted longer. ANP had no effect on food intake. Urine volume decreased dose relatedly after icv injection of ghrelin but not by ANP. Intravenous injection of ghrelin had no effect on urine volume. Because drinking usually occurs with feeding, food was withdrawn to remove the prandial drinking. Then the antidipsogenic effect of ghrelin became more potent than that of ANP and continued longer than when food was available. Expression of Fos was increased in the area postrema and the nucleus of the tractus solitarius by using immunohistochemistry after icv and iv injection of ghrelin. The present study convincingly showed that ghrelin is a potent antidisogenic peptide in rats.

  3. New insights into the molecular complexity of the ghrelin gene locus.

    PubMed

    Seim, Inge; Herington, Adrian C; Chopin, Lisa K

    2009-08-01

    Ghrelin is a multi-functional peptide hormone that affects a range of processes, including growth hormone and insulin release, appetite regulation, reproduction, and cancer cell proliferation. The main focus of this review is to advance the hypothesis that the ghrelin gene locus encodes an array of biologically active molecules in addition to ghrelin and is far more complex than currently appreciated. Alternative splicing and the use of alternative post-translational cleavages sites may give rise to novel ghrelin gene-derived peptides that potentially act through different receptors and have novel biological functions.

  4. Ghrelin reduces hypertonic saline intake in a variety of natriorexigenic conditions.

    PubMed

    Mietlicki, Elizabeth G; Daniels, Derek

    2011-10-01

    Ghrelin is a gut peptide that has been studied extensively for its role in food intake and energy balance. More recent studies show that ghrelin reduces water intake in rats and some non-mammalian species. Despite the importance of the regulation of NaCl intake in body fluid homeostasis, the effects of ghrelin on saline intake have not been investigated. Accordingly, we tested the effect of ghrelin on water and 1.8% NaCl intake in two-bottle test conditions with the following five stimuli that increase hypertonic saline intake: central angiotensin II administration; 24 h fluid deprivation; water deprivation followed by partial rehydration; dietary sodium deficiency; and polyethylene glycol administration combined with dietary sodium deficiency. We found that ghrelin attenuated saline intake stimulated by angiotensin II, by water deprivation followed by partial rehydration and by dietary sodium deficiency. We did not detect an effect of ghrelin on saline intake after 24 h fluid deprivation without partial rehydration or after the combination of polyethylene glycol and dietary sodium deficiency. The finding that ghrelin reduced hypertonic saline intake in some, but not all, natriorexigenic conditions mirrors the previously published findings that in one-bottle tests of drinking, ghrelin reduces water intake in only some conditions. The results provide evidence for a new role for ghrelin in the regulation of body fluid homeostasis.

  5. Reduction in total plasma ghrelin levels following catecholamine depletion: relation to bulimic and depressive symptoms.

    PubMed

    Homan, Philipp; Grob, Simona; Milos, Gabriella; Schnyder, Ulrich; Hasler, Gregor

    2013-09-01

    There is increasing preclinical and clinical evidence of the important role played by the gastric peptide hormone ghrelin in the pathogenesis of symptoms of depression and eating disorders. To investigate the role of ghrelin and its considered counterpart, peptide tyrosine tyrosine (PYY), in the development of bulimic and depressive symptoms induced by catecholamine depletion, we administered the tyrosine hydroxylase inhibitor alpha-methyl-paratyrosine (AMPT) in a randomized, double-blind, placebo-controlled crossover, single-site experimental trial to 29 healthy controls and 20 subjects with fully recovered bulimia nervosa (rBN). We found a decrease between preprandial and postprandial plasma ghrelin levels (p<0.0001) and a postprandial rise in plasma PYY levels (p<0.0001) in both conditions in the entire study population. Plasma ghrelin levels decreased in the entire study population after treatment with AMPT compared to placebo (p<0.006). AMPT-induced changes in plasma ghrelin levels were negatively correlated with AMPT-induced depressive symptoms (p<0.004). Plasma ghrelin and plasma PYY levels were also negatively correlated (p<0.05). We did not observe a difference in ghrelin or PYY response to catecholamine depletion between rBN subjects and healthy controls, and there was no correlation between plasma ghrelin and PYY levels and bulimic symptoms induced by catecholamine depletion. These findings suggest a relationship between catecholamines and ghrelin with depressive symptoms.

  6. Naphthalene Derivatives Induce Acyl Chain Interdigitation in Dipalmitoylphosphatidylcholine Bilayers.

    PubMed

    Kamal, Md Arif; Raghunathan, V A

    2016-01-14

    The interdigitated phase of the lipid bilayer results when acyl chains from opposing monolayers fully interpenetrate such that the terminal methyl groups of the respective lipid chains are located at the interfacial region on the opposite sides of the bilayer. Usually, chain interdigitation is not encountered in a symmetric chain phosphatidylcholine (PC) membrane but can be induced under certain special conditions. In this article, we elucidate the contribution of small amphiphatic molecules in altering the physical properties of a symmetric chain PC bilayer membrane, which results in acyl chain interdigitation. Using small-angle X-ray scattering (SAXS), we have carried out a systematic investigation of the physical interactions of three naphthalene derivatives containing hydroxyl groups: β-naphthol, 2,3-dihydroxynaphthalene, and 2,7-dihydroxynaphthalene, with dipalmitoylphosphatidylcholine (DPPC) bilayers. On the basis of the diffraction patterns, we have determined the temperature-composition phase diagrams of these binary mixtures. The present study not only enables us to gain insight into the role played by small molecules in altering the packing arrangement of the acyl chains of the constituting PC lipids of the bilayer but also brings to light some important features that have not yet been reported hitherto. One such feature is the stabilization of the enigmatic asymmetric ripple phase over a wide temperature and concentration range. The results presented here strongly point toward a clear correlation between chain interdigitation and the stability of the ripple phase.

  7. Fatty acyl-CoA reductase

    SciTech Connect

    Reiser, Steven E.; Somerville, Chris R.

    1998-12-01

    The present invention relates to bacterial enzymes, in particular to an acyl-CoA reductase and a gene encoding an acyl-CoA reductase, the amino acid and nucleic acid sequences corresponding to the reductase polypeptide and gene, respectively, and to methods of obtaining such enzymes, amino acid sequences and nucleic acid sequences. The invention also relates to the use of such sequences to provide transgenic host cells capable of producing fatty alcohols and fatty aldehydes.

  8. Diurnal secretion of ghrelin, growth hormone, insulin binding proteins, and prolactin in normal weight and overweight subjects with and without the night eating syndrome.

    PubMed

    Birketvedt, Grethe S; Geliebter, Allan; Kristiansen, Ingrid; Firgenschau, Yngve; Goll, Rasmus; Florholmen, Jon R

    2012-12-01

    The regulatory peptide ghrelin has been proposed to help mediate both hunger and sleep. The neuroendocrine circadian patterns in the night eating syndrome (NES) have been distinguished by an attenuated nocturnal rise in the plasma concentrations of melatonin and leptin and a greater increase in the concentrations of cortisol. In this study we wanted to test the hypothesis that night eaters have disturbances in the circadian levels of ghrelin, growth hormone (GH) and associated regulatory peptides. In 12 female night eaters (6 normal weight and 6 overweight), and 25 healthy controls (12 normal weight and 13 overweight), blood was sampled over a 24-hour period. Four meals were served from 8 AM to 8 PM, and blood samples were drawn every second hour for determination of plasma ghrelin concentrations and GH by radioimmunoassay (RIA). Analysis of serum GH, IGF-1, IGFBP-3 and prolactin were performed by ELISA. In healthy normal weight subjects there was a slight but non significant nocturnal increase of ghrelin, whereas a more or less flat curve was observed for healthy overweight, NES normal weight and NES overweight patients. The RMANOVA analysis showed a significant independent lowering effect of overweight on the grand mean of ghrelin. No direct effects on NES normal weight and overweight subjects were found, but a near-significant interaction was found between healthy overweight and overweight NES subjects. There were independent significant lowering effects of overweight and NES on the serum GH levels. During the time course no changes in the serum levels of IGF-1 or IGFB-3 were observed. Independent significant lowering effects of overweight and NES on the levels of IGF-1 were detected, whereas a near significant reduction in the global levels of IGFBP-3 was observed in both NES groups. Finally, significant nocturnal changes were observed for serum levels of prolactin in all four subgroups. Grand mean levels tended to be higher in NES subjects whereas the opposite

  9. Self-structuring foods based on acid-sensitive low and high acyl mixed gellan systems to impact on satiety

    PubMed Central

    Bradbeer, Jennifer F.; Hancocks, Robin; Spyropoulos, Fotios; Norton, Ian T.

    2014-01-01

    This study investigated the in vitro acid-induced gelation of mixed systems of two biopolymers; low acyl and high acyl gellan gum. Rheological and texture analysis showed that these mixed gels displayed textures that lay between the material properties exhibited for the low and high acyl variants. DSC analysis showed that mixtures of the low acyl and high acyl forms exhibit two separate conformational transitions at temperatures coincident with each of the individual biopolymers. Various metabolically relevant pH environments and hydrocolloid concentrations were investigated. These resulted in very different acid gelled structures, which were characterised by texture analysis. The structures of the acid gels were shown to depend upon the pH, hydrocolloid concentration and proportion of each biopolymer used during their production. A selection of these mixed gellan structures were assessed post-production in terms of their response to prolonged exposure to an acidic (pH 1), stomach-like, environment. This resulted in a significant increase in the gel strength, regardless of the biopolymer proportions. The high acyl gellan was less acid-sensitive, and subsequently no evidence of acid gelation was observed with high acyl gellan at a proportion greater than 60% of the total biopolymer. The findings presented here demonstrate that structuring as well as de-structuring of mixed gellan acid gels can be controlled in acidic environments similar to those that are present in the stomach after food consumption. PMID:24882914

  10. Ghrelin, GLP-1, and leptin responses during exposure to moderate hypoxia.

    PubMed

    Morishima, Takuma; Goto, Kazushige

    2016-04-01

    Severe hypoxia has been indicated to cause acute changes in appetite-related hormones, which attenuate perceived appetite. However, the effects of moderate hypoxia on appetite-related hormonal regulation and perceived appetite have not been elucidated. Therefore, we examined the effects of moderate hypoxia on appetite-related hormonal regulation and perceived appetite. Eight healthy males (21.0 ± 0.6 years; 173 ± 2.3 cm; 70.6 ± 5.0 kg; 23.4 ± 1.1 kg/m(2)) completed two experimental trials on separate days: a rest trial in normoxia (FiO2 = 20.9%) and a rest trial in hypoxia (FiO2 = 15.0%). The experimental trials were performed over 7 h in an environmental chamber. Blood samples and scores of subjective appetite were collected over 7 h. Standard meals were provided 1 h (745 kcal) and 4 h (731 kcal) after initiating exposure to hypoxia or normoxia within the chamber. Although each meal significantly reduced plasma active ghrelin concentrations (P < 0.05), the response did not differ significantly between the trials over 7 h. No significant differences in the area under the curves for plasma active ghrelin concentrations over 7 h were observed between the two trials. No significant differences were observed in glucagon-like peptide 1 or leptin concentrations over 7 h between the trials. The subjective feeling of hunger and fullness acutely changed in response to meal ingestions. However, these responses were not affected by exposure to moderate hypoxia. In conclusion, 7 h of exposure to moderate hypoxia did not change appetite-related hormonal responses or perceived appetite in healthy males.

  11. On the central mechanism underlying ghrelin's chronic pro-obesity effects in rats: new insights from studies exploiting a potent ghrelin receptor antagonist.

    PubMed

    Salomé, N; Hansson, C; Taube, M; Gustafsson-Ericson, L; Egecioglu, E; Karlsson-Lindahl, L; Fehrentz, J A; Martinez, J; Perrissoud, D; Dickson, S L

    2009-09-01

    In the present study, we explore the central nervous system mechanism underlying the chronic central effects of ghrelin with respect to increasing body weight and body fat. Specifically, using a recently developed ghrelin receptor antagonist, GHS-R1A (JMV2959), we investigate the role of GHS-R1A in mediating the effects of ghrelin on energy balance and on hypothalamic gene expression. As expected, in adult male rats, chronic central treatment with ghrelin for 14 days, when compared to vehicle-treated control rats, resulted in an increased body weight, lean mass and fat mass (assessed by dual X-ray absorptiometry), dissected white fat pad weight, cumulative food intake, food efficiency, respiratory exchange ratio and a decrease of energy expenditure. Co-administration of the ghrelin receptor antagonist JMV2959 suppressed/blocked the majority of these effects, with the notable exception of ghrelin-induced food intake and food efficiency. The hypothesis emerging from these data, namely that GHS-R1A mediates the chronic effects of ghrelin on fat accumulation, at least partly independent of food intake, is discussed in light of the accompanying data regarding the hypothalamic genes coding for peptides and receptors involved in energy balance regulation, which were found to have altered expression in these studies.

  12. Motilin Stimulates Gastric Acid Secretion in Coordination with Ghrelin in Suncus murinus.

    PubMed

    Goswami, Chayon; Shimada, Yoshiaki; Yoshimura, Makoto; Mondal, Anupom; Oda, Sen-ichi; Tanaka, Toru; Sakai, Takafumi; Sakata, Ichiro

    2015-01-01

    Motilin and ghrelin constitute a peptide family, and these hormones are important for the regulation of gastrointestinal motility. In this study, we examined the effect of motilin and ghrelin on gastric acid secretion in anesthetized suncus (house musk shrew, Suncus murinus), a ghrelin- and motilin-producing mammal. We first established a gastric lumen-perfusion system in the suncus and confirmed that intravenous (i.v.) administration of histamine (1 mg/kg body weight) stimulated acid secretion. Motilin (0.1, 1.0, and 10 μg/kg BW) stimulated the acid output in a dose-dependent manner in suncus, whereas ghrelin (0.1, 1.0, and 10 μg/kg BW) alone did not induce acid output. Furthermore, in comparison with the vehicle administration, the co-administration of low-dose (1 μg/kg BW) motilin and ghrelin significantly stimulated gastric acid secretion, whereas either motilin (1 μg/kg BW) or ghrelin (1 μg/kg BW) alone did not significantly induce gastric acid secretion. This indicates an additive role of ghrelin in motilin-induced gastric acid secretion. We then investigated the pathways of motilin/motilin and ghrelin-stimulated acid secretion using receptor antagonists. Treatment with YM 022 (a CCK-B receptor antagonist) and atropine (a muscarinic acetylcholine receptor antagonist) had no effect on motilin or motilin-ghrelin co-administration-induced acid output. In contrast, famotidine (a histamine H2 receptor antagonist) completely inhibited motilin-stimulated acid secretion and co-administration of motilin and ghrelin induced gastric acid output. This is the first report demonstrating that motilin stimulates gastric secretion in mammals. Our results also suggest that motilin and co-administration of motilin and ghrelin stimulate gastric acid secretion via the histamine-mediated pathway in suncus. PMID:26115342

  13. Cloning of a novel insulin-regulated ghrelin transcript in prostate cancer.

    PubMed

    Seim, Inge; Lubik, Amy A; Lehman, Melanie L; Tomlinson, Nadine; Whiteside, Eliza J; Herington, Adrian C; Nelson, Colleen C; Chopin, Lisa K

    2013-04-01

    Ghrelin is a multifunctional hormone, with roles in stimulating appetite and regulating energy balance, insulin secretion and glucose homoeostasis. The ghrelin gene locus (GHRL) is highly complex and gives rise to a range of novel transcripts derived from alternative first exons and internally spliced exons. The wild-type transcript encodes a 117 amino acid preprohormone that is processed to yield the 28 amino acid peptide ghrelin. Here, we identified insulin-responsive transcription corresponding to cryptic exons in intron 2 of the human ghrelin gene. A transcript, termed in2c-ghrelin (intron 2-cryptic), was cloned from the testis and the LNCaP prostate cancer cell line. This transcript may encode an 83 amino acid preproghrelin isoform that codes for ghrelin, but not obestatin. It is expressed in a limited number of normal tissues and in tumours of the prostate, testis, breast and ovary. Finally, we confirmed that in2c-ghrelin transcript expression, as well as the recently described in1-ghrelin transcript, is significantly upregulated by insulin in cultured prostate cancer cells. Metabolic syndrome and hyperinsulinaemia have been associated with prostate cancer risk and progression. This may be particularly significant after androgen deprivation therapy for prostate cancer, which induces hyperinsulinaemia, and this could contribute to castrate-resistant prostate cancer growth. We have previously demonstrated that ghrelin stimulates prostate cancer cell line proliferation in vitro. This study is the first description of insulin regulation of a ghrelin transcript in cancer and should provide further impetus for studies into the expression, regulation and function of ghrelin gene products.

  14. Motilin Stimulates Gastric Acid Secretion in Coordination with Ghrelin in Suncus murinus

    PubMed Central

    Goswami, Chayon; Shimada, Yoshiaki; Yoshimura, Makoto; Mondal, Anupom; Oda, Sen-ichi; Tanaka, Toru; Sakai, Takafumi; Sakata, Ichiro

    2015-01-01

    Motilin and ghrelin constitute a peptide family, and these hormones are important for the regulation of gastrointestinal motility. In this study, we examined the effect of motilin and ghrelin on gastric acid secretion in anesthetized suncus (house musk shrew, Suncus murinus), a ghrelin- and motilin-producing mammal. We first established a gastric lumen-perfusion system in the suncus and confirmed that intravenous (i.v.) administration of histamine (1 mg/kg body weight) stimulated acid secretion. Motilin (0.1, 1.0, and 10 μg/kg BW) stimulated the acid output in a dose-dependent manner in suncus, whereas ghrelin (0.1, 1.0, and 10 μg/kg BW) alone did not induce acid output. Furthermore, in comparison with the vehicle administration, the co-administration of low-dose (1 μg/kg BW) motilin and ghrelin significantly stimulated gastric acid secretion, whereas either motilin (1 μg/kg BW) or ghrelin (1 μg/kg BW) alone did not significantly induce gastric acid secretion. This indicates an additive role of ghrelin in motilin-induced gastric acid secretion. We then investigated the pathways of motilin/motilin and ghrelin-stimulated acid secretion using receptor antagonists. Treatment with YM 022 (a CCK-B receptor antagonist) and atropine (a muscarinic acetylcholine receptor antagonist) had no effect on motilin or motilin-ghrelin co-administration-induced acid output. In contrast, famotidine (a histamine H2 receptor antagonist) completely inhibited motilin-stimulated acid secretion and co-administration of motilin and ghrelin induced gastric acid output. This is the first report demonstrating that motilin stimulates gastric secretion in mammals. Our results also suggest that motilin and co-administration of motilin and ghrelin stimulate gastric acid secretion via the histamine-mediated pathway in suncus. PMID:26115342

  15. Ghrelin regulates cell cycle-related gene expression in cultured hippocampal neural stem cells.

    PubMed

    Chung, Hyunju; Park, Seungjoon

    2016-08-01

    We have previously demonstrated that ghrelin stimulates the cellular proliferation of cultured adult rat hippocampal neural stem cells (NSCs). However, little is known about the molecular mechanisms by which ghrelin regulates cell cycle progression. The purpose of this study was to investigate the potential effects of ghrelin on cell cycle regulatory molecules in cultured hippocampal NSCs. Ghrelin treatment increased proliferation assessed by CCK-8 proliferation assay. The expression levels of proliferating cell nuclear antigen and cell division control 2, well-known cell-proliferating markers, were also increased by ghrelin. Fluorescence-activated cell sorting analysis revealed that ghrelin promoted progression of cell cycle from G0/G1 to S phase, whereas this progression was attenuated by the pretreatment with specific inhibitors of MEK/extracellular signal-regulated kinase 1/2, phosphoinositide 3-kinase/Akt, mammalian target of rapamycin, and janus kinase 2/signal transducer and activator of transcription 3. Ghrelin-induced proliferative effect was associated with increased expression of E2F1 transcription factor in the nucleus, as determined by Western blotting and immunofluorescence. We also found that ghrelin caused an increase in protein levels of positive regulators of cell cycle, such as cyclin A and cyclin-dependent kinase (CDK) 2. Moreover, p27(KIP1) and p57(KIP2) protein levels were reduced when cell were exposed to ghrelin, suggesting downregulation of CDK inhibitors may contribute to proliferative effect of ghrelin. Our data suggest that ghrelin targets both cell cycle positive and negative regulators to stimulate proliferation of cultured hippocampal NSCs. PMID:27325242

  16. Neuroprotective Actions of Ghrelin and Growth Hormone Secretagogues

    PubMed Central

    Frago, Laura M.; Baquedano, Eva; Argente, Jesús; Chowen, Julie A.

    2011-01-01

    The brain incorporates and coordinates information based on the hormonal environment, receiving information from peripheral tissues through the circulation. Although it was initially thought that hormones only acted on the hypothalamus to perform endocrine functions, it is now known that they in fact exert diverse actions on many different brain regions including the hypothalamus. Ghrelin is a gastric hormone that stimulates growth hormone secretion and food intake to regulate energy homeostasis and body weight by binding to its receptor, growth hormone secretagogues–GH secretagogue-receptor, which is most highly expressed in the pituitary and hypothalamus. In addition, ghrelin has effects on learning and memory, reward and motivation, anxiety, and depression, and could be a potential therapeutic agent in neurodegenerative disorders where excitotoxic neuronal cell death and inflammatory processes are involved. PMID:21994488

  17. Monogalactosyldiacylglycerol biosynthesis by direct acyl transfer in Anabaene variabilis

    SciTech Connect

    Chen, H.H.; Wickrema, A.; Jaworski, J.

    1987-04-01

    The authors previously reported the direct acylation of monogalactosyldiacylglycerol (MGDG) by an enzyme in the membranes of the cyanobacterium Anabaena variabilis. The enzyme requires acyl-acyl carrier protein (acyl-ACP) as substrate, but had no other additional cofactor requirements. Palmitoyl-, stearoyl- and oleoyl-ACP were all effective substrates. The A. variabilis membranes also had a hydrolase activity which metabolized the acyl-ACP to yield free fatty acid and ACP. Possible mechanisms for the acylation reaction include either acyl exchange with existing MGDG or direct acyl transfer to a lyso-MGDG, with concomitant release of free ACP. The mechanism of this reaction has been resolved using a double labelled (/sup 14/C)acyl-(/sup 14/)ACP substrate prepared with E. coli acyl-ACP synthetase. Following incubation with the enzyme, the unreacted (/sup 14/)acyl-(/sup 14/)ACP was isolated and the (/sup 14/)acyl/(/sup 14/)ACP ratio determined. Comparison of this ratio to that of the original substrate indicated no change and eliminated acyl exchange as a possible mechanism. Therefore, the direct acylation of lyso-MGDG is the proposed mechanism for this enzyme.

  18. Influence of season and nutritional status on the direct effects of leptin, orexin-A and ghrelin on luteinizing hormone and growth hormone secretion in the ovine pituitary explant model.

    PubMed

    Kirsz, K; Szczesna, M; Dudek, K; Bartlewski, P M; Zieba, D A

    2014-07-01

    The aim of this study was to examine whether leptin (anorexigenic peptide), orexin-A, and ghrelin (orexigenic peptides) could directly (ie, independently of hypothalamic influences) affect the secretion of luteinizing hormone (LH) and growth hormone (GH) by adenohypophyseal (AP) explants obtained from normally fed or fasted (48 h) ewes during the breeding and nonbreeding seasons. In addition, a specific ovine super leptin antagonist (SLAN-3) was used to assess the interactions between leptin and ghrelin and/or orexin-A. Pituitary glands from 16 ovariectomized Polish Longwool ewes that had received estradiol-releasing subcutaneous implants were collected in the breeding (November; n = 8) and nonbreeding (May; n = 8) seasons. The AP explants were incubated for 240 min in a gas-liquid interface and treated with leptin (50 ng/mL), ghrelin (100 ng/mL), orexin-A (100 ng/mL), and SLAN-3 (500 ng/mL) with orexin-A or ghrelin. Treatments with leptin and SLAN-3 + orexin-A increased (P < 0.05) LH concentrations in the cultures of AP explants from fasted animals in the breeding season. Orexin-A increased (P < 0.05) LH secretion by AP explants from both fasted and fed animals in the breeding season. Ghrelin stimulated (P < 0.05) GH secretion by AP explants collected from fasted animals in nonbreeding season and from normally fed ewes in both seasons. Leptin decreased (P < 0.05) GH secretion by AP explants collected from fasted ewes in both seasons and from nonfasted ewes in the breeding season. However, the treatment with SLAN-3 + ghrelin resulted in greater (P < 0.05) GH concentrations compared with leptin treatment of AP explants from fasted ewes in the breeding season and from normally fed ewes in nonbreeding season. In summary, leptin, orexin-A, and ghrelin exerted direct effects on AP secretory function in an ex situ model and both the reproductive season and nutritional status of the animals impinged on the direct effects of the peptides on LH and GH release

  19. Aberrant protein acylation is a common observation in inborn errors of acyl-CoA metabolism.

    PubMed

    Pougovkina, Olga; Te Brinke, Heleen; Wanders, Ronald J A; Houten, Sander M; de Boer, Vincent C J

    2014-09-01

    Inherited disorders of acyl-CoA metabolism, such as defects in amino acid metabolism and fatty acid oxidation can present with severe clinical symptoms either neonatally or later in life, but the pathophysiological mechanisms are often incompletely understood. We now report the discovery of a novel biochemical mechanism that could contribute to the pathophysiology of these disorders. We identified increased protein lysine butyrylation in short-chain acyl-CoA dehydrogenase (SCAD) deficient mice as a result of the accumulation of butyryl-CoA. Similarly, in SCAD deficient fibroblasts, lysine butyrylation was increased. Furthermore, malonyl-CoA decarboxylase (MCD) deficient patient cells had increased levels of malonylated lysines and propionyl-CoA carboxylase (PCC) deficient patient cells had increased propionylation of lysines. Since lysine acylation can greatly impact protein function, aberrant lysine acylation in inherited disorders associated with acyl-CoA accumulation may well play a role in their disease pathophysiology. PMID:24531926

  20. Microbial Tailoring of Acyl Peptidic Siderophores

    PubMed Central

    2015-01-01

    Marine bacteria produce an abundance of suites of acylated siderophores characterized by a unique, species-dependent headgroup that binds iron(III) and one of a series of fatty acid appendages. Marinobacter sp. DS40M6 produces a suite of seven acylated marinobactins, with fatty acids ranging from saturated and unsaturated C12–C18 fatty acids. In the present study, we report that in the late log phase of growth, the fatty acids are hydrolyzed by an amide hydrolase producing the peptidic marinobactin headgroup. Halomonas aquamarina str. DS40M3, another marine bacterium isolated originally from the same sample of open ocean water as Marinobacter sp. DS40M6, produces the acyl aquachelins, also as a suite composed of a peptidic headgroup distinct from that of the marinobactins. In contrast to the acyl marinobactins, hydrolysis of the suite of acyl aquachelins is not detected, even when H. aquamarina str. DS40M3 is grown into the stationary phase. The Marinobacter cell-free extract containing the acyl amide hydrolase is active toward exogenous acyl-peptidic siderophores (e.g., aquachelin C, loihichelin C, as well as octanoyl homoserine lactone used in quorum sensing). Further, when H. aquamarina str. DS40M3 is cultured together with Marinobacter sp. DS40M6, the fatty acids of both suites of siderophores are hydrolyzed, and the aquachelin headgroup is also produced. The present study demonstrates that coculturing bacteria leads to metabolically tailored metabolites compared to growth in a single pure culture, which is interesting given the importance of siderophore-mediated iron acquisition for bacterial growth and that Marinobacter sp. DS40M6 and H. aquamarina str. DS40M3 were isolated from the same sample of seawater. PMID:24735218

  1. Ghrelin receptor regulates adipose tissue inflammation in aging

    PubMed Central

    Buras, Eric D.; Yu, Kaijiang; Wang, Ruitao; Smith, C. Wayne; Wu, Huaizhu; Sheikh-Hamad, David; Sun, Yuxiang

    2016-01-01

    Aging is commonly associated with low-grade adipose inflammation, which is closely linked to insulin resistance. Ghrelin is the only circulating orexigenic hormone which is known to increase obesity and insulin resistance. We previously reported that the expression of the ghrelin receptor, growth hormone secretagogue receptor (GHS-R), increases in adipose tissues during aging, and old Ghsr−/− mice exhibit a lean and insulin-sensitive phenotype. Macrophages are major mediators of adipose tissue inflammation, which consist of pro-inflammatory M1 and anti-inflammatory M2 subtypes. Here, we show that in aged mice, GHS-R ablation promotes macrophage phenotypical shift toward anti-inflammatory M2. Old Ghsr−/− mice have reduced macrophage infiltration, M1/M2 ratio, and pro-inflammatory cytokine expression in white and brown adipose tissues. We also found that peritoneal macrophages of old Ghsr−/− mice produce higher norepinephrine, which is in line with increased alternatively-activated M2 macrophages. Our data further reveal that GHS-R has cell-autonomous effects in macrophages, and GHS-R antagonist suppresses lipopolysaccharide (LPS)-induced inflammatory responses in macrophages. Collectively, our studies demonstrate that ghrelin signaling has an important role in macrophage polarization and adipose tissue inflammation during aging. GHS-R antagonists may serve as a novel and effective therapeutic option for age-associated adipose tissue inflammation and insulin resistance. PMID:26837433

  2. Therapeutic potential of ghrelin in restricting-type anorexia nervosa.

    PubMed

    Hotta, Mari; Ohwada, Rina; Akamizu, Takashi; Shibasaki, Tamotsu; Kangawa, Kenji

    2012-01-01

    Anorexia nervosa (AN) is an eating disorder characterized by a decrease in caloric intake and malnutrition. It is associated with a variety of medical morbidities as well as significant mortality. Nutritional support is of paramount importance to prevent impaired quality of life later in life in affected patients. Some patients with restricting-type AN who are fully motivated to gain body weight cannot increase their food intake because of malnutrition-induced gastrointestinal dysfunction. Chronicity of AN prevents participation in social activities and leads to increased medical expenses. Therefore, there is a pressing need for effective appetite-stimulating therapies for patients with AN. Ghrelin is the only orexigenic hormone that can be given intravenously. Intravenous infusion of ghrelin is reported to increase food intake and body weight in healthy subjects as well as in patients with poor nutritional status. Here, we introduce the results of a pilot study that investigated the effects of ghrelin on appetite, energy intake, and nutritional parameters in five patients with restricting-type AN, who are fully motivated to gain body weight but could not increase their food intake because of malnutrition-induced gastrointestinal dysfunction.

  3. Ghrelin, Sleep Reduction and Evening Preference: Relationships to CLOCK 3111 T/C SNP and Weight Loss

    PubMed Central

    Garaulet, Marta; Sánchez-Moreno, Carmen; Smith, Caren E.; Lee, Yu-Chi; Nicolás, Francisco; Ordovás, Jose M.

    2011-01-01

    Background Circadian Locomotor Output Cycles Kaput (CLOCK), an essential element of the positive regulatory arm in the human biological clock, is involved in metabolic regulation. The aim was to investigate the behavioral (sleep duration, eating patterns and chronobiological characteristics) and hormonal (plasma ghrelin and leptin concentrations) factors which could explain the previously reported association between the CLOCK 3111T/C SNP and weight loss. Methodology/Principal Findings We recruited 1495 overweight/obese subjects (BMI: 25–40 kg/m2) of 20–65 y. who attended outpatient obesity clinics in Murcia, in southeastern Spain. We detected an association between the CLOCK 3111T/C SNP and weight loss, which was particularly evident after 12–14 weeks of treatment (P = 0.038). Specifically, carriers of the minor C allele were more resistant to weight loss than TT individuals (Mean±SEM) (8.71±0.59 kg vs 10.4±0.57 kg) C and TT respectively. In addition, our data show that minor C allele carriers had: 1. shorter sleep duration Mean ± SEM (7.0±0.05 vs 7.3±0.05) C and TT respectively (P = 0.039), 2. higher plasma ghrelin concentrations Mean ± SEM (pg/ml) (1108±49 vs 976±47)(P = 0.034); 3. delayed breakfast time; 4. evening preference and 5. less compliance with a Mediterranean Diet pattern, as compared with TT homozygotes. Conclusions/Significance Sleep reduction, changes in ghrelin values, alterations of eating behaviors and evening preference that characterized CLOCK 3111C carriers could be affecting weight loss. Our results support the hypothesis that the influence of the CLOCK gene may extend to a broad range of variables linked with human behaviors. PMID:21386998

  4. Impaired wake-promoting mechanisms in ghrelin receptor-deficient mice.

    PubMed

    Esposito, Matthew; Pellinen, Jacob; Kapás, Levente; Szentirmai, Éva

    2012-01-01

    Ghrelin receptors are expressed by key components of the arousal system. Exogenous ghrelin induces behavioral activation, promotes wakefulness and stimulates eating. We hypothesized that ghrelin-sensitive mechanisms play a role in the arousal system. To test this, we investigated the responsiveness of ghrelin receptor knockout (KO) mice to two natural wake-promoting stimuli. Additionally, we assessed the integrity of their homeostatic sleep-promoting system using sleep deprivation. There was no significant difference in the spontaneous sleep-wake activity between ghrelin receptor KO and wild-type (WT) mice. WT mice mounted robust arousal responses to a novel environment and food deprivation. Wakefulness increased for 6 h after cage change accompanied by increases in body temperature and locomotor activity. Ghrelin receptor KO mice completely lacked the wake and body temperature responses to new environment. When subjected to 48 h food deprivation, WT mice showed marked increases in their waking time during the dark periods of both days. Ghrelin receptor KO mice failed to mount an arousal response on the first night and wake increases were attenuated on the second day. The responsiveness to sleep deprivation did not differ between the two genotypes. These results indicate that the ghrelin-receptive mechanisms play an essential role in the function of the arousal system but not in homeostatic sleep-promoting mechanisms.

  5. Ghrelin receptors in human gastrointestinal tract during prenatal and early postnatal development.

    PubMed

    Mitrović, Olivera; Čokić, Vladan; Đikić, Dragoslava; Budeč, Mirela; Vignjević, Sanja; Subotički, Tijana; Diklić, Miloš; Ajtić, Rastko

    2014-07-01

    The aim of our study was to investigate the appearance, density and distribution of ghrelin cells and GHS-R1a and GHS-R1b in the human stomach and duodenum during prenatal and early postnatal development. We examined chromogranin-A and ghrelin cells in duodenum, and GHS-R1a and GHS-R1b expression in stomach and duodenum by immunohistochemistry in embryos, fetuses, and infants. Chromogranin-A and ghrelin cells were identified in the duodenum at weeks 10 and 11 of gestation. Ghrelin cells were detected individually or clustered within the base of duodenal crypts and villi during the first trimester, while they were presented separately within the basal and apical parts of crypts and villi during the second and third trimesters. Ghrelin cells were the most numerous during the first (∼11%) and third (∼10%) trimesters of gestation development. GHS-R1a and GHS-R1b were detected at 11 and 16 weeks of gestation, showed the highest level of expression in Brunner's gland and in lower parts of duodenal crypts and villi during the second trimester in antrum, and during the third trimester in corpus and duodenum. Our findings demonstrated for the first time abundant duodenal expression of ghrelin cells and ghrelin receptors during human prenatal development indicating a role of ghrelin in the regulation of growth and differentiation of human gastrointestinal tract.

  6. The Anti-apoptotic Effect of Ghrelin on Restraint Stress-Induced Thymus Atrophy in Mice.

    PubMed

    Lee, Jun Ho; Kim, Tae-Jin; Kim, Jie Wan; Yoon, Jeong Seon; Kim, Hyuk Soon; Lee, Kyung-Mi

    2016-08-01

    Thymic atrophy is a complication that results from exposure to many environmental stressors, disease treatments, and microbial challenges. Such acute stress-associated thymic loss can have a dramatic impact on the host's ability to replenish the necessary naïve T cell output to reconstitute the peripheral T cell numbers and repertoire to respond to new antigenic challenges. We have previously reported that treatment with the orexigenic hormone ghrelin results in an increase in the number and proliferation of thymocytes after dexamethasone challenge, suggesting a role for ghrelin in restraint stress-induced thymic involution and cell apoptosis and its potential use as a thymostimulatory agent. In an effort to understand how ghrelin suppresses thymic T cell apoptosis, we have examined the various signaling pathways induced by receptor-specific ghrelin stimulation using a restraint stress mouse model. In this model, stress-induced apoptosis in thymocytes was effectively blocked by ghrelin. Western blot analysis demonstrated that ghrelin prevents the cleavage of pro-apoptotic proteins such as Bim, Caspase-3, and PARP. In addition, ghrelin stimulation activates the Akt and Mitogen-activated protein kinases (MAPK) signaling pathways in a time/dose-dependent manner. Moreover, we also revealed the involvement of the FoxO3a pathway in the phosphorylation of Akt and ERK1/2. Together, these findings suggest that ghrelin inhibits apoptosis by modulating the stress-induced apoptotic signal pathway in the restraint-induced thymic apoptosis. PMID:27574503

  7. Chemosensory signalling pathways involved in sensing of amino acids by the ghrelin cell

    PubMed Central

    Vancleef, L.; Van Den Broeck, T.; Thijs, T.; Steensels, S.; Briand, L.; Tack, J.; Depoortere, I.

    2015-01-01

    Taste receptors on enteroendocrine cells sense nutrients and transmit signals that control gut hormone release. This study aimed to investigate the amino acid (AA) sensing mechanisms of the ghrelin cell in a gastric ghrelinoma cell line, tissue segments and mice. Peptone and specific classes of amino acids stimulate ghrelin secretion in the ghrelinoma cell line. Sensing of L-Phe occurs via the CaSR, monosodium glutamate via the TAS1R1-TAS1R3 while L-Ala and peptone act via 2 different amino acid taste receptors: CaSR & TAS1R1-TAS1R3 and CaSR & GPRC6A, respectively. The stimulatory effect of peptone on ghrelin release was mimicked ex vivo in gastric but not in jejunal tissue segments, where peptone inhibited ghrelin release. The latter effect could not be blocked by receptor antagonists for CCK, GLP-1 or somatostatin. In vivo, plasma ghrelin levels were reduced both upon intragastric (peptone or L-Phe) or intravenous (L-Phe) administration, indicating that AA- sensing is not polarized and is due to inhibition of ghrelin release from the stomach or duodenum respectively. In conclusion, functional AA taste receptors regulate AA-induced ghrelin release in vitro. The effects differ between stomach and jejunum but these local nutrient sensing mechanisms are overruled in vivo by indirect mechanisms inhibiting ghrelin release. PMID:26510380

  8. Ghrelin stimulates milk intake by affecting adult type feeding behaviour in postnatal rats.

    PubMed

    Piao, H; Hosoda, H; Kangawa, K; Murata, T; Narita, K; Higuchi, T

    2008-03-01

    The influence of ghrelin on feeding behaviour during infancy is unknown. To determine whether ghrelin influences milk intake in rat pups, newborn rats received a single i.p. injection of either rat ghrelin (100 microg/kg) or rabbit anti-ghrelin immunoglobulin G (100 microg/kg) every 5 days from postpartum day 5 to day 30 (P5-P30). Milk intake was then assessed by body weight gain following a 2-h suckling period. Ghrelin significantly increased weight gain relative to vehicle-injected controls in P20, P25 and P30 pups, but not in younger animals. Similarly, after 8 h of milk restriction, anti-ghrelin injections significantly decreased weight gain in P25 and P30, but not in younger pups. Interestingly, however, ghrelin did increase independent feeding in P10 and P15 pups using a paradigm in which pups consumed milk from a milk-soaked paper towel. We therefore conclude that ghrelin stimulates milk intake at an early postnatal stage, primarily by affecting adult-type feeding behaviour. PMID:18194428

  9. Sex biased expression of ghrelin and GHSR associated with sexual size dimorphism in yellow catfish.

    PubMed

    Zhang, Jin; Ma, Wenge; He, Yan; Wu, Junjie; Dawar, Farman Ullah; Ren, Fan; Zhao, Xiaohan; Mei, Jie

    2016-03-10

    Sexual size dimorphism has been observed in many cultivable fish species including yellow catfish, in which male fish grow much faster than female fish. Ghrelin is a potent stimulator of pituitary growth hormone (GH) release and known to potentially promote food intake and body weight gain. In order to investigate the molecular mechanism of sexual size dimorphism in yellow catfish (Pelteobagrus fulvidraco), ghrelin and its functional receptor, growth hormone secretagogue receptor (GHSR) cDNAs were cloned. Real-time PCR indicated that both ghrelin and GHSR were more highly expressed in hypothalamus and gut of male fish than female. During normal larval development, expression of ghrelin and GHSR genes was significantly higher in males than in females. 17a-Methyltestosterone (MT) treatment enhanced the expression of ghrelin in female larval fish and GHSR in both sexes, whereas the expression of ghrelin in male larval fish increased in the beginning, then decreased as the treatment time prolonged. Furthermore, the expression of ghrelin and GHSR in male juvenile was significantly increased compared with female juvenile, in short and long term fasting periods, suggesting that male fish may have a better appetite than female during fasting. Our results demonstrate that sex difference in the expression of ghrelin and GHSR may be involved in sexual size dimorphism by regulating feeding and GH/IGF signaling in yellow catfish. PMID:26692148

  10. 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. PMID:24808912

  11. Caloric restriction stimulates autophagy in rat cortical neurons through neuropeptide Y and ghrelin receptors activation

    PubMed Central

    Carmo-Silva, Sara; Botelho, Mariana; de Almeida, Luís Pereira; Cavadas, Cláudia

    2016-01-01

    Caloric restriction is an anti-aging intervention known to extend lifespan in several experimental models, at least in part, by stimulating autophagy. Caloric restriction increases neuropeptide Y (NPY) in the hypothalamus and plasma ghrelin, a peripheral gut hormone that acts in hypothalamus to modulate energy homeostasis. NPY and ghrelin have been shown to be neuroprotective in different brain areas and to induce several physiological modifications similar to those induced by caloric restriction. However, the effect of NPY and ghrelin in autophagy in cortical neurons is currently not known. Using a cell culture of rat cortical neurons we investigate the involvement of NPY and ghrelin in caloric restriction-induced autophagy. We observed that a caloric restriction mimetic cell culture medium stimulates autophagy in rat cortical neurons and NPY or ghrelin receptor antagonists blocked this effect. On the other hand, exogenous NPY or ghrelin stimulate autophagy in rat cortical neurons. Moreover, NPY mediates the stimulatory effect of ghrelin on autophagy in rat cortical neurons. Since autophagy impairment occurs in aging and age-related neurodegenerative diseases, NPY and ghrelin synergistic effect on autophagy stimulation may suggest a new strategy to delay aging process. PMID:27441412

  12. [Serum ghrelin, IL-6 and TNF-α levels in patients with chronic obstructive pulmonary disease.].

    PubMed

    Deveci, Yasemin; Deveci, Figen; Ilhan, Nevin; Karaca, Ilgın; Turgut, Teyfik; Muz, Mehmet Hamdi

    2010-01-01

    It is determined that endocrine factors can play role on cachexia in chronic obstructive pulmonary disease (COPD). High levels of ghrelin is reported in cachectic COPD cases but its' relation couldn't shown statistically. In our study, it is aimed to detect serum ghrelin levels in COPD, its' relation with proinflammatory cytokines and whether serum ghrelin is associated with cachexia. Sixty stable COPD patients and 15 healthy volunteers were included in the study. COPD patients were divided into two groups, cachectic and normal weight, according to their body mass index. Spirometric assessments were performed and serum tumor necrosis factor-alpha (TNF-a), interleukin-6 (IL-6) and ghrelin levels were measured in all cases. When COPD patients were compared with control group; serum ghrelin levels were statistically lower, TNF-a and IL-6 levels were statistically higher in COPD group. For cachectic COPD patients; serum ghrelin levels were statistically lower and IL-6 levels were statistically higher, compared with normal weight COPD patients. Although, serum TNF-a levels were higher for cachectic COPD patients; these levels were not significant. Positive correlation between serum ghrelin levels and body mass index was detected in patients with COPD. As a result; it is thought that increased proinflammatory cytokines and decreased serum active ghrelin levels may contribute to the development of weight loss.

  13. The suppression of ghrelin signaling mitigates age-associated thermogenic impairment

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Aging is associated with severe thermogenic impairment, which contributes to obesity and diabetes in aging. We previously reported that ablation of the ghrelin receptor, growth hormone secretagogue receptor (GHS-R), attenuates age-associated obesity and insulin resistance. Ghrelin and obestatin are ...

  14. Ghrelin and leptin interplay in prevention of testicular damage due to cryptochidism

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Ghrelin, the endogenous ligand to the growth hormone secretagogue receptor (ghsr), is centrally implicated in body weight homeostasis. A novel murine model for ghrelin and its physiologic antagonist, leptin, was developed at this institution. Mice with a deletion of ghsr (ghsr -/-) or a targeted dis...

  15. Sea bass ghrelin: molecular cloning and mRNA quantification during fasting and refeeding.

    PubMed

    Terova, Genciana; Rimoldi, Simona; Bernardini, Giovanni; Gornati, Rosalba; Saroglia, Marco

    2008-01-15

    Ghrelin is a novel appetite-inducing peptide hormone secreted by the stomach. The purpose of this study was first to identify the cDNA encoding sequence for ghrelin in sea bass (Dicentrarchus labrax). Using molecular cloning techniques we sequenced the cDNA corresponding to sea bass ghrelin mRNA. A total of 798 bases including a 5'-untranslated region (89 bp), an open reading frame (ORF) (324 bp), and a 3'-untranslated region (385 bp) were detected. Nucleotide sequence (ORF) encoded a 108 amino acid prepropeptide that demonstrated complete conservation of the N-terminal "biological active core" (GSSF) of the predicted mature ghrelin peptide. We also analyzed fasting-induced changes in the expression of ghrelin mRNA, using a one-tube two-temperature real-time RT-PCR with which the gene expression can be absolutely quantified using the standard curve method. Our results revealed that ghrelin was highly expressed in the stomach with much lower levels of expression in the proximal intestine and brain. Levels of ghrelin mRNA in the stomach were upregulated under conditions of negative energy balance, such as starvation, and downregulated during positive energy balance, such as refeeding. These findings offer new information about the sea bass ghrelin gene and support a role of this orexigenic hormone in the regulation of food intake in sea bass.

  16. Chemosensory signalling pathways involved in sensing of amino acids by the ghrelin cell.

    PubMed

    Vancleef, L; Van Den Broeck, T; Thijs, T; Steensels, S; Briand, L; Tack, J; Depoortere, I

    2015-01-01

    Taste receptors on enteroendocrine cells sense nutrients and transmit signals that control gut hormone release. This study aimed to investigate the amino acid (AA) sensing mechanisms of the ghrelin cell in a gastric ghrelinoma cell line, tissue segments and mice. Peptone and specific classes of amino acids stimulate ghrelin secretion in the ghrelinoma cell line. Sensing of L-Phe occurs via the CaSR, monosodium glutamate via the TAS1R1-TAS1R3 while L-Ala and peptone act via 2 different amino acid taste receptors: CaSR &TAS1R1-TAS1R3 and CaSR &GPRC6A, respectively. The stimulatory effect of peptone on ghrelin release was mimicked ex vivo in gastric but not in jejunal tissue segments, where peptone inhibited ghrelin release. The latter effect could not be blocked by receptor antagonists for CCK, GLP-1 or somatostatin. In vivo, plasma ghrelin levels were reduced both upon intragastric (peptone or L-Phe) or intravenous (L-Phe) administration, indicating that AA- sensing is not polarized and is due to inhibition of ghrelin release from the stomach or duodenum respectively. In conclusion, functional AA taste receptors regulate AA-induced ghrelin release in vitro. The effects differ between stomach and jejunum but these local nutrient sensing mechanisms are overruled in vivo by indirect mechanisms inhibiting ghrelin release. PMID:26510380

  17. The effect of ingested macronutrients on postprandial ghrelin response: a critical review of existing literature data.

    PubMed

    Koliaki, Chrysi; Kokkinos, Alexander; Tentolouris, Nicholas; Katsilambros, Nicholas

    2010-01-01

    Ghrelin is a powerful orexigenic gut hormone with growth hormone releasing activity. It plays a pivotal role for long-term energy balance and short-term food intake. It is also recognized as a potent signal for meal initiation. Ghrelin levels rise sharply before feeding onset, and are strongly suppressed by food ingestion. Postprandial ghrelin response is totally macronutrient specific in normal weight subjects, but is rather independent of macronutrient composition in obese. In rodents and lean individuals, isoenergetic meals of different macronutrient content suppress ghrelin to a variable extent. Carbohydrate appears to be the most effective macronutrient for ghrelin suppression, because of its rapid absorption and insulin-secreting effect. Protein induces prolonged ghrelin suppression and is considered to be the most satiating macronutrient. Fat, on the other hand, exhibits rather weak and insufficient ghrelin-suppressing capacity. The principal mediators involved in meal-induced ghrelin regulation are glucose, insulin, gastrointestinal hormones released in the postabsorptive phase, vagal activity, gastric emptying rate, and postprandial alterations in intestinal osmolarity. PMID:20798765

  18. The Anti-apoptotic Effect of Ghrelin on Restraint Stress-Induced Thymus Atrophy in Mice

    PubMed Central

    Kim, Tae-Jin; Kim, Jie Wan; Yoon, Jeong Seon; Kim, Hyuk Soon

    2016-01-01

    Thymic atrophy is a complication that results from exposure to many environmental stressors, disease treatments, and microbial challenges. Such acute stress-associated thymic loss can have a dramatic impact on the host's ability to replenish the necessary naïve T cell output to reconstitute the peripheral T cell numbers and repertoire to respond to new antigenic challenges. We have previously reported that treatment with the orexigenic hormone ghrelin results in an increase in the number and proliferation of thymocytes after dexamethasone challenge, suggesting a role for ghrelin in restraint stress-induced thymic involution and cell apoptosis and its potential use as a thymostimulatory agent. In an effort to understand how ghrelin suppresses thymic T cell apoptosis, we have examined the various signaling pathways induced by receptor-specific ghrelin stimulation using a restraint stress mouse model. In this model, stress-induced apoptosis in thymocytes was effectively blocked by ghrelin. Western blot analysis demonstrated that ghrelin prevents the cleavage of pro-apoptotic proteins such as Bim, Caspase-3, and PARP. In addition, ghrelin stimulation activates the Akt and Mitogen-activated protein kinases (MAPK) signaling pathways in a time/dose-dependent manner. Moreover, we also revealed the involvement of the FoxO3a pathway in the phosphorylation of Akt and ERK1/2. Together, these findings suggest that ghrelin inhibits apoptosis by modulating the stress-induced apoptotic signal pathway in the restraint-induced thymic apoptosis. PMID:27574503

  19. Ligand binding to the ACBD6 protein regulates the acyl-CoA transferase reactions in membranes[S

    PubMed Central

    Soupene, Eric; Kuypers, Frans A.

    2015-01-01

    The binding determinants of the human acyl-CoA binding domain-containing protein (ACBD) 6 and its function in lipid renewal of membranes were investigated. ACBD6 binds acyl-CoAs of a chain length of 6 to 20 carbons. The stoichiometry of the association could not be fitted to a 1-to-1 model. Saturation of ACBD6 by C16:0-CoA required higher concentration than less abundant acyl-CoAs. In contrast to ACBD1 and ACBD3, ligand binding did not result in the dimerization of ACBD6. The presence of fatty acids affected the binding of C18:1-CoA to ACBD6, dependent on the length, the degree of unsaturation, and the stereoisomeric conformation of their aliphatic chain. ACBD1 and ACBD6 negatively affected the formation of phosphatidylcholine (PC) and phosphatidylethanolamine in the red blood cell membrane. The acylation rate of lysophosphatidylcholine into PC catalyzed by the red cell lysophosphatidylcholine-acyltransferase 1 protein was limited by the transfer of the acyl-CoA substrate from ACBD6 to the acyltransferase enzyme. These findings provide evidence that the binding properties of ACBD6 are adapted to prevent its constant saturation by the very abundant C16:0-CoA and protect membrane systems from the detergent nature of free acyl-CoAs by controlling their release to acyl-CoA-utilizing enzymes. PMID:26290611

  20. The relationship between active ghrelin levels and human obesity involves alterations in resting energy expenditure.

    PubMed

    Marzullo, Paolo; Verti, Barbara; Savia, Giulio; Walker, Gillian E; Guzzaloni, Gabriele; Tagliaferri, Mariantonella; Di Blasio, Annamaria; Liuzzi, Antonio

    2004-02-01

    Ghrelin is a gastric hormone that exerts a stimulatory effect on appetite and fat accumulation. Ser(3) octanoylation is regarded as a prerequisite for ghrelin biological activity, although des-octanoylated forms may retain biological functions in vitro. Circulating ghrelin levels are usually low in obesity and in states of positive energy balance. Hence, the aim of our study was to analyze plasma active and serum total ghrelin levels in 20 obese (ages, 22-42 yr; body mass index, 41.3 +/- 1.1 kg/m(2)) and 20 lean subjects (ages, 22-43 yr; body mass index, 22.4 +/- 0.6 kg/m(2)) as well as their relationship to measures of glucose homeostasis, body fat, and resting energy expenditure (REE). The measured/predicted REE percentage ratio was calculated to subdivide groups into those with positive (> or = 100% ) and negative (<100%) ratio values. In obese patients, plasma active (180 +/- 18 vs. 411 +/- 57 pg/ml; P < 0.001) and serum total ghrelin levels (3650 +/- 408 vs. 5263 +/- 643 pg/ml; P < 0.05) were significantly lower when compared with lean subjects. Hence, ghrelin activity, defined as the proportion of active over total ghrelin levels, was similarly reduced in the obese state (6.1 +/- 0.9% vs. 8.4 +/- 1%; P < 0.05). There was a significant correlation between active and total ghrelin (r = 0.62; P < 0.001), and between total ghrelin and insulin (r = -0.53; P < 0.001) or insulin resistance using the homeostatis model of assessment-insulin resistance (r = -0.49; P < 0.001) approach. Significantly higher active ghrelin levels (214 +/- 22 vs. 159 +/- 30 pg/ml; P < 0.05) and ghrelin activity (8 +/- 1.7% vs. 4.9 +/- 0.9%; P < 0.05) were observed in patients with positive compared with negative measured/predicted REE ratio values. Our study shows that obesity is associated with an impairment of the entire ghrelin system. The observation that ghrelin is further decreased in cases of abnormal energy profit adds new evidence to the relationship between ghrelin activity and

  1. Chromatographic investigation on acyl migration in betacyanins and their decarboxylated derivatives.

    PubMed

    Wybraniec, Sławomir

    2008-01-01

    Chemopreventive and antioxidant action of betalain pigments can differ in dependence on their stereoselective properties, therefore, it is necessary to use relevant methods for monitoring of their possible stereoisomers. Chromatographic characterisation of a group of new isomers of various 6'-O-acylated betacyanins and decarboxylated betacyanins which were generated at low concentration by intramolecular pH-dependent acyl migration was studied in aqueous solutions by HPLC separation with diode-array and mass spectrometric detection. Under alkaline conditions (pH 10.5) the rate of migration was dramatically accelerated, however, always favouring the 6'-O-position and it was much less prominent at lower pH (under 7.0). The possible products of the partial rearrangement were tentatively identified as the 3'-O- and 4'-O-acylated forms and their relative retention times were provided. In malonylated betacyanins and 17-decarboxy-betacyanins the 4'-O-forms were characterised in RP-HPLC by higher retention than the 6'-O forms, whereas the 3'-O-forms were always the most polar. In contrast, the isomerisation of hylocerenin and 17-decarboxy-hylocerenin resulted in different chromatographic profiles of the migration products. In 2-decarboxy- and 2,17-bidecarboxy-betacyanins the 3'-O- and 4'-O-acylated forms eluted always before the 6'-O-acylated betacyanins. The investigations on acyl migration in isolated 4'-O-malonyl-betanin confirmed the strong tendency of reverse acyl migration (4'-->6') and also partial 4'-->3' rearrangement which were leading to the final monoester regioisomeric distribution (%) close to 87:7:6 (6'-O-, 4'-O-, 3'-O-).

  2. Comparative analysis reveals loss of the appetite-regulating peptide hormone ghrelin in falcons.

    PubMed

    Seim, Inge; Jeffery, Penny L; Herington, Adrian C; Chopin, Lisa K

    2015-05-15

    Ghrelin and leptin are key peripherally secreted appetite-regulating hormones in vertebrates. Here we consider the ghrelin gene (GHRL) of birds (class Aves), where it has been reported that ghrelin inhibits rather than augments feeding. Thirty-one bird species were compared, revealing that most species harbour a functional copy of GHRL and the coding region for its derived peptides ghrelin and obestatin. We provide evidence for loss of GHRL in saker and peregrine falcons, and this is likely to result from the insertion of an ERVK retrotransposon in intron 0. We hypothesise that the loss of anorexigenic ghrelin is a predatory adaptation that results in increased food-seeking behaviour and feeding in falcons.

  3. Activation of c-fos expression in the rat inferior olivary nucleus by ghrelin.

    PubMed

    Zhang, Weizhen; Lin, Theodore R; Hu, Yuexian; Fan, Yongyi; Zhao, Lili; Mulholland, Michael W

    2003-12-26

    Ghrelin, a novel 28-amino-acid hormone secreted by gastric oxyntic glands, stimulates food intake and induces adiposity. We examined whether ghrelin activates the inferior olivary nucleus. Systemic administration of ghrelin (37 nmol/kg) induced the expression of c-fos immunoreactivity in inferior olive neurons (n=6 rats). The number of neurons containing c-fos staining was significantly increased in the ghrelin-treated rats (65+/-14 vs.11+/-6 positive neurons, n=5). No significant difference in c-fos-positive neurons was observed between left (32+/-5) and right (33+/-6) inferior olivary nuclei. The number of c-fos-positive neurons in rats with bilateral vagotomy was not significantly different from those with intact vagal nerves. The present study demonstrates that ghrelin induces c-fos expression in inferior olivary nucleus via a central mechanism.

  4. Tissue distribution and developmental changes of ghrelin and GOAT expression in broiler chickens during embryogenesis.

    PubMed

    Ma, Jinyou; Yu, Yan; Xue, Jiajia; Ou, Changbo; Mo, Haizhen; Liu, Xingyou

    2015-03-01

    Ghrelin plays important roles, such as regulating growth hormone release and energy metabolism, but little is known about its developmental changes in the proventriculi of chicken embryos. This study was designed to elucidate the distributions and developmental changes of ghrelin and ghrelin-O-acyltransferase (GOAT) expression in broiler embryos using qRT-PCR and immunohistochemistry. Our results demonstrated the following: (1) on E18, ghrelin and GOAT are ubiquitously expressed in every tissue examined. The expression level of ghrelin mRNA was the highest in the proventriculus, reaching a level that was 50-fold higher than that in the hypothalamus, while GOAT mRNA expression was low in the proventriculus and it was only 67.6% as high as that of hypothalamus; (2) ghrelin and GOAT mRNA expression were detected in the proventriculus on E9, but only at 1.9% and 1.7% of the level expressed on E18, respectively, and their expression levels increased rapidly from E18 to E21. There was similar developmental pattern in the ghrelin and GOAT mRNA expression; and (3) ghrelin-immunopositive cells were first detected in the proventriculus on E15, were located only in the compound tubular glands of the proventriculus, and were of the closed-cell type. The density of ghrelin-immunopositive cells increased significantly from E15 to E21. These results suggest that ghrelin may be an important regulating factor that plays a vital role during the development of chicken embryos. PMID:25449181

  5. 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. PMID:27298204

  6. Seven transmembrane G protein-coupled receptor repertoire of gastric ghrelin cells★

    PubMed Central

    Engelstoft, Maja S.; Park, Won-mee; Sakata, Ichiro; Kristensen, Line V.; Husted, Anna Sofie; Osborne-Lawrence, Sherri; Piper, Paul K.; Walker, Angela K.; Pedersen, Maria H.; Nøhr, Mark K.; Pan, Jie; Sinz, Christopher J.; Carrington, Paul E.; Akiyama, Taro E.; Jones, Robert M.; Tang, Cong; Ahmed, Kashan; Offermanns, Stefan; Egerod, Kristoffer L.; Zigman, Jeffrey M.; Schwartz, Thue W.

    2013-01-01

    The molecular mechanisms regulating secretion of the orexigenic-glucoregulatory hormone ghrelin remain unclear. Based on qPCR analysis of FACS-purified gastric ghrelin cells, highly expressed and enriched 7TM receptors were comprehensively identified and functionally characterized using in vitro, ex vivo and in vivo methods. Five Gαs-coupled receptors efficiently stimulated ghrelin secretion: as expected the β1-adrenergic, the GIP and the secretin receptors but surprisingly also the composite receptor for the sensory neuropeptide CGRP and the melanocortin 4 receptor. A number of Gαi/o-coupled receptors inhibited ghrelin secretion including somatostatin receptors SSTR1, SSTR2 and SSTR3 and unexpectedly the highly enriched lactate receptor, GPR81. Three other metabolite receptors known to be both Gαi/o- and Gαq/11-coupled all inhibited ghrelin secretion through a pertussis toxin-sensitive Gαi/o pathway: FFAR2 (short chain fatty acid receptor; GPR43), FFAR4 (long chain fatty acid receptor; GPR120) and CasR (calcium sensing receptor). In addition to the common Gα subunits three non-common Gαi/o subunits were highly enriched in ghrelin cells: GαoA, GαoB and Gαz. Inhibition of Gαi/o signaling via ghrelin cell-selective pertussis toxin expression markedly enhanced circulating ghrelin. These 7TM receptors and associated Gα subunits constitute a major part of the molecular machinery directly mediating neuronal and endocrine stimulation versus metabolite and somatostatin inhibition of ghrelin secretion including a series of novel receptor targets not previously identified on the ghrelin cell. PMID:24327954

  7. Seven transmembrane G protein-coupled receptor repertoire of gastric ghrelin cells.

    PubMed

    Engelstoft, Maja S; Park, Won-Mee; Sakata, Ichiro; Kristensen, Line V; Husted, Anna Sofie; Osborne-Lawrence, Sherri; Piper, Paul K; Walker, Angela K; Pedersen, Maria H; Nøhr, Mark K; Pan, Jie; Sinz, Christopher J; Carrington, Paul E; Akiyama, Taro E; Jones, Robert M; Tang, Cong; Ahmed, Kashan; Offermanns, Stefan; Egerod, Kristoffer L; Zigman, Jeffrey M; Schwartz, Thue W

    2013-01-01

    The molecular mechanisms regulating secretion of the orexigenic-glucoregulatory hormone ghrelin remain unclear. Based on qPCR analysis of FACS-purified gastric ghrelin cells, highly expressed and enriched 7TM receptors were comprehensively identified and functionally characterized using in vitro, ex vivo and in vivo methods. Five Gαs-coupled receptors efficiently stimulated ghrelin secretion: as expected the β1-adrenergic, the GIP and the secretin receptors but surprisingly also the composite receptor for the sensory neuropeptide CGRP and the melanocortin 4 receptor. A number of Gαi/o-coupled receptors inhibited ghrelin secretion including somatostatin receptors SSTR1, SSTR2 and SSTR3 and unexpectedly the highly enriched lactate receptor, GPR81. Three other metabolite receptors known to be both Gαi/o- and Gαq/11-coupled all inhibited ghrelin secretion through a pertussis toxin-sensitive Gαi/o pathway: FFAR2 (short chain fatty acid receptor; GPR43), FFAR4 (long chain fatty acid receptor; GPR120) and CasR (calcium sensing receptor). In addition to the common Gα subunits three non-common Gαi/o subunits were highly enriched in ghrelin cells: GαoA, GαoB and Gαz. Inhibition of Gαi/o signaling via ghrelin cell-selective pertussis toxin expression markedly enhanced circulating ghrelin. These 7TM receptors and associated Gα subunits constitute a major part of the molecular machinery directly mediating neuronal and endocrine stimulation versus metabolite and somatostatin inhibition of ghrelin secretion including a series of novel receptor targets not previously identified on the ghrelin cell.

  8. 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.

  9. Ghrelin-Derived Peptides: A Link between Appetite/Reward, GH Axis, and Psychiatric Disorders?

    PubMed Central

    Labarthe, Alexandra; Fiquet, Oriane; Hassouna, Rim; Zizzari, Philippe; Lanfumey, Laurence; Ramoz, Nicolas; Grouselle, Dominique; Epelbaum, Jacques; Tolle, Virginie

    2014-01-01

    Psychiatric disorders are often associated with metabolic and hormonal alterations, including obesity, diabetes, metabolic syndrome as well as modifications in several biological rhythms including appetite, stress, sleep–wake cycles, and secretion of their corresponding endocrine regulators. Among the gastrointestinal hormones that regulate appetite and adapt the metabolism in response to nutritional, hedonic, and emotional dysfunctions, at the interface between endocrine, metabolic, and psychiatric disorders, ghrelin plays a unique role as the only one increasing appetite. The secretion of ghrelin is altered in several psychiatric disorders (anorexia, schizophrenia) as well as in metabolic disorders (obesity) and in animal models in response to emotional triggers (psychological stress …) but the relationship between these modifications and the physiopathology of psychiatric disorders remains unclear. Recently, a large literature showed that this key metabolic/endocrine regulator is involved in stress and reward-oriented behaviors and regulates anxiety and mood. In addition, preproghrelin is a complex prohormone but the roles of the other ghrelin-derived peptides, thought to act as functional ghrelin antagonists, are largely unknown. Altered ghrelin secretion and/or signaling in psychiatric diseases are thought to participate in altered appetite, hedonic response and reward. Whether this can contribute to the mechanism responsible for the development of the disease or can help to minimize some symptoms associated with these psychiatric disorders is discussed in the present review. We will thus describe (1) the biological actions of ghrelin and ghrelin-derived peptides on food and drugs reward, anxiety and depression, and the physiological consequences of ghrelin invalidation on these parameters, (2) how ghrelin and ghrelin-derived peptides are regulated in animal models of psychiatric diseases and in human psychiatric disorders in relation with the GH axis

  10. Ghrelin-Derived Peptides: A Link between Appetite/Reward, GH Axis, and Psychiatric Disorders?

    PubMed

    Labarthe, Alexandra; Fiquet, Oriane; Hassouna, Rim; Zizzari, Philippe; Lanfumey, Laurence; Ramoz, Nicolas; Grouselle, Dominique; Epelbaum, Jacques; Tolle, Virginie

    2014-01-01

    Psychiatric disorders are often associated with metabolic and hormonal alterations, including obesity, diabetes, metabolic syndrome as well as modifications in several biological rhythms including appetite, stress, sleep-wake cycles, and secretion of their corresponding endocrine regulators. Among the gastrointestinal hormones that regulate appetite and adapt the metabolism in response to nutritional, hedonic, and emotional dysfunctions, at the interface between endocrine, metabolic, and psychiatric disorders, ghrelin plays a unique role as the only one increasing appetite. The secretion of ghrelin is altered in several psychiatric disorders (anorexia, schizophrenia) as well as in metabolic disorders (obesity) and in animal models in response to emotional triggers (psychological stress …) but the relationship between these modifications and the physiopathology of psychiatric disorders remains unclear. Recently, a large literature showed that this key metabolic/endocrine regulator is involved in stress and reward-oriented behaviors and regulates anxiety and mood. In addition, preproghrelin is a complex prohormone but the roles of the other ghrelin-derived peptides, thought to act as functional ghrelin antagonists, are largely unknown. Altered ghrelin secretion and/or signaling in psychiatric diseases are thought to participate in altered appetite, hedonic response and reward. Whether this can contribute to the mechanism responsible for the development of the disease or can help to minimize some symptoms associated with these psychiatric disorders is discussed in the present review. We will thus describe (1) the biological actions of ghrelin and ghrelin-derived peptides on food and drugs reward, anxiety and depression, and the physiological consequences of ghrelin invalidation on these parameters, (2) how ghrelin and ghrelin-derived peptides are regulated in animal models of psychiatric diseases and in human psychiatric disorders in relation with the GH axis.

  11. 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

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

    PubMed

    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. Nesfatin-1 suppresses energy intake, co-localises ghrelin in the brain and gut, and alters ghrelin, cholecystokinin and orexin mRNA expression in goldfish.

    PubMed

    Kerbel, B; Unniappan, S

    2012-02-01

    Nesfatin-1 is a novel anorectic peptide encoded in the precursor protein nucleobindin-2 (NUCB2). We recently reported the presence and appetite suppressing effects of nesfatin-1 in goldfish. Nesfatin-1 has been co-localised with ghrelin in the stomach of rats. Whether nesfatin-1 influences other appetite regulatory peptides in goldfish remains unclear. The main objectives of the present study were to investigate whether nesfatin-1 co-localises ghrelin in goldfish, and to test whether exogenous nesfatin-1 influences endogenous ghrelin, cholecystokinin (CCK) and orexin A (OXA). We found co-localisation of nesfatin-1-like and ghrelin-like immunoreactivity in the enteroendocrine cells of the goldfish anterior intestine (J-loop). Furthermore, co-localisation of ghrelin and nesfatin-1 was also observed in the posterior nucleus lateralis tuberis of the goldfish hypothalamus, a brain region implicated in the regulation of food intake. These findings suggest a functional relationship between ghrelin and nesfatin-1 in goldfish. In support of this, i.c.v. administration of goldfish (gf) nesfatin-1 [25 ng/g body weight (BW)], suppressed food intake and the expression of mRNAs encoding preproghrelin, ghrelin receptor (GHS-R 1a-1), CCK and NUCB2 in the forebrain of fed fish, as well as ghrelin and NUCB2 mRNA in the hypothalamus of unfed fish, both at 1 h post-injection. Nesfatin-1 stimulated hypothalamic CCK mRNA expression at 30 min post-injection in fed fish, and inhibited OXA mRNA in the unfed fish hypothalamus 1 h post-injection. Similarly, i.c.v. injections of gfghrelin (1 ng/g BW), although stimulating food intake, suppressed NUCB2 and preproghrelin mRNAs, but not ghrelin receptor mRNA expression in the forebrain. It is also evident that exogenous ghrelin and nesfatin-1 mRNAs encoding these peptides. Our novel results indicate interactions between nesfatin-1 and ghrelin, CCK and orexin, and show that nesfatin-1 acts on other appetite regulatory peptides in a time

  14. Acyl-coenzyme A:cholesterol acyltransferases

    PubMed Central

    Chang, Ta-Yuan; Li, Bo-Liang; Chang, Catherine C. Y.; Urano, Yasuomi

    2009-01-01

    The enzymes acyl-coenzyme A (CoA):cholesterol acyltransferases (ACATs) are membrane-bound proteins that utilize long-chain fatty acyl-CoA and cholesterol as substrates to form cholesteryl esters. In mammals, two isoenzymes, ACAT1 and ACAT2, encoded by two different genes, exist. ACATs play important roles in cellular cholesterol homeostasis in various tissues. This chapter summarizes the current knowledge on ACAT-related research in two areas: 1) ACAT genes and proteins and 2) ACAT enzymes as drug targets for atherosclerosis and for Alzheimer's disease. PMID:19141679

  15. Acyl silicates and acyl aluminates as activated intermediates in peptide formation on clays

    NASA Technical Reports Server (NTRS)

    White, D. H.; Kennedy, R. M.; Macklin, J.

    1984-01-01

    Glycine reacts with heating on dried clays and other minerals to give peptides in much better yield than in the absence of mineral. This reaction was proposed to occur by way of an activated intermediate such as an acyl silicate or acyl aluminate analogous to acyl phosphates involved in several biochemical reactions including peptide bond synthesis. The proposed mechanism has been confirmed by trapping the intermediate, as well as by direct spectroscopic observation of a related intermediate. The reaction of amino acids on periodically dried mineral surfaces represents a widespead, geologically realistic setting for prebiotic peptide formation via in situ activation.

  16. Synthesis, Surface Active Properties and Cytotoxicity of Sodium N-Acyl Prolines.

    PubMed

    Sreenu, Madhumanchi; Narayana Prasad, Rachapudi Badari; Sujitha, Pombala; Kumar, Chityal Ganesh

    2015-01-01

    Sodium N-acyl prolines (NaNAPro) were synthesized using mixture of fatty acids obtained from coconut, palm, karanja, Sterculia foetida and high oleic sunflower oils via Schotten-Baumann reaction in 58-75% yields to study the synergetic effect of mixture of hydrophobic fatty acyl functionalities like saturation, unsaturation and cyclopropene fatty acids with different chain lengths and aliphatic hetero cyclic proline head group on their surface and cytotoxicity activities. The products were characterized by chromatographic and spectral techniques. The synthesized products were evaluated for their surface active properties such as surface tension, wetting power, foaming characteristics, emulsion stability, calcium tolerance, critical micelle concentration (CMC) and thermodynamic properties. The results revealed that all the products exhibited superior surface active properties like CMC, calcium tolerance and emulsion stability as compared to the standard surfactant, sodium lauryl sulphate (SLS). In addition, palm, Sterculia foetida and high oleic sunflower fatty N-acyl prolines exhibited promising cytotoxicity against different tumor cell lines.

  17. A novel sodium N-fatty acyl amino acid surfactant using silkworm pupae as stock material.

    PubMed

    Wu, Min-Hui; Wan, Liang-Ze; Zhang, Yu-Qing

    2014-01-01

    A novel sodium N-fatty acyl amino acid (SFAAA) surfactant was synthesized using pupa oil and pupa protein hydrolysates (PPH) from a waste product of the silk industry. The aliphatic acids from pupa oil were modified into N-fatty acyl chlorides by thionyl chloride (SOCl2). SFAAA was synthesized using acyl chlorides and PPH. GC-MS analysis showed fatty acids from pupa oil consist mainly of unsaturated linolenic and linoleic acids and saturated palmitic and stearic acids. SFAAA had a low critical micelle concentration, great efficiency in lowering surface tension and strong adsorption at an air/water interface. SFAAA had a high emulsifying power, as well as a high foaming power. The emulsifying power of PPH and SFAAA in an oil/water emulsion was better with ethyl acetate as the oil phase compared to n-hexane. The environment-friendly surfactant made entirely from silkworm pupae could promote sustainable development of the silk industry. PMID:24651079

  18. A novel sodium N-fatty acyl amino acid surfactant using silkworm pupae as stock material.

    PubMed

    Wu, Min-Hui; Wan, Liang-Ze; Zhang, Yu-Qing

    2014-03-21

    A novel sodium N-fatty acyl amino acid (SFAAA) surfactant was synthesized using pupa oil and pupa protein hydrolysates (PPH) from a waste product of the silk industry. The aliphatic acids from pupa oil were modified into N-fatty acyl chlorides by thionyl chloride (SOCl2). SFAAA was synthesized using acyl chlorides and PPH. GC-MS analysis showed fatty acids from pupa oil consist mainly of unsaturated linolenic and linoleic acids and saturated palmitic and stearic acids. SFAAA had a low critical micelle concentration, great efficiency in lowering surface tension and strong adsorption at an air/water interface. SFAAA had a high emulsifying power, as well as a high foaming power. The emulsifying power of PPH and SFAAA in an oil/water emulsion was better with ethyl acetate as the oil phase compared to n-hexane. The environment-friendly surfactant made entirely from silkworm pupae could promote sustainable development of the silk industry.

  19. A novel sodium N-fatty acyl amino acid surfactant using silkworm pupae as stock material

    NASA Astrophysics Data System (ADS)

    Wu, Min-Hui; Wan, Liang-Ze; Zhang, Yu-Qing

    2014-03-01

    A novel sodium N-fatty acyl amino acid (SFAAA) surfactant was synthesized using pupa oil and pupa protein hydrolysates (PPH) from a waste product of the silk industry. The aliphatic acids from pupa oil were modified into N-fatty acyl chlorides by thionyl chloride (SOCl2). SFAAA was synthesized using acyl chlorides and PPH. GC-MS analysis showed fatty acids from pupa oil consist mainly of unsaturated linolenic and linoleic acids and saturated palmitic and stearic acids. SFAAA had a low critical micelle concentration, great efficiency in lowering surface tension and strong adsorption at an air/water interface. SFAAA had a high emulsifying power, as well as a high foaming power. The emulsifying power of PPH and SFAAA in an oil/water emulsion was better with ethyl acetate as the oil phase compared to n-hexane. The environment-friendly surfactant made entirely from silkworm pupae could promote sustainable development of the silk industry.

  20. Identification of N-Acyl Phosphatidylserine Molecules in Eukaryotic Cells

    PubMed Central

    Guan, Ziqiang; Li, Shengrong; Smith, Dale C.; Shaw, Walter A.; Raetz, Christian R. H.

    2008-01-01

    While profiling the lipidome of the mouse brain by mass spectrometry, we discovered a novel family of N-acyl phosphatidylserine (N-acyl-PS) molecules. These N-acyl-PS species were enriched by DEAE-cellulose column chromatography, and they were then characterized by accurate mass measurements, tandem mass spectrometry, liquid chromatography/mass spectrometry, and comparison to an authentic standard. Mouse brain N-acyl-PS molecules are heterogeneous and constitute about 0.1 % of the total lipid. In addition to various ester-linked fatty acyl chains on their glycerol backbones, the complexity of the N-acyl-PS series is further increased by the presence of diverse amide-linked N-acyl chains, which include saturated, mono-unsaturated and poly-unsaturated species. N-acyl-PS molecular species were also detected in the lipids of pig brain, mouse RAW264.7 macrophage tumor cells and yeast, but not E. coli. N-acyl-PSs may be biosynthetic precursors of N-acyl serine molecules, such as the recently reported signaling lipid N-arachidonoyl serine from bovine brain. We suggest that a phospholipase D might cleave N-acyl-PS to generate N-acyl serine, in analogy to the biosynthesis of the endocannabinoid N-arachidonoyl ethanolamine (anadamide) from N-arachidonoyl phosphatidylethanolamine. PMID:18031065

  1. Thioesterase superfamily member 2 (Them2)/acyl-CoA thioesterase 13 (Acot13): a homotetrameric hotdog fold thioesterase with selectivity for long-chain fatty acyl-CoAs

    PubMed Central

    Wei, Jie; Kang, Hye Won; Cohen, David E.

    2011-01-01

    Them2 (thioesterase superfamily member 2) is a 140-aminoacid protein of unknown biological function that comprises a single hotdog fold thioesterase domain. On the basis of its putative association with mitochondria, accentuated expression in oxidative tissues and interaction with StarD2 (also known as phosphatidylcholine-transfer protein, PC-TP), a regulator of fatty acid metabolism, we explored whether Them2 functions as a physiologically relevant fatty acyl-CoA thioesterase. In solution, Them2 formed a stable homotetramer, which denatured in a single transition at 59.3 °C. Them2 exhibited thioesterase activity for medium- and long-chain acyl-CoAs, with Km values that decreased exponentially as a function of increasing acyl chain length. Steady-state kinetic parameters for Them2 were characteristic of long-chain mammalian acyl-CoA thioesterases, with minimal values of Km and maximal values of kcat/Km observed for myristoyl-CoA and palmitoyl-CoA. For these acyl-CoAs, substrate inhibition was observed when concentrations approached their critical micellar concentrations. The acyl-CoA thioesterase activity of Them2 was optimized at physiological temperature, ionic strength and pH. For both myristoyl-CoA and palmitoyl-CoA, the addition of StarD2 increased the kcat of Them2. Enzymatic activity was decreased by the addition of phosphatidic acid/phosphatidylcholine small unilamellar vesicles. Them2 expression, which was most pronounced in mouse heart, was associated with mitochondria and was induced by activation of PPARα (peroxisome-proliferator-activated receptor α). We conclude that, under biological conditions, Them2 probably functions as a homotetrameric long-chain acyl-CoA thioesterase. Accordingly, Them2 has been designated as the 13th member of the mammalian acyl-CoA thioesterase family, Acot13. PMID:19405909

  2. KATP channels in the nodose ganglia mediate the orexigenic actions of ghrelin

    PubMed Central

    Grabauskas, Gintautas; Wu, Xiaoyin; Lu, Yuanxu; Heldsinger, Andrea; Song, Il; Zhou, Shi-Yi; Owyang, Chung

    2015-01-01

    Abstract Ghrelin is the only known hunger signal derived from the peripheral tissues. Ghrelin overcomes the satiety signals evoked by anorexigenic molecules, such as cholecystokinin (CCK) and leptin, to stimulate feeding. The mechanisms by which ghrelin reduces the sensory signals evoked by anorexigenic hormones, which act via the vagus nerve to stimulate feeding, are unknown. Patch clamp recordings of isolated rat vagal neurons show that ghrelin hyperpolarizes neurons by activating K+ conductance. Administering a KATP channel antagonist or silencing Kir6.2, a major subunit of the KATP channel, abolished ghrelin inhibition in vitro and in vivo. Patch clamp studies show that ghrelin inhibits currents evoked by leptin and CCK-8, which operate through independent ionic channels. The inhibitory actions of ghrelin were abolished by treating the vagal ganglia neurons with pertussis toxin, as well as phosphatidylinositol 3-kinase (PI3K) or extracellular signal-regulated kinase 1 and 2 (Erk1/2) small interfering RNA. In vivo gene silencing of PI3K and Erk1/2 in the nodose ganglia prevented ghrelin inhibition of leptin- or CCK-8-evoked vagal firing. Feeding experiments showed that silencing Kir6.2 in the vagal ganglia abolished the orexigenic actions of ghrelin. These data indicate that ghrelin modulates vagal ganglia neuron excitability by activating KATP conductance via the growth hormone secretagogue receptor subtype 1a–Gαi–PI3K–Erk1/2–KATP pathway. The resulting hyperpolarization renders the neurons less responsive to signals evoked by anorexigenic hormones. This provides a mechanism to explain the actions of ghrelin with respect to overcoming anorexigenic signals that act via the vagal afferent pathways. Key points Ghrelin, a hunger signalling peptide derived from the peripheral tissues, overcomes the satiety signals evoked by anorexigenic molecules, such as cholecystokinin (CCK) and leptin, to stimulate feeding. Using in vivo and in vitro electrophysiological

  3. Ghrelin Inhibition Restores Glucose Homeostasis in Hepatocyte Nuclear Factor-1α (MODY3)-Deficient Mice.

    PubMed

    Brial, François; Lussier, Carine R; Belleville, Karine; Sarret, Philippe; Boudreau, François

    2015-09-01

    Hepatocyte nuclear factor-1α (HNF1α) is a transcription factor expressed in tissues of endoderm origin. Mutations in HNF1A are associated with maturity-onset diabetes of the young 3 (MODY3). Mice deficient for Hnf1α are hyperglycemic, with their pancreatic β-cells being defective in glucose-sensing insulin secretion. The specific mechanisms involved in this defect are unclear. Gut hormones control glucose homeostasis. Our objective was to explore whether changes in these hormones play a role in glucose homeostasis in the absence of Hnf1α. An increase in ghrelin gene transcript and a decrease in glucose-dependent insulinotropic polypeptide (GIP) gene transcripts were observed in the gut of Hnf1α-null mice. These changes correlated with an increase of ghrelin and a decrease of GIP-labeled cells. Ghrelin serological levels were significantly induced in Hnf1α-null mice. Paradoxically, GIP levels were also induced in these mice. Treatment of Hnf1α-null mice with a ghrelin antagonist led to a recovery of the diabetic symptoms. We conclude that upregulation of ghrelin in the absence of Hnf1α impairs insulin secretion and can be reversed by pharmacological inhibition of ghrelin/GHS-R interaction. These observations open up on future strategies to counteract ghrelin action in a program that could become beneficial in controlling non-insulin-dependent diabetes. PMID:25979074

  4. Site-specific effects of ghrelin on the neuronal activity in the hypothalamic arcuate nucleus.

    PubMed

    Riediger, Thomas; Traebert, Martin; Schmid, Herbert A; Scheel, Caroline; Lutz, Thomas A; Scharrer, Erwin

    2003-05-01

    The recently discovered hormone ghrelin, which is secreted from the stomach during fasting and hypoglycemia opposes the homeostatic functions of leptin by increasing food intake and decreasing energy expenditure. The hypothalamic arcuate nucleus (Arc) mediates the effects of leptin and contains a high density of ghrelin receptors. The leptin- and ghrelin-responsive network involves the hypothalamic neuropeptide Y/alpha-melanocyte stimulating hormone (NPY/alpha-MSH) system. In the rat, neurons expressing the orexigenic peptide NPY are mainly located in the ventromedial Arc (ArcM), while pro-opiomelanocortin (POMC) neurons, synthesizing the anorectic peptide alpha-MSH, predominate in the ventrolateral Arc (ArcL). In extracellular single unit recordings from in vitro slice preparations of the Arc, superfusion of ghrelin (10(-8) M) exerted predominantly excitatory effects on ArcM neurons (73%, n=93), while a high number ArcL neurons were inhibited in response to ghrelin (42%, n=43). The excitatory effect of ghrelin on neuronal activity was postsynaptic since it was unaffected by synaptic blockade (low Ca(2+)/high Mg(2+) solution). In contrast, the inhibitory response in the ArcL was abolished by the blockade of synaptic interactions indicating a presynaptic mechanism. These results indicate that circulating ghrelin may oppose the actions of leptin by directly activating NPY-neurons of the ArcM and by indirectly inhibiting POMC neurons of the ArcL.

  5. Roles of leptin and ghrelin in adipogenesis and lipid metabolism of rainbow trout adipocytes in vitro.

    PubMed

    Salmerón, Cristina; Johansson, Marcus; Asaad, Maryam; Angotzi, Anna R; Rønnestad, Ivar; Stefansson, Sigurd O; Jönsson, Elisabeth; Björnsson, Björn Thrandur; Gutiérrez, Joaquim; Navarro, Isabel; Capilla, Encarnación

    2015-10-01

    Leptin and ghrelin are important regulators of energy homeostasis in mammals, whereas their physiological roles in fish have not been fully elucidated. In the present study, the effects of leptin and ghrelin on adipogenesis, lipolysis and on expression of lipid metabolism-related genes were examined in rainbow trout adipocytes in vitro. Leptin expression and release increased from preadipocytes to mature adipocytes in culture, but did not affect the process of adipogenesis. While ghrelin and its receptor were identified in cultured differentiated adipocytes, ghrelin did not influence either preadipocyte proliferation or differentiation, indicating that it may have other adipose-related roles. Leptin and ghrelin increased lipolysis in mature freshly isolated adipocytes, but mRNA expression of lipolysis markers was not significantly modified. Leptin significantly suppressed the fatty acid transporter-1 expression, suggesting a decrease in fatty acid uptake and storage, but did not affect expression of any of the lipogenesis or β-oxidation genes studied. Ghrelin significantly increased the mRNA levels of lipoprotein lipase, fatty acid synthase and peroxisome proliferator-activated receptor-β, and thus appears to stimulate synthesis of triglycerides as well as their mobilization. Overall, the study indicates that ghrelin, but not leptin seems to be an enhancer of lipid turn-over in adipose tissue of rainbow trout, and this regulation may at least partly be mediated through autocrine/paracrine mechanisms. The mode of action of both hormones needs to be further explored to better understand their roles in regulating adiposity in fish.

  6. Central administration of ghrelin alters emotional responses in rats: behavioural, electrophysiological and molecular evidence.

    PubMed

    Hansson, C; Haage, D; Taube, M; Egecioglu, E; Salomé, N; Dickson, S L

    2011-04-28

    The orexigenic and pro-obesity hormone ghrelin targets key hypothalamic and mesolimbic circuits involved in energy balance, appetite and reward. Given that such circuits are closely integrated with those regulating mood and cognition, we sought to determine whether chronic (>2 weeks) CNS exposure to ghrelin alters anxiety- and depression-like behaviour in rats as well as some physiological correlates. Rats bearing chronically implanted i.c.v. catheters were treated with ghrelin (10 μg/d) or vehicle for 4 weeks. Tests used to assess anxiety- and depression-like behaviour were undertaken during weeks 3-4 of the infusion. These revealed an increase in anxiety- and depression-like behaviour in the ghrelin-treated rats relative to controls. At the end of the 4-week infusion, brains were removed and the amygdala dissected for subsequent qPCR analysis that revealed changes in expression of a number of genes representing key systems implicated in these behavioural changes. Finally, given the key role of the dorsal raphe serotonin system in emotional reactivity, we examined the electrophysiological response of dorsal raphe neurons after a ghrelin challenge, and found mainly inhibitory responses in this region. We demonstrate that the central ghrelin signalling system is involved in emotional reactivity in rats, eliciting pro-anxiety and pro-depression effects and have begun to explore novel target systems for ghrelin that may be of importance for these effects.

  7. SKF 83566 attenuates the effects of ghrelin on performance in the object location memory task.

    PubMed

    Jacoby, Sarah M; Currie, Paul J

    2011-10-31

    Increasing research implicates ghrelin, a metabolic signaling peptide, in memory processes including acquisition, consolidation, and retention. The present study investigated the effects of ghrelin on spatial memory acquisition by utilizing the object location memory task paradigm. Given the co-expression of ghrelin and dopamine D(1) receptors within hippocampal neurons, we examined a potential interaction between these two systems on memory performance. When injected into the dorsal third ventricle (D3V) of male Sprague-Dawley rats, proximal to hippocampal tissue, ghrelin (500 pmol) increased the amount of time spent with objects in novel locations. This effect was completely reversed by the D(1) antagonist SKF 83566 (100 μg/kg IP), although when administered alone, the antagonist had no effect on task performance (10-100 μg/kg). We also examined the feeding effects of D3V ghrelin and found that the peptide reliably increased food intake (500 pmol) but that this effect was not blocked by SKF 83566 (100 μg/kg). When given alone, SKF 83566 did not alter food intake (10-100 μg/kg). Our findings indicate that, in addition to an orexigenic effect, ghrelin improves acquisition of spatial location memories. Furthermore, D(1) receptor activation is necessary for ghrelin to improve the encoding of spatial memories but does not impact the increase in food intake elicited by the peptide.

  8. Ghrelin inhibits sodium metabisulfite induced oxidative stress and apoptosis in rat gastric mucosa.

    PubMed

    Ercan, Sevim; Basaranlar, Goksun; Gungor, Nazlı Ece; Kencebay, Ceren; Sahin, Pınar; Celik-Ozenci, Ciler; Derin, Narin

    2013-06-01

    This study aimed to investigate the effect of ghrelin administration on sulfite induced oxidative and apoptotic changes in rat gastric mucosa. Forty male albino Wistar rats were randomized into control (C), sodium metabisulfite (Na2S2O5) treated (S), ghrelin treated (G) and, Na2S2O5+ghrelin treated (SG) groups. Sodium metabisulfite (100 mg/kg/day) was given by gastric gavage and, ghrelin (20 μg/kg/day) was given intraperitoneally for 5 weeks. Plasma-S-sulfonate level was increased in S and SG groups. Na2S2O5 administration significantly elevated total oxidant status (TOS) levels while depleting total antioxidant status (TAS) levels in gastric mucosa. Ghrelin significantly decreased gastric TOS levels in the SG group compared with the S group. Additionally, TAS levels were found to be higher in SG group in reference to S group. Na2S2O5 administration also markedly increased the number of apoptotic cells, cleaved caspase-3 and PAR expression (PARP activity indicator) and, decreased Ki67 expression (cell proliferation index) in gastric mucosal cells. Ghrelin treatment decreased the number apoptotic cells, cytochrome C release, PAR and, caspase-3 expressions while increasing Ki67 expression in gastric mucosa exposed to Na2S2O5. In conclusion, we suggest that ghrelin treatment might ameliorate ingested-Na2S2O5 induced gastric mucosal injury stemming from apoptosis and oxidative stress in rats.

  9. Ghrelin protects musculocutaneous tissue from ischemic necrosis by improving microvascular perfusion.

    PubMed

    Rezaeian, F; Wettstein, R; Scheuer, C; Bäumker, K; Bächle, A; Vollmar, B; Menger, M D; Harder, Y

    2012-02-01

    Persistent ischemia in musculocutaneous tissue may lead to wound breakdown and necrosis. The objective of this experimental study was to analyze, whether the gastric peptide ghrelin prevents musculocutaneous tissue from necrosis and to elucidate underlying mechanisms. Thirty-two C57BL/6 mice equipped with a dorsal skinfold chamber containing ischemic musculocutaneous tissue were allocated to four groups: 1) ghrelin; 2) N(ω)-nitro-l-arginine methyl ester (l-NAME); 3) ghrelin and l-NAME; and 4) control. Microcirculation, inflammation, angiogenesis, and tissue survival were assessed by fluorescence microscopy. Inducible and endothelial nitric oxide synthase (iNOS I and eNOS), vascular endothelial growth factor (VEGF), as well as nuclear factor κB (NF-κB) were assessed by Western blot analysis. Ghrelin-treated animals showed an increased expression of iNOS and eNOS in critically perfused tissue compared with controls. This was associated with arteriolar dilation, increased arteriolar perfusion, and a sustained functional capillary density. Ghrelin further upregulated NF-κB and VEGF and induced angiogenesis. Finally, ghrelin reduced microvascular leukocyte-endothelial cell interactions, apoptosis, and overall tissue necrosis (P < 0.05 vs. control). Inhibition of nitric oxide by l-NAME did not affect the anti-inflammatory and angiogenic action of ghrelin but completely blunted the ghrelin-induced tissue protection by abrogating the arteriolar dilation, the improved capillary perfusion, and the increased tissue survival. Ghrelin prevents critically perfused tissue from ischemic necrosis. Tissue protection is the result of a nitric oxide synthase-mediated improvement of the microcirculation but not due to induction of angiogenesis or attenuation of inflammation. This might represent a promising, noninvasive, and clinically applicable approach to protect musculocutaneous tissue from ischemia. PMID:22159999

  10. Ghrelin-induced hypophagia is mediated by the β2 adrenergic receptor in chicken.

    PubMed

    Zendehdel, Morteza; Hassanpour, Shahin

    2014-09-01

    The purpose of this study was to examine the effects of intracerebroventricular injection of metoprolol (a β1 adrenergic receptor antagonist), ICI 118,551 (a β2 adrenergic receptor antagonist), and SR 59230R (a β3 adrenergic receptor antagonist) on ghrelin-induced food and water intake by 3-h food-deprived (FD3) cockerels. The chickens were randomly allocated to 4 treatment groups with 8 replicates in each group. A cannula was surgically implanted into the lateral ventricle of the brain. In experiment 1, chickens received the β1 adrenergic receptor antagonist (24 nmol) before injection of the ghrelin (0.6 nmol). In experiment 2, chickens received the β2 adrenergic receptor antagonist (5 nmol) before injection of the ghrelin (0.6 nmol). In experiment 3, birds were injected with ghrelin (0.6 nmol) after the β3 adrenergic receptor antagonist (20 nmol). Cumulative food and water intake were recorded 3-h post injection and analyzed by two-way analysis of variance. According to the results, ghrelin injection reduced food and water intake by broiler cockerels (p≤0.05). The effect of ghrelin on food intake was significantly attenuated by pretreatment with the β2 receptor antagonist (p≤0.05). Furthermore, the β2 receptor antagonist had no effect on water intake induced by ghrelin. Also, pretreatment with the β1 and β3 receptors antagonists had no effect on ghrelin-induced food and water intake. These results suggest that the effect of ghrelin on cumulative food intake by cockerels is mediated via β2 adrenergic receptors.

  11. MTII attenuates ghrelin- and food deprivation-induced increases in food hoarding and food intake.

    PubMed

    Keen-Rhinehart, Erin; Bartness, Timothy J

    2007-12-01

    Food deprivation triggers a constellation of physiological and behavioral changes including increases in peripherally-produced ghrelin and centrally-produced agouti-related protein (AgRP). Upon refeeding, food intake is increased in most species, however hamsters primarily increase food hoarding. Food deprivation-induced increases in food hoarding by Siberian hamsters are mimicked by peripheral ghrelin and central AgRP injections. Because food deprivation stimulates ghrelin as well as AgRP synthesis/release, food deprivation-induced increases in hoarding may be mediated by melanocortin 3 or 4 receptor (MC3/4-R) antagonism via AgRP, the MC3/4-R inverse agonist. Therefore, we asked: Can a MC3/4-R agonist block food deprivation- or ghrelin-induced increases in foraging, food hoarding and food intake? This was accomplished by injecting melanotan II (MTII), a synthetic MC3/4-R agonist, into the 3rd ventricle in food deprived, fed or peripheral ghrelin injected hamsters and housed in a running wheel-based food delivery foraging system. Three foraging conditions were used: a) no running wheel access, non-contingent food, b) running wheel access, non-contingent food or c) a foraging requirement for food (10 revolutions/pellet). Food deprivation was a more potent stimulator of foraging and hoarding than ghrelin. Concurrent injections of MTII completely blocked food deprivation- and ghrelin-induced increases in food intake and attenuated, but did not always completely block, food deprivation- and ghrelin-induced increases in food hoarding. Collectively, these data suggest that the MC3/4-R are involved in ghrelin- and food deprivation-induced increases in food intake, but other neurochemical systems, such as previously demonstrated with neuropeptide Y, also are involved in increases in food hoarding as well as foraging.

  12. The expanding roles of the ghrelin-gene derived peptide obestatin in health and disease.

    PubMed

    Seim, Inge; Walpole, Carina; Amorim, Laura; Josh, Peter; Herington, Adrian; Chopin, Lisa

    2011-06-20

    Obestatin is a 23 amino acid, ghrelin gene-derived peptide hormone produced in the stomach and a range of other tissues throughout the body. While it was initially reported that obestatin opposed the actions of ghrelin with regards to appetite and food intake, it is now clear that obestatin is not an endogenous ghrelin antagonist, but it is a multi-functional peptide hormone in its own right. In this review we will discuss the controversies associated with the discovery of obestatin and explore emerging central and peripheral roles of obestatin, which includes adipogenesis, pancreatic homeostasis and cancer.

  13. Discovery of PF-5190457, a Potent, Selective, and Orally Bioavailable Ghrelin Receptor Inverse Agonist Clinical Candidate

    PubMed Central

    2014-01-01

    The identification of potent, highly selective orally bioavailable ghrelin receptor inverse agonists from a spiro-azetidino-piperidine series is described. Examples from this series have promising in vivo pharmacokinetics and increase glucose-stimulated insulin secretion in human whole and dispersed islets. A physicochemistry-based strategy to increase lipophilic efficiency for ghrelin receptor potency and retain low clearance and satisfactory permeability while reducing off-target pharmacology led to the discovery of 16h. Compound 16h has a superior balance of ghrelin receptor pharmacology and off-target selectivity. On the basis of its promising pharmacological and safety profile, 16h was advanced to human clinical trials. PMID:24900864

  14. The Pentapeptide RM-131 Promotes Food Intake and Adiposity in Wildtype Mice but Not in Mice Lacking the Ghrelin Receptor

    PubMed Central

    Fischer, Katrin; Finan, Brian; Clemmensen, Christoffer; van der Ploeg, Lex H. T.; Tschöp, Matthias H.; Müller, Timo D.

    2015-01-01

    The gastrointestinal peptide hormone ghrelin is the endogenous ligand of the growth hormone secretagogue receptor (a.k.a. ghrelin receptor, GHR). Currently, ghrelin is the only circulating peripheral hormone with the ability to promote a positive energy balance by stimulating food intake while decreasing energy expenditure and body fat utilization, as defined in rodents. Based on these and additional, beneficial effects on metabolism, the endogenous ghrelin system is considered an attractive target to treat diverse pathological conditions including those associated with eating/wasting disorders and cachexia. As the pharmacological potential of ghrelin is hampered by its relatively short half-life, ghrelin analogs with enhanced pharmacokinetics offer the potential to sustainably improve metabolism. One of these ghrelin analogs is the pentapeptide RM-131, which promotes food intake and adiposity with higher potency as compared to native ghrelin in rodents. Whereas, the effect of RM-131 on energy metabolism is solidly confirmed in rodents, it remains elusive whether RM-131 exerts its effect solely via the ghrelin receptor. Accordingly, we assessed the receptor specificity of RM-131 to promote food intake and adiposity in mice lacking the GHR. Our data show that in wildtype mice RM-131 potently promotes weight gain and adiposity through stimulation of food intake. However, RM-131 fails to affect food intake and body weight in mice lacking the GHR, underlining that the anabolic effects of RM-131 are mediated via the ghrelin receptor in mice. PMID:25988130

  15. Remodeling of host phosphatidylcholine by Chlamydia acyltransferase is regulated by acyl-CoA binding protein ACBD6 associated with lipid droplets

    PubMed Central

    Soupene, Eric; Wang, Derek; Kuypers, Frans A

    2015-01-01

    The bacterial human pathogen Chlamydia trachomatis invades cells as an infectious elementary body (EB). The EB is internalized into a vacuole that is hidden from the host defense mechanism, and is modified to sustain the development of the replicative reticulate body (RB). Inside this parasitophorous compartment, called the inclusion, the pathogen survives supported by an active exchange of nutrients and proteins with the host cell. We show that host lipids are scavenged and modified into bacterial-specific lipids by the action of a shared human-bacterial acylation mechanism. The bacterial acylating enzymes for the essential lipids 1-acyl-sn-glycerol 3-phosphate and 1-acyl-sn-phosphatidylcholine were identified as CT453 and CT775, respectively. Bacterial CT775 was found to be associated with lipid droplets (LDs). During the development of C. trachomatis, the human acyl-CoA carrier hACBD6 was recruited to cytosolic LDs and translocated into the inclusion. hACBD6 protein modulated the activity of CT775 in an acyl-CoA dependent fashion and sustained the activity of the bacterial acyltransferase by buffering the concentration of acyl-CoAs. We propose that disruption of the binding activity of the acyl-CoA carrier might represent a new drug-target to prevent growth of C. trachomatis. PMID:25604091

  16. Synthesis of rapeseed biodiesel using short-chained alkyl acetates as acyl acceptor.

    PubMed

    Jeong, Gwi-Taek; Park, Don-Hee

    2010-05-01

    In this study, we conducted experiments using a response surface methodology to determine the optimal reaction conditions for the enzymatic synthesis of biodiesel from rapeseed oil and short-chained alkyl acetates, such as methyl acetate or ethyl acetate, as the acyl acceptor at 40 degrees C. Based on our response surface methodology experiments, the optimal reaction conditions for the synthesis of biodiesel were as follows: methyl acetate as acyl acceptor, catalyst concentration of 16.50%, oil-to-methyl acetate molar ratio of 1:12.44, and reaction time of 19.70 h; ethyl acetate as acyl acceptor, catalyst concentration of 16.95%, oil-to-ethyl acetate molar ratio of 1:12.56, and reaction time of 19.73 h. The fatty acid ester content under the above conditions when methyl acetate and ethyl acetate were used as the acyl acceptor was 58.0% and 62.6%, respectively. The statistical method described in this study can be applied to effectively optimize the enzymatic conditions required for biodiesel production with short-chained alkyl acetates.

  17. Synthesis of rapeseed biodiesel using short-chained alkyl acetates as acyl acceptor.

    PubMed

    Jeong, Gwi-Taek; Park, Don-Hee

    2010-05-01

    In this study, we conducted experiments using a response surface methodology to determine the optimal reaction conditions for the enzymatic synthesis of biodiesel from rapeseed oil and short-chained alkyl acetates, such as methyl acetate or ethyl acetate, as the acyl acceptor at 40 degrees C. Based on our response surface methodology experiments, the optimal reaction conditions for the synthesis of biodiesel were as follows: methyl acetate as acyl acceptor, catalyst concentration of 16.50%, oil-to-methyl acetate molar ratio of 1:12.44, and reaction time of 19.70 h; ethyl acetate as acyl acceptor, catalyst concentration of 16.95%, oil-to-ethyl acetate molar ratio of 1:12.56, and reaction time of 19.73 h. The fatty acid ester content under the above conditions when methyl acetate and ethyl acetate were used as the acyl acceptor was 58.0% and 62.6%, respectively. The statistical method described in this study can be applied to effectively optimize the enzymatic conditions required for biodiesel production with short-chained alkyl acetates. PMID:19802734

  18. First evidence of Okadaic acid acyl-derivative and Dinophysistoxin-3 in mussel samples collected in Chiloe Island, Southern Chile.

    PubMed

    García, Carlos; Pruzzo, Matías; Rodríguez-Unda, Nelson; Contreras, Cristóbal; Lagos, Néstor

    2010-06-01

    This paper shows the detection of Diarrhetic Shellfish Poison (DSP) phycotoxins, using HPLC-FLD with pre-column derivatization procedure and HPLC-MS methods, in the analysis of shellfish extracts tested positive with the official DSP mouse bioassay. The shellfish samples were collected in Chiloe Island, Southern of Chile. The amount of Dinophysistoxin-3 (DTX-3) measured in the shellfish extracts were in average above the international safe limits for DSP content in the shellfish extracts analyzed. As internal control of detection and recovery, DTX-1 analytical standard was spiked into dichloromethane-clean shellfish extracts in order to calculate de extraction recovery of DTX-1. The average recovery was 97%. From all DSP toxins analyzed, the hydrolyzed extract samples appeared mainly DTX-3 in concentrations ranging from 99.40 +/- 1.22 to 257.73 +/- 12.46 ng/g digestive-glands. The acyl-Okadaic Acid (acyl-OA) was also detected in some samples, ranging from 1.02 +/- 1.4 to 3.07. +/- 1.6 ng of DSP toxin/g digestive-glands. This is the first report of acyl-OA ever found in Chilean shellfish samples. This data shows that shellfish samples were contaminated with a complex DSP toxins profile, in which DTX-3 is the major DSP toxin component, followed by DTX-1 and the acyl-OA as the minor one. The important findings showed in this study are the presence of both acyl-derivates (DTX-3 and Acyl-OA) which are the product of a main metabolic biotransformation that occurred inside the shellfish, in order to chelate DTX-1 and OA, transforming them into DTX-3 and the acyl-OA respectively. This metabolic biotransformation must be performed to avoid self-inhibition of their Protein Phosphatase 2A done by DTX-1 and OA, since both acyl-derivates (DTX-3 and acyl-OA) do not inhibit Protein Phosphatase 2A. This complex DSP toxins profile and the permanent presence of both acyl-derivates (DTX-3 and Acyl-OA) could explain the permanent diarrhea symptoms that experience patients who have

  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. Effects of ghrelin on the feeding behavior of Lymantria dispar L. (Lymantriidae) caterpillars.

    PubMed

    Perić-Mataruga, Vesna; Mircić, Dejan; Vlahović, Milena; Mrdaković, Marija; Todorović, Dajana; Stevanović, Darko; Milosević, Verica

    2009-08-01

    Ghrelin is a 28-amino acid peptide which has significant effects on animal appetite, thus influencing body mass. The aim of our study was to examine the effects of ghrelin on the feeding behavior and physiology 4th instar caterpillars of the pest insect, Lymantria dispar L. Treatment of 4th instar caterpillars with four subpicomolar amounts of ghrelin had a positive influence on daily food intake, frass elimination, body mass. Also, locomotor activity increased, while stadium duration decreased in treated caterpillars. The similarity between the effects of ghrelin on caterpillar physiology and those in mammals suggests that using this model system for further studies of neuroendocrinological processes underlying feeding could lead to essential information about more complex organisms.

  1. 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

  2. The role of the central ghrelin system in reward from food and chemical drugs.

    PubMed

    Dickson, Suzanne L; Egecioglu, Emil; Landgren, Sara; Skibicka, Karolina P; Engel, Jörgen A; Jerlhag, Elisabet

    2011-06-20

    Here we review recent advances that identify a role for the central ghrelin signalling system in reward from both natural rewards (such as food) and artificial rewards (that include alcohol and drugs of abuse). Whereas ghrelin emerged as a stomach-derived hormone involved in energy balance, hunger and meal initiation via hypothalamic circuits, it now seems clear that it also has a role in motivated reward-driven behaviours via activation of the so-called "cholinergic-dopaminergic reward link". This reward link comprises a dopamine projection from the ventral tegmental area (VTA) to the nucleus accumbens together with a cholinergic input, arising primarily from the laterodorsal tegmental area. Ghrelin administration into the VTA or LDTg activates the "cholinergic-dopaminergic" reward link, suggesting that ghrelin may increase the incentive value of motivated behaviours such as reward-seeking behaviour ("wanting" or "incentive motivation"). Further, direct injection of ghrelin into the brain ventricles or into the VTA increases the consumption of rewarding foods as well as alcohol in mice and rats. Studies in rodents show beneficial effects of ghrelin receptor (GHS-R1A) antagonists to suppress the intake of palatable food, to reduce preference for caloric foods, to suppress food reward and motivated behaviour for food. They have also been shown to reduce alcohol consumption, suppress reward induced by alcohol, cocaine and amphetamine. Furthermore, variations in the GHS-R1A and pro-ghrelin genes have been associated with high alcohol consumption, smoking and increased weight gain in alcohol dependent individuals as well as with bulimia nervosa and obesity. Thus, the central ghrelin signalling system interfaces neurobiological circuits involved in reward from food as well as chemical drugs; agents that directly or indirectly suppress this system emerge as potential candidate drugs for suppressing problematic over-eating that leads to obesity as well as for the

  3. Photoperiodic regulation of the orexigenic effects of ghrelin in Siberian hamsters.

    PubMed

    Bradley, Sean P; Pattullo, Lucia M; Patel, Priyesh N; Prendergast, Brian J

    2010-09-01

    Animals living in temperate climates with predictable seasonal changes in food availability may use seasonal information to engage different metabolic strategies. Siberian hamsters decrease costs of thermoregulation during winter by reducing food intake and body mass in response to decreasing or short-day lengths (SD). These experiments examined whether SD reduction in food intake in hamsters is driven, at least in part, by altered behavioral responses to ghrelin, a gut-derived orexigenic peptide which induces food intake via NPY-dependent mechanisms. Relative to hamsters housed in long-day (LD) photoperiods, SD hamsters consumed less food in response to i.p. treatment with ghrelin across a range of doses from 0.03 to 3 mg/kg. To determine whether changes in photoperiod alter behavioral responses to ghrelin-induced activation of NPY neurons, c-Fos and NPY expression were quantified in the arcuate nucleus (ARC) via double-label fluorescent immunocytochemistry following i.p. treatment with 0.3 mg/kg ghrelin or saline. Ghrelin induced c-Fos immunoreactivity (-ir) in a greater proportion of NPY-ir neurons of LD relative to SD hamsters. In addition, following ghrelin treatment, a greater proportion of ARC c-Fos-ir neurons were identifiable as NPY-ir in LD relative to SD hamsters. Changes in day length markedly alter the behavioral response to ghrelin. The data also identify photoperiod-induced changes in the ability of ghrelin to activate ARC NPY neurons as a possible mechanism by which changes in day length alter food intake.

  4. Identification of neurons that express ghrelin receptors in autonomic pathways originating from the spinal cord.

    PubMed

    Furness, John B; Cho, Hyun-Jung; Hunne, Billie; Hirayama, Haruko; Callaghan, Brid P; Lomax, Alan E; Brock, James A

    2012-06-01

    Functional studies have shown that subsets of autonomic preganglionic neurons respond to ghrelin and ghrelin mimetics and in situ hybridisation has revealed receptor gene expression in the cell bodies of some preganglionic neurons. Our present goal has been to determine which preganglionic neurons express ghrelin receptors by using mice expressing enhanced green fluorescent protein (EGFP) under the control of the promoter for the ghrelin receptor (also called growth hormone secretagogue receptor). The retrograde tracer Fast Blue was injected into target organs of reporter mice under anaesthesia to identify specific functional subsets of postganglionic sympathetic neurons. Cryo-sections were immunohistochemically stained by using anti-EGFP and antibodies to neuronal markers. EGFP was detected in nerve terminal varicosities in all sympathetic chain, prevertebral and pelvic ganglia and in the adrenal medulla. Non-varicose fibres associated with the ganglia were also immunoreactive. No postganglionic cell bodies contained EGFP. In sympathetic chain ganglia, most neurons were surrounded by EGFP-positive terminals. In the stellate ganglion, neurons with choline acetyltransferase immunoreactivity, some being sudomotor neurons, lacked surrounding ghrelin-receptor-expressing terminals, although these terminals were found around other neurons. In the superior cervical ganglion, the ghrelin receptor terminals innervated subgroups of neurons including neuropeptide Y (NPY)-immunoreactive neurons that projected to the anterior chamber of the eye. However, large NPY-negative neurons projecting to the acini of the submaxillary gland were not innervated by EGFP-positive varicosities. In the celiaco-superior mesenteric ganglion, almost all neurons were surrounded by positive terminals but the VIP-immunoreactive terminals of intestinofugal neurons were EGFP-negative. The pelvic ganglia contained groups of neurons without ghrelin receptor terminal innervation and other groups with

  5. 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.

  6. The role of ghrelin signalling for sexual behaviour in male mice.

    PubMed

    Egecioglu, Emil; Prieto-Garcia, Luna; Studer, Erik; Westberg, Lars; Jerlhag, Elisabet

    2016-03-01

    Ghrelin, a gut-brain signal, is well known to regulate energy homeostasis, food intake and appetite foremost via hypothalamic ghrelin receptors (GHS-R1A). In addition, ghrelin activates the reward systems in the brain, namely the mesolimbic dopamine system, and regulates thereby the rewarding properties of addictive drugs as well as of palatable foods. Given that the mesolimbic dopamine system mandates the reinforcing properties of addictive drugs and natural rewards, such as sexual behaviour, we hypothesize that ghrelin plays an important role for male sexual behaviour, a subject for the present studies. Herein we show that ghrelin treatment increases, whereas pharmacological suppression (using the GHSR-1A antagonist JMV2959) or genetic deletion of the GHS-R1A in male mice decreases the sexual motivation for as well as sexual behaviour with female mice in oestrus. Pre-treatment with L-dopa (a dopamine precursor) prior to treatment with JMV2959 significantly increased the preference for female mouse compared with vehicle treatment. On the contrary, treatment with 5-hydroxythyptohan (a precursor for serotonin) prior to treatment with JMV2959 decreased the sexual motivation compared to vehicle. In separate experiments, we show that ghrelin and GHS-R1A antagonism do not affect the time spent over female bedding as measured in the androgen-dependent bedding test. Collectively, these data show that the hunger hormone ghrelin and its receptor are required for normal sexual behaviour in male mice and that the effects of the ghrelin signalling system on sexual behaviour involve dopamine neurotransmission.

  7. Ghrelin ameliorates intestinal barrier dysfunction in experimental colitis by inhibiting the activation of nuclear factor-kappa B

    SciTech Connect

    Cheng, Jian; Zhang, Lin; Dai, Weiqi; Mao, Yuqing; Li, Sainan; Wang, Jingjie; Li, Huanqing; Guo, Chuanyong; Fan, Xiaoming

    2015-02-27

    Aim: This study aimed to investigate the effect and underlying mechanism of ghrelin on intestinal barrier dysfunction in dextran sulfate sodium (DSS)-induced colitis. Methods and results: Acute colitis was induced in C57BL/6J mice by administering 2.5% DSS. Saline or 25, 125, 250 μg/kg ghrelin was administrated intraperitoneally (IP) to mice 1 day before colitis induction and on days 4, 5, and 6 after DSS administration. IP injection of a ghrelin receptor antagonist, [D-lys{sup 3}]-GHRP-6, was performed immediately prior to ghrelin injection. Ghrelin (125 or 250 μg/kg) could reduce the disease activity index, histological score, and myeloperoxidase activities in experimental colitis, and also prevented shortening of the colon. Ghrelin could prevent the reduction of transepithelial electrical resistance and tight junction expression, and bolstered tight junction structural integrity and regulated cytokine secretion. Ultimately, ghrelin inhibited nuclear factor kappa B (NF-κB), inhibitory κB-α, myosin light chain kinase, and phosphorylated myosin light chain 2 activation. Conclusions: Ghrelin prevented the breakdown of intestinal barrier function in DSS-induced colitis. The protective effects of ghrelin on intestinal barrier function were mediated by its receptor GHSR-1a. The inhibition of NF-κB activation might be part of the mechanism underlying the effects of ghrelin that protect against barrier dysfunction. - Highlights: • Ghrelin ameliorates intestinal barrier dysfunction in experimental colitis. • The effect of ghrelin is mediated by GHSR-1a. • Inhibition of NF-κB activation.

  8. 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.

  9. Ghrelin Enhances Olfactory Sensitivity and Exploratory Sniffing in Rodents and Humans

    PubMed Central

    Tong, Jenny; Mannea, Erica; Aime, Pascaline; Pfluger, Paul T.; Yi, Chun-Xia; Castaneda, Tamara R.; Davis, Harold W.; Ren, Xueying; Pixley, Sarah; Benoit, Stephen; Julliard, Karyne; Woods, Stephen C; Horvath, Tamas L.; Sleeman, Mark M.; D’Alessio, David; Obici, Silvana; Frank, Robert; Tschöp, Matthias H.

    2011-01-01

    Olfaction is an integral part of feeding providing predictive cues that anticipate ingestion. Although olfactory function is modulated by factors such as prolonged fasting, the underlying neural mechanisms remain poorly understood. We recently identified ghrelin receptors in olfactory circuits in the brain. We therefore investigated the role of the appetite-stimulating hormone ghrelin in olfactory processing in rodents and humans, testing the hypothesis that ghrelin lowers olfactory detection thresholds and enhances exploratory sniffing, both being related to food-seeking. In rats, intracerebroventricular ghrelin decreased odor detection thresholds and increased sniffing frequency. In humans, systemic ghrelin infusions significantly enhanced sniff magnitudes in response to both food and non-food odorants and air in comparison to control saline infusions but did not affect the pleasantness ratings of odors. This is consistent with a specific effect on odor detection and not the hedonic value of odors. Collectively, our findings indicate that ghrelin stimulates exploratory sniffing and increases olfactory sensitivity, presumably enhancing the ability to locate, identify and select foods. This novel role is consistent with ghrelin’s overall function as a signal amplifier at the molecular interface between environmental and nutritional cues and neuroendocrine circuits controlling energy homeostasis. PMID:21490225

  10. Ghrelin enhances cue-induced bar pressing for high fat food.

    PubMed

    St-Onge, Veronique; Watts, Alexander; Abizaid, Alfonso

    2016-02-01

    Ghrelin is an orexigenic hormone produced by the stomach that acts on growth hormone secretagogue receptors (GHSRs) both peripherally and centrally. The presence of GHSRs in the ventral tegmental area (VTA) suggests that ghrelin signaling at this level may increase the incentive value of palatable foods as well as other natural and artificial rewards. The present investigation sought to determine if ghrelin plays a role in relapse to such foods following a period of abstinence. To achieve this, thirty-six male Long Evans rats were trained to press a lever to obtain a high fat chocolate food reward on a fixed ratio schedule of 1. Following an extinction period during which lever presses were not reinforced, rats were implanted with a cannula connected to a minipump that continuously delivered ghrelin, a GHSR antagonist ([d-Lys-3]-GHRP-6), or saline in the VTA for 14days. One week later, food reward-associated cues, food reward priming, and an overnight fast were used to induce reinstatement of the lever pressing response. Our results indicate that intra-VTA ghrelin enhances cue-induced reinstatement of responses for palatable food pellets. To the extent that the reinstatement paradigm is considered a valid model of relapse in humans, this suggests that ghrelin signaling facilitates relapse to preferred foods in response to food cues through GHSR signaling in the VTA. PMID:26592452

  11. Immunohistochemical expression of ghrelin in capsaicin-treated rat ovaries during the different developmental periods.

    PubMed

    Tütüncü, Ş; İlhan, T; Özfiliz, N

    2016-01-01

    Red hot pepper is a plant that belongs to the Solanaceae family and is known as Capsicum annuum. Capsaicin is the active ingredient of cayenne pepper. Ghrelin is a hormone, which consists of polypeptide structure. Ghrelin also contributes to growth hormone secretion, energy balance, food intake and body weight regulator. The aim of this study was the localization and expression of ghrelin in the ovaries of rats treated with capsaicin during the postnatal development. Ninety female Sprague-Dawley rats (21 d) were used. The rats were randomly divided into 3 groups (n=30 each) as pubertal, post pubertal and adult. Each group was subdivided into three groups. The first subgroup (control) was given no injections. The second subgroup (vehicle) received only 0.3 cc solvent and the third subgroup (experiment) received subcutaneous injection of equal volume of capsaicin (1 mg/kg/d) for 42, 56, and 70 days. Ghrelin immunoreactivity was determined in ovarian follicular granulosa cells, interstitial cells and corpus luteal cells. A ghrelin immunopositive reaction located in the cytoplasm of cells in all groups. These results indicate that prolonged administration of low dose capsaicin does not affect ghrelin expression. However, follicular atresia was seen in lower rate in capsaicin treated group in comparison to other groups. PMID:27656230

  12. Beyond the metabolic role of ghrelin: a new player in the regulation of reproductive function.

    PubMed

    Muccioli, Giampiero; Lorenzi, Teresa; Lorenzi, Maria; Ghè, Corrado; Arnoletti, Elisa; Raso, Giuseppina Mattace; Castellucci, Mario; Gualillo, Oreste; Meli, Rosaria

    2011-12-01

    Ghrelin is a gastric peptide, discovered by Kojima et al. (1999) [55] as a result of the search for an endogenous ligand interacting with the "orphan receptor" GHS-R1a (growth hormone secretagogue receptor type 1a). Ghrelin is composed of 28 aminoacids and is produced mostly by specific cells of the stomach, by the hypothalamus and hypophysis, even if its presence, as well as that of its receptors, has been demonstrated in many other tissues, not least in gonads. Ghrelin potently stimulates GH release and participates in the regulation of energy homeostasis, increasing food intake, decreasing energy output and exerting a lipogenetic effect. Furthermore, ghrelin influences the secretion and motility of the gastrointestinal tract, especially of the stomach, and, above all, profoundly affects pancreatic functions. Despite of these previously envisaged activities, it has recently been hypothesized that ghrelin regulates several aspects of reproductive physiology and pathology. In conclusion, ghrelin not only cooperates with other neuroendocrine factors, such as leptin, in the modulation of energy homeostasis, but also has a crucial role in the regulation of the hypothalamic-pituitary gonadal axis. In the current review we summarize the main targets of this gastric peptide, especially focusing on the reproductive system.

  13. Immunohistochemical expression of ghrelin in capsaicin-treated rat ovaries during the different developmental periods

    PubMed Central

    Tütüncü, Ş.; İlhan, T.; Özfiliz, N.

    2016-01-01

    Red hot pepper is a plant that belongs to the Solanaceae family and is known as Capsicum annuum. Capsaicin is the active ingredient of cayenne pepper. Ghrelin is a hormone, which consists of polypeptide structure. Ghrelin also contributes to growth hormone secretion, energy balance, food intake and body weight regulator. The aim of this study was the localization and expression of ghrelin in the ovaries of rats treated with capsaicin during the postnatal development. Ninety female Sprague-Dawley rats (21 d) were used. The rats were randomly divided into 3 groups (n=30 each) as pubertal, post pubertal and adult. Each group was subdivided into three groups. The first subgroup (control) was given no injections. The second subgroup (vehicle) received only 0.3 cc solvent and the third subgroup (experiment) received subcutaneous injection of equal volume of capsaicin (1 mg/kg/d) for 42, 56, and 70 days. Ghrelin immunoreactivity was determined in ovarian follicular granulosa cells, interstitial cells and corpus luteal cells. A ghrelin immunopositive reaction located in the cytoplasm of cells in all groups. These results indicate that prolonged administration of low dose capsaicin does not affect ghrelin expression. However, follicular atresia was seen in lower rate in capsaicin treated group in comparison to other groups. PMID:27656230

  14. Effects of Helicobacter pylori infection on gut appetite peptide (leptin, ghrelin) expression in elderly inpatients.

    PubMed

    Salles, Nathalie; Ménard, Armelle; Georges, Agnès; Salzmann, Mélanie; de Ledinghen, Victor; de Mascarel, Antoine; Emeriau, Jean-Paul; Lamouliatte, Hervé; Mégraud, Francis

    2006-11-01

    The aim of the study was to investigate the relationship between gastritis and leptin and ghrelin in elderly patients. Patients older than 75 years undergoing an endoscopy were included. We reported data on nutritional status and Helicobacter pylori infection diagnosis (serology, 13C-urea breath test, culture, histology, and polymerase chain reaction on gastric biopsies). Gastric messenger RNA expression of leptin and ghrelin were quantified by real-time polymerase chain reaction. Sixty-two patients were included (84.7 +/- 5.2 years). H. pylori infection was associated with decreased gastric expression of leptin (p = .021), ghrelin (p =.002), and plasma ghrelin levels (p = .018). Atrophy was associated with decreased gastric leptin (p = .007) and ghrelin (p = .02). H. pylori infection correlated negatively with patient energy intake (r = -0.36; p = .001) and body mass index (r = -0.34; p = .018). The negative association between ghrelin and H. pylori infection may be related to a higher prevalence of atrophy and raises the possibility that H. pylori may be contributing to undernutrition in some older people.

  15. The suppression of ghrelin signaling mitigates age-associated thermogenic impairment

    PubMed Central

    Bongmba, Odelia Y. N.; Ma, Xiaojun; Zhu, Xiongwei; Sheikh-Hamad, David; Sun, Yuxiang

    2014-01-01

    Aging is associated with severe thermogenic impairment, which contributes to obesity and diabetes in aging. We previously reported that ablation of the ghrelin receptor, growth hormone secretagogue receptor (GHS-R), attenuates age-associated obesity and insulin resistance. Ghrelin and obestatin are derived from the same preproghrelin gene. Here we showed that in brown adipocytes, ghrelin decreases the expression of thermogenic regulator but obestatin increases it, thus showing the opposite effects. We also found that during aging, plasma ghrelin and GHS-R expression in brown adipose tissue (BAT) are increased, but plasma obestatin is unchanged. Increased plasma ghrelin and unchanged obestatin during aging may lead to an imbalance of thermogenic regulation, which may in turn exacerbate thermogenic impairment in aging. Moreover, we found that GHS-R ablation activates thermogenic signaling, enhances insulin activation, increases mitochondrial biogenesis, and improves mitochondrial dynamics of BAT. In addition, we detected increased norepinephrine in the circulation, and observed that GHS-R knockdown in brown adipocytes directly stimulates thermogenic activity, suggesting that GHS-R regulates thermogenesis via both central and peripheral mechanisms. Collectively, our studies demonstrate that ghrelin signaling is an important thermogenic regulator in aging. Antagonists of GHS-R may serve as unique anti-obesity agents, combating obesity by activating thermogenesis. PMID:25543537

  16. Ghrelin enhances cue-induced bar pressing for high fat food.

    PubMed

    St-Onge, Veronique; Watts, Alexander; Abizaid, Alfonso

    2016-02-01

    Ghrelin is an orexigenic hormone produced by the stomach that acts on growth hormone secretagogue receptors (GHSRs) both peripherally and centrally. The presence of GHSRs in the ventral tegmental area (VTA) suggests that ghrelin signaling at this level may increase the incentive value of palatable foods as well as other natural and artificial rewards. The present investigation sought to determine if ghrelin plays a role in relapse to such foods following a period of abstinence. To achieve this, thirty-six male Long Evans rats were trained to press a lever to obtain a high fat chocolate food reward on a fixed ratio schedule of 1. Following an extinction period during which lever presses were not reinforced, rats were implanted with a cannula connected to a minipump that continuously delivered ghrelin, a GHSR antagonist ([d-Lys-3]-GHRP-6), or saline in the VTA for 14days. One week later, food reward-associated cues, food reward priming, and an overnight fast were used to induce reinstatement of the lever pressing response. Our results indicate that intra-VTA ghrelin enhances cue-induced reinstatement of responses for palatable food pellets. To the extent that the reinstatement paradigm is considered a valid model of relapse in humans, this suggests that ghrelin signaling facilitates relapse to preferred foods in response to food cues through GHSR signaling in the VTA.

  17. Enhanced ghrelin secretion in the cephalic phase of food ingestion in women with bulimia nervosa.

    PubMed

    Monteleone, Palmiero; Serritella, Cristina; Scognamiglio, Pasquale; Maj, Mario

    2010-02-01

    In humans, the cephalic phase response to food ingestion consists mostly of vagal efferent activation, which promotes the secretion of entero-pancreatic hormones, including ghrelin. Since symptomatic patients with bulimia nervosa (BN) are characterized by increased vagal tone, we hypothesized an enhanced ghrelin secretion in the cephalic phase of vagal stimulation. Therefore, we investigated ghrelin response to modified sham feeding (MSF) in both BN and healthy women. Six drug-free BN women and 7 age-matched healthy females underwent MSF with initially seeing and smelling a meal, and then chewing the food without swallowing it. Blood samples were drawn immediately before and after MSF for hormone assay. Circulating ghrelin increased after MSF in both groups with BN individuals exhibiting a greater ghrelin increase, which positively correlated with the patients' weekly frequency of binge-purging. These results show for the first time an increased ghrelin secretion in the cephalic phase of vagal stimulation in symptomatic BN patients, likely resulting in a potentiation of the peripheral hunger signal, which might contribute to their aberrant binge-purging behavior.

  18. Immunohistochemical expression of ghrelin in capsaicin-treated rat ovaries during the different developmental periods.

    PubMed

    Tütüncü, Ş; İlhan, T; Özfiliz, N

    2016-01-01

    Red hot pepper is a plant that belongs to the Solanaceae family and is known as Capsicum annuum. Capsaicin is the active ingredient of cayenne pepper. Ghrelin is a hormone, which consists of polypeptide structure. Ghrelin also contributes to growth hormone secretion, energy balance, food intake and body weight regulator. The aim of this study was the localization and expression of ghrelin in the ovaries of rats treated with capsaicin during the postnatal development. Ninety female Sprague-Dawley rats (21 d) were used. The rats were randomly divided into 3 groups (n=30 each) as pubertal, post pubertal and adult. Each group was subdivided into three groups. The first subgroup (control) was given no injections. The second subgroup (vehicle) received only 0.3 cc solvent and the third subgroup (experiment) received subcutaneous injection of equal volume of capsaicin (1 mg/kg/d) for 42, 56, and 70 days. Ghrelin immunoreactivity was determined in ovarian follicular granulosa cells, interstitial cells and corpus luteal cells. A ghrelin immunopositive reaction located in the cytoplasm of cells in all groups. These results indicate that prolonged administration of low dose capsaicin does not affect ghrelin expression. However, follicular atresia was seen in lower rate in capsaicin treated group in comparison to other groups.

  19. Immunohistochemical expression of ghrelin in capsaicin-treated rat ovaries during the different developmental periods

    PubMed Central

    Tütüncü, Ş.; İlhan, T.; Özfiliz, N.

    2016-01-01

    Red hot pepper is a plant that belongs to the Solanaceae family and is known as Capsicum annuum. Capsaicin is the active ingredient of cayenne pepper. Ghrelin is a hormone, which consists of polypeptide structure. Ghrelin also contributes to growth hormone secretion, energy balance, food intake and body weight regulator. The aim of this study was the localization and expression of ghrelin in the ovaries of rats treated with capsaicin during the postnatal development. Ninety female Sprague-Dawley rats (21 d) were used. The rats were randomly divided into 3 groups (n=30 each) as pubertal, post pubertal and adult. Each group was subdivided into three groups. The first subgroup (control) was given no injections. The second subgroup (vehicle) received only 0.3 cc solvent and the third subgroup (experiment) received subcutaneous injection of equal volume of capsaicin (1 mg/kg/d) for 42, 56, and 70 days. Ghrelin immunoreactivity was determined in ovarian follicular granulosa cells, interstitial cells and corpus luteal cells. A ghrelin immunopositive reaction located in the cytoplasm of cells in all groups. These results indicate that prolonged administration of low dose capsaicin does not affect ghrelin expression. However, follicular atresia was seen in lower rate in capsaicin treated group in comparison to other groups.

  20. Role of the ghrelin system in alcoholism: Acting on the growth hormone secretagogue receptor to treat alcohol-related diseases.

    PubMed

    Leggio, L

    2010-04-01

    There exists a substantial need to identify new neuropharmacological targets to treat alcohol-dependent individuals. Ghrelin represents a gut-brain peptide, initially discovered as the endogenous ligand for the growth hormone secretagogue receptor (GHS-R). The existing literature clearly demonstrates that ghrelin affects appetite and food intake. Both animal and human studies provide evidence that ghrelin not only influences hunger but also has a role in the search for rewarding substances, such as alcohol. Animal studies provide evidence that ghrelin stimulates the reward system, acting on specific brain reward nodes, and that ghrelin signaling is required for stimulation of the reward system by alcohol. Human studies show that ethanol acutely affects ghrelin levels. Interestingly, human studies with alcohol-dependent individuals suggest that higher ghrelin levels are associated with higher self-reported measurements of alcohol craving. Altogether, these findings suggest that the ghrelin system plays a role in alcohol dependence. Ghrelin antagonists (i.e., GHS-R1a antagonists and/or inverse agonists) might affect alcohol-seeking behavior, thus having therapeutic potential in alcohol use disorders. Future laboratory and clinical studies testing this hypothesis are warranted. PMID:20440417

  1. Intraportal infusion of ghrelin could inhibit glucose-stimulated GLP-1 secretion by enteric neural net in Wistar rat.

    PubMed

    Zhang, Xiyao; Li, Wensong; Li, Ping; Chang, Manli; Huang, Xu; Li, Qiang; Cui, Can

    2014-01-01

    As a regulator of food intake and energy metabolism, the role of ghrelin in glucose metabolism is still not fully understood. In this study, we determined the in vivo effect of ghrelin on incretin effect. We demonstrated that ghrelin inhibited the glucose-stimulated release of glucagon-like peptide-1 (GLP-1) when infused into the portal vein of Wistar rat. Hepatic vagotomy diminished the inhibitory effect of ghrelin on glucose-stimulated GLP-1 secretion. In addition, phentolamine, a nonselective α receptor antagonist, could recover the decrease of GLP-1 release induced by ghrelin infusion. Pralmorelin (an artificial growth hormone release peptide) infusion into the portal vein could also inhibit the glucose-stimulated release of GLP-1. And growth hormone secretagogue receptor antagonist, [D-lys3]-GHRP-6, infusion showed comparable increases of glucose stimulated GLP-1 release compared to ghrelin infusion into the portal vein. The data showed that intraportal infusion of ghrelin exerted an inhibitory effect on GLP-1 secretion through growth hormone secretagogue receptor 1α (GHS1α receptor), which indicated that the downregulation of ghrelin secretion after food intake was necessary for incretin effect. Furthermore, our results suggested that the enteric neural net involved hepatic vagal nerve and sympathetic nerve mediated inhibition effect of ghrelin on incretin effect. PMID:25247193

  2. Ghrelin and its interactions with growth hormone, leptin and orexins: implications for the sleep-wake cycle and metabolism.

    PubMed

    García-García, Fabio; Juárez-Aguilar, Enrique; Santiago-García, Juan; Cardinali, Daniel P

    2014-02-01

    Several studies have shown that ghrelin administration promotes wakefulness in rodents, while in human males it induces sleep but has no effect in women. Ghrelin also plays an important role in metabolism and appetite regulation, and as described in this review may participate in the energy balance during sleep. In this review, we summarize some of the effects induced by ghrelin administration on the sleep-wake cycle in relation to the effects of other hormones, such as growth hormone, leptin, and orexin. Finally we discuss the relationship between sleep deprivation, obesity and ghrelin secretion pattern.

  3. Protein-energy wasting modifies the association of ghrelin with inflammation, leptin, and mortality in hemodialysis patients.

    PubMed

    Carrero, Juan J; Nakashima, Ayumu; Qureshi, Abdul R; Lindholm, Bengt; Heimbürger, Olof; Bárány, Peter; Stenvinkel, Peter

    2011-04-01

    Ghrelin abnormalities contribute to anorexia, inflammation, and cardiovascular risk in hemodialysis patients, leading to worse outcome. However, ghrelin levels are influenced by the nutritional status of the individual. We hypothesized that the consequences of ghrelin alterations in hemodialysis patients are context sensitive and dependent on the presence of protein-energy wasting (PEW). In this cross-sectional study of 217 prevalent hemodialysis patients followed for 31 months, we measured ghrelin, leptin, PEW (subjective global assessment), and C-reactive protein (an index of inflammation). Compared to patients in the middle and upper tertile of ghrelin levels, those in the lowest tertile were older, had higher leptin levels and body mass index, and presented an increased mortality risk that persisted after adjustment for age, gender, and dialysis vintage. This risk was lost after correction for comorbidities. Patients with PEW and low ghrelin values had abnormally high C-reactive protein and leptin by multivariate analysis of variance, and the highest mortality risk compared to non-PEW with high ghrelin from all-cause and cardiovascular-related mortality (adjusted hazard ratios of 3.34 and 3.54, respectively). Low ghrelin values in protein-energy wasted hemodialysis patients were linked to a markedly increased cardiovascular mortality risk. Thus, since these patients were more anorectic, our results provide a clinical scenario where ghrelin therapies may be particularly useful.

  4. The ghrelin receptor agonist HM01 mimics the neuronal effects of ghrelin in the arcuate nucleus and attenuates anorexia-cachexia syndrome in tumor-bearing rats.

    PubMed

    Borner, Tito; Loi, Laura; Pietra, Claudio; Giuliano, Claudio; Lutz, Thomas A; Riediger, Thomas

    2016-07-01

    The gastric hormone ghrelin positively affects energy balance by increasing food intake and reducing energy expenditure. Ghrelin mimetics are a possible treatment against cancer anorexia-cachexia syndrome (CACS). This study aimed to characterize the action of the nonpeptidergic ghrelin receptor agonist HM01 on neuronal function, energy homeostasis and muscle mass in healthy rats and to evaluate its possible usefulness for the treatment of CACS in a rat tumor model. Using extracellular single-unit recordings, we tested whether HM01 mimics the effects of ghrelin on neuronal activity in the arcuate nucleus (Arc). Furthermore, we assessed the effect of chronic HM01 treatment on food intake (FI), body weight (BW), lean and fat volumes, and muscle mass in healthy rats. Using a hepatoma model, we investigated the possible beneficial effects of HM01 on tumor-induced anorexia, BW loss, muscle wasting, and metabolic rate. HM01 (10(-7)-10(-6) M) mimicked the effect of ghrelin (10(-8) M) by increasing the firing rate in 76% of Arc neurons. HM01 delivered chronically for 12 days via osmotic minipumps (50 μg/h) increased FI in healthy rats by 24%, paralleled by increased BW, higher fat and lean volumes, and higher muscle mass. Tumor-bearing rats treated with HM01 had 30% higher FI than tumor-bearing controls and were protected against BW loss. HM01 treatment resulted in higher muscle mass and fat mass. Moreover, tumor-bearing rats reduced their metabolic rate following HM01 treatment. Our studies substantiate the possible therapeutic usefulness of ghrelin receptor agonists like HM01 for the treatment of CACS and possibly other forms of disease-related anorexia and cachexia. PMID:27147616

  5. The ghrelin receptor agonist HM01 mimics the neuronal effects of ghrelin in the arcuate nucleus and attenuates anorexia-cachexia syndrome in tumor-bearing rats.

    PubMed

    Borner, Tito; Loi, Laura; Pietra, Claudio; Giuliano, Claudio; Lutz, Thomas A; Riediger, Thomas

    2016-07-01

    The gastric hormone ghrelin positively affects energy balance by increasing food intake and reducing energy expenditure. Ghrelin mimetics are a possible treatment against cancer anorexia-cachexia syndrome (CACS). This study aimed to characterize the action of the nonpeptidergic ghrelin receptor agonist HM01 on neuronal function, energy homeostasis and muscle mass in healthy rats and to evaluate its possible usefulness for the treatment of CACS in a rat tumor model. Using extracellular single-unit recordings, we tested whether HM01 mimics the effects of ghrelin on neuronal activity in the arcuate nucleus (Arc). Furthermore, we assessed the effect of chronic HM01 treatment on food intake (FI), body weight (BW), lean and fat volumes, and muscle mass in healthy rats. Using a hepatoma model, we investigated the possible beneficial effects of HM01 on tumor-induced anorexia, BW loss, muscle wasting, and metabolic rate. HM01 (10(-7)-10(-6) M) mimicked the effect of ghrelin (10(-8) M) by increasing the firing rate in 76% of Arc neurons. HM01 delivered chronically for 12 days via osmotic minipumps (50 μg/h) increased FI in healthy rats by 24%, paralleled by increased BW, higher fat and lean volumes, and higher muscle mass. Tumor-bearing rats treated with HM01 had 30% higher FI than tumor-bearing controls and were protected against BW loss. HM01 treatment resulted in higher muscle mass and fat mass. Moreover, tumor-bearing rats reduced their metabolic rate following HM01 treatment. Our studies substantiate the possible therapeutic usefulness of ghrelin receptor agonists like HM01 for the treatment of CACS and possibly other forms of disease-related anorexia and cachexia.

  6. The role of acyl-glucose in anthocyanin modifications.

    PubMed

    Sasaki, Nobuhiro; Nishizaki, Yuzo; Ozeki, Yoshihiro; Miyahara, Taira

    2014-11-14

    Higher plants can produce a wide variety of anthocyanin molecules through modification of the six common anthocyanin aglycons that they present. Thus, hydrophilic anthocyanin molecules can be formed and stabilized by glycosylation and acylation. Two types of glycosyltransferase (GT) and acyltransferase (AT) have been identified, namely cytoplasmic GT and AT and vacuolar GT and AT. Cytoplasmic GT and AT utilize UDP-sugar and acyl-CoA as donor molecules, respectively, whereas both vacuolar GT and AT use acyl-glucoses as donor molecules. In carnation plants, vacuolar GT uses aromatic acyl-glucoses as the glucose donor in vivo; independently, vacuolar AT uses malylglucose, an aliphatic acyl-glucose, as the acyl-donor. In delphinium and Arabidopsis, p-hydroxybenzoylglucose and sinapoylglucose are used in vivo as bi-functional donor molecules by vacuolar GT and AT, respectively. The evolution of these enzymes has allowed delphinium and Arabidopsis to utilize unique donor molecules for production of highly modified anthocyanins.

  7. Physiological Consequences of Compartmentalized Acyl-CoA Metabolism*

    PubMed Central

    Cooper, Daniel E.; Young, Pamela A.; Klett, Eric L.; Coleman, Rosalind A.

    2015-01-01

    Meeting the complex physiological demands of mammalian life requires strict control of the metabolism of long-chain fatty acyl-CoAs because of the multiplicity of their cellular functions. Acyl-CoAs are substrates for energy production; stored within lipid droplets as triacylglycerol, cholesterol esters, and retinol esters; esterified to form membrane phospholipids; or used to activate transcriptional and signaling pathways. Indirect evidence suggests that acyl-CoAs do not wander freely within cells, but instead, are channeled into specific pathways. In this review, we will discuss the evidence for acyl-CoA compartmentalization, highlight the key modes of acyl-CoA regulation, and diagram potential mechanisms for controlling acyl-CoA partitioning. PMID:26124277

  8. Inhibition of peroxisomal fatty acyl-CoA oxidase by antimycin A.

    PubMed Central

    Vamecq, J; Schepers, L; Parmentier, G; Mannaerts, G P

    1987-01-01

    Peroxisomal fatty acyl-CoA oxidase was inhibited by micromolar concentrations of antimycin A, an inhibitor of mitochondrial respiration. The inhibition was observed with all three substrates tested, i.e. palmitoyl-CoA, trihydroxycoprostanoyl-CoA and hexadecanedioyl-CoA. The peroxisomal D-amino acid oxidase was also inhibited by antimycin, but the peroxisomal L-alpha-hydroxyacid oxidase and uric acid oxidase and the mitochondrial monoamine oxidase were not. The degree of inhibition of acyl-CoA oxidase by antimycin was strongly dependent on the amount of cellular protein present in the assay mixture: at a fixed antimycin concentration, the inhibition was gradually lost with increasing protein concentrations. At a fixed cellular protein concentration in the assay mixtures, the mitochondrial oxidation of glutamate or palmitoylcarnitine was inhibited at antimycin concentrations that were much lower than those required for the inhibition of fatty acyl-CoA oxidase. Our results, nevertheless, demonstrate that antimycin A must be used with caution, when it is added to homogenates or subcellular fractions in order to distinguish between mitochondrial and peroxisomal fatty acid oxidation. PMID:3435468

  9. In Situ Localization and Rhythmic Expression of Ghrelin and ghs-r1 Ghrelin Receptor in the Brain and Gastrointestinal Tract of Goldfish (Carassius auratus).

    PubMed

    Sánchez-Bretaño, Aída; Blanco, Ayelén M; Unniappan, Suraj; Kah, Olivier; Gueguen, Marie-M; Bertucci, Juan I; Alonso-Gómez, Ángel L; Valenciano, Ana I; Isorna, Esther; Delgado, María J

    2015-01-01

    Ghrelin is a gut-brain peptide hormone, which binds to the growth hormone secretagogue receptor (GHS-R) to regulate a wide variety of biological processes in fish. Despite these prominent physiological roles, no studies have reported the anatomical distribution of preproghrelin transcripts using in situ hybridization in a non-mammalian vertebrate, and its mapping within the different encephalic areas remains unknown. Similarly, no information is available on the possible 24-h variations in the expression of preproghrelin and its receptor in any vertebrate species. The first aim of this study was to investigate the anatomical distribution of ghrelin and GHS-R1a ghrelin receptor subtype in brain and gastrointestinal tract of goldfish (Carassius auratus) using immunohistochemistry and in situ hybridization. Our second aim was to characterize possible daily variations of preproghrelin and ghs-r1 mRNA expression in central and peripheral tissues using real-time reverse transcription-quantitative PCR. Results show ghrelin expression and immunoreactivity in the gastrointestinal tract, with the most abundant signal observed in the mucosal epithelium. These are in agreement with previous findings on mucosal cells as the primary synthesizing site of ghrelin in goldfish. Ghrelin receptor was observed mainly in the hypothalamus with low expression in telencephalon, pineal and cerebellum, and in the same gastrointestinal areas as ghrelin. Daily rhythms in mRNA expression were found for preproghrelin and ghs-r1 in hypothalamus and pituitary with the acrophase occurring at nighttime. Preproghrelin, but not ghs-r1a, displayed a similar daily expression rhythm in the gastrointestinal tract with an amplitude 3-fold higher than the rest of tissues. Together, these results described for the first time in fish the mapping of preproghrelin and ghrelin receptor ghs-r1a in brain and gastrointestinal tract of goldfish, and provide the first evidence for a daily regulation of both genes

  10. In Situ Localization and Rhythmic Expression of Ghrelin and ghs-r1 Ghrelin Receptor in the Brain and Gastrointestinal Tract of Goldfish (Carassius auratus)

    PubMed Central

    Unniappan, Suraj; Kah, Olivier; Gueguen, Marie-M.; Bertucci, Juan I.; Alonso-Gómez, Ángel L.; Valenciano, Ana I.; Isorna, Esther; Delgado, María J.

    2015-01-01

    Ghrelin is a gut-brain peptide hormone, which binds to the growth hormone secretagogue receptor (GHS-R) to regulate a wide variety of biological processes in fish. Despite these prominent physiological roles, no studies have reported the anatomical distribution of preproghrelin transcripts using in situ hybridization in a non-mammalian vertebrate, and its mapping within the different encephalic areas remains unknown. Similarly, no information is available on the possible 24-h variations in the expression of preproghrelin and its receptor in any vertebrate species. The first aim of this study was to investigate the anatomical distribution of ghrelin and GHS-R1a ghrelin receptor subtype in brain and gastrointestinal tract of goldfish (Carassius auratus) using immunohistochemistry and in situ hybridization. Our second aim was to characterize possible daily variations of preproghrelin and ghs-r1 mRNA expression in central and peripheral tissues using real-time reverse transcription-quantitative PCR. Results show ghrelin expression and immunoreactivity in the gastrointestinal tract, with the most abundant signal observed in the mucosal epithelium. These are in agreement with previous findings on mucosal cells as the primary synthesizing site of ghrelin in goldfish. Ghrelin receptor was observed mainly in the hypothalamus with low expression in telencephalon, pineal and cerebellum, and in the same gastrointestinal areas as ghrelin. Daily rhythms in mRNA expression were found for preproghrelin and ghs-r1 in hypothalamus and pituitary with the acrophase occurring at nighttime. Preproghrelin, but not ghs-r1a, displayed a similar daily expression rhythm in the gastrointestinal tract with an amplitude 3-fold higher than the rest of tissues. Together, these results described for the first time in fish the mapping of preproghrelin and ghrelin receptor ghs-r1a in brain and gastrointestinal tract of goldfish, and provide the first evidence for a daily regulation of both genes

  11. Ghrelin and memory: differential effects on acquisition and retrieval.

    PubMed

    Carlini, Valeria P; Ghersi, Marisa; Schiöth, Helgi B; de Barioglio, Susana R

    2010-06-01

    In a previous paper we have demonstrated that the orexigenic peptide Ghrelin (Ghr), increases memory retention in rats and mice. In the present work we evaluated the Ghr effect when it was administered previous the training session or previous the test session (24h after training) on the memory performance, using step-down test. The results showed that the intra-hippocampal Ghr administration previous the training session improved the long-term memory in this task, but did not modify the short-term memory. Nevertheless, when the Ghr was administrated previous the test session, no changes were observed in the memory performance. Taking into account these results and other previously published by our group, we could hypothesizes that Ghr may modulate specific molecular intermediates involved in memory acquisition/consolidation but not in the retrieval. PMID:20214944

  12. Plasma ghrelin and growth hormone regulation in response to metabolic state in hybrid striped bass: effects of feeding, ghrelin and insulin-like growth factor-I on in vivo and in vitro GH secretion.

    PubMed

    Picha, Matthew E; Strom, Christina N; Riley, Larry G; Walker, Alicia A; Won, Eugene T; Johnstone, William M; Borski, Russell J

    2009-05-01

    The regulation of growth hormone (GH) secretion by ghrelin during variable metabolic states is poorly understood. We examined plasma GH and ghrelin in hybrid striped bass (HSB) undergoing seasonally-based feeding and temperature manipulations. Fasting for 21 days (d) at 24 degrees C resulted in catabolism and up-regulation of plasma GH and ghrelin relative to fed controls. Continued fasting during cold-banking (14 degrees C, 90 d) resulted in a further 43-fold increase in ghrelin while GH remained elevated. A subsequent 19 day refeeding period at 24 degrees C elicited hyperphagic and compensatory growth responses, accompanied by declines in ghrelin and GH. We then tested the role of ghrelin in stimulating GH release in vivo and in vitro. Intraperitoneal injections of ghrelin resulted in dose-dependent increases in plasma GH after 6 hours (h). Ghrelin also increased GH release from HSB pituitaries during 6h incubations. Lastly, we assessed how metabolic state, ghrelin and insulin-like growth factor-I (IGF-I) affect in vitro pituitary GH release. Spontaneous GH release was 5.2-fold higher from pituitaries of fasted compared with fed animals. Ghrelin was equally effective in stimulating GH release from pituitaries of fed and starved animals, while it was ineffective in enhancing GH release from pituitaries of starved (21 d) then refed (4d) HSB. Incubation with IGF-I inhibited GH release regardless of metabolic state. These studies are the first to show that seasonally-based periods of feed deprivation and low temperature yield sustained increases in GH secretion that are likely mediated, at least partially, through elevated ghrelin, reduced IGF-I negative feedback and fasting-induced spontaneous GH release.

  13. Ghrelin inhibits the apoptosis of MC3T3-E1 cells through ERK and AKT signaling pathway

    SciTech Connect

    Liang, Qiu-Hua; Liu, Yuan; Wu, Shan-Shan; Cui, Rong-Rong; Yuan, Ling-Qing Liao, Er-Yuan

    2013-11-01

    Ghrelin is a 28-amino-acid peptide that acts as a natural endogenous ligand of the growth hormone secretagogue receptor (GHSR) and strongly stimulates the release of growth hormone from the hypothalamus–pituitary axis. Previous studies have identified the important physiological effects of ghrelin on bone metabolism, such as regulating proliferation and differentiation of osteoblasts, independent of GH/IGF-1 axis. However, research on effects and mechanisms of ghrelin on osteoblast apoptosis is still rare. In this study, we identified expression of GHSR in MC3T3-E1 cells and determined the effects of ghrelin on the apoptosis of osteoblastic MC3T3-E1 cells and the mechanism involved. Our data demonstrated that ghrelin inhibited the apoptosis of osteoblastic MC3T3-E1 cells induced by serum deprivation, as determined by terminal deoxynucleotidyl transferase-mediated deoxyribonucleotide triphosphate nick end-labeling (TUNEL) and ELISA assays. Moreover, ghrelin upregulated Bcl-2 expression and downregulated Bax expression in a dose-dependent manner. Our study also showed decreased activated caspase-3 activity under the treatment of ghrelin. Further study suggested that ghrelin stimulated the phosphorylation of ERK and AKT. Pretreatment of cells with the ERK inhibitor PD98059, PI3K inhibitor LY294002, and GHSR-siRNA blocked the ghrelin-induced activation of ERK and AKT, respectively; however, ghrelin did not stimulate the phosphorylation of p38 or JNK. PD90859, LY294002 and GHSR-siRNA attenuated the anti-apoptosis effect of ghrelin in MC3T3-E1 cells. In conclusion, ghrelin inhibits the apoptosis of osteoblastic MC3T3-E1 cells induced by serum deprivation, which may be mediated by activating the GHSR/ERK and GHSR/PI3K/AKT signaling pathways. - Highlights: • We explored the effects of ghrelin on serum deprivation-induced MC3T3-E1 cells apoptosis. • Both ELISA and TUNEL were used to detect the apoptosis. • The receptor of ghrelin, GHSR, was expressed in MC3T3-E1

  14. Central ghrelin increases food foraging/hoarding that is blocked by GHSR antagonism and attenuates hypothalamic paraventricular nucleus neuronal activation.

    PubMed

    Thomas, Michael A; Ryu, Vitaly; Bartness, Timothy J

    2016-02-01

    The stomach-derived "hunger hormone" ghrelin increases in the circulation in direct response to time since the last meal, increasing preprandially and falling immediately following food consumption. We found previously that peripheral injection of ghrelin potently stimulates food foraging (FF), food hoarding (FH), and food intake (FI) in Siberian hamsters. It remains, however, largely unknown if central ghrelin stimulation is necessary/sufficient to increase these behaviors regardless of peripheral stimulation of the ghrelin receptor [growth hormone secretagogue receptor (GHSR)]. We injected three doses (0.01, 0.1, and 1.0 μg) of ghrelin into the third ventricle (3V) of Siberian hamsters and measured changes in FF, FH, and FI. To test the effects of 3V ghrelin receptor blockade, we used the potent GHSR antagonist JMV2959 to block these behaviors in response to food deprivation or a peripheral ghrelin challenge. Finally, we examined neuronal activation in the arcuate nucleus and paraventricular hypothalamic nucleus in response to peripheral ghrelin administration and 3V GHSR antagonism. Third ventricular ghrelin injection significantly increased FI through 24 h and FH through day 4. Pretreatment with 3V JMV2959 successfully blocked peripheral ghrelin-induced increases in FF, FH, and FI at all time points and food deprivation-induced increases in FF, FH, and FI up to 4 h. c-Fos immunoreactivity was significantly reduced in the paraventricular hypothalamic nucleus, but not in the arcuate nucleus, following pretreatment with intraperitoneal JMV2959 and ghrelin. Collectively, these data suggest that central GHSR activation is both necessary and sufficient to increase appetitive and consummatory behaviors in Siberian hamsters.

  15. Hierarchical autoinduction in Ralstonia solanacearum: control of acyl-homoserine lactone production by a novel autoregulatory system responsive to 3-hydroxypalmitic acid methyl ester.

    PubMed Central

    Flavier, A B; Ganova-Raeva, L M; Schell, M A; Denny, T P

    1997-01-01

    Bacteria employ autoinduction systems to sense the onset of appropriate cell density for expression of developmental genes. In many gram-negative bacteria, autoinduction involves the production of and response to diffusible acylated-homoserine lactones (acyl-HSLs) and is mediated by members of the LuxR and LuxI families. Ralstonia (Pseudomonas) solanacearum, a phytopathogenic bacterium that appears to autoregulate its virulence genes, produces compounds that promote expression of several heterologous acyl-HSL-responsive reporter gene constructs. High-pressure liquid chromatography of highly concentrated ethyl acetate extracts revealed that culture supernatants of strain AW1 contained two compounds with retention times similar to N-hexanoyl- and N-octanoyl-HSL. To investigate the role of these acyl-HSLs in R. solanacearum virulence gene expression, transposon mutants that were deficient for inducing an acyl-HSL-responsive reporter in Agrobacterium tumefaciens were generated. Three loci involved in normal acyl-HSL production were identified, one of which was shown to contain the divergently transcribed solR and solI genes, the luxR and luxI homologs, respectively. A 4.1-kb fragment containing solR and solI enabled all of the mutants (regardless of the locus inactivated) and a naturally acyl-HSL-defective strain of R. solanacearum to produce acyl-HSLs. Inactivation of solI abolished production of all detectable acyl-HSLs but affected neither the expression of virulence genes in culture nor the ability to wilt tomato plants. AW1 has a functional autoinduction system, because (i) expression of solI required SolR and acyl-HSL and (ii) expression of a gene linked to solR and solI, designated aidA, was acyl-HSL dependent. Because AidA has no homologs in the protein databases, its discovery provided no clues as to the role of acyl-HSLs in R. solanacearum gene regulation. However, expression of solR and solI required the global LysR-type virulence regulator PhcA, and both

  16. Efficient production of di- and tri-acylated mannosylerythritol lipids as glycolipid biosurfactants by Pseudozyma parantarctica JCM 11752(T).

    PubMed

    Morita, Tomotake; Konishi, Masaaki; Fukuoka, Tokuma; Imura, Tomohiro; Sakai, Hideki; Kitamoto, Dai

    2008-01-01

    Mannosylerythritol lipids (MELs) are one of the most promising biosurfactants known, because of their multifunctionality and biocompatibility. In order to attain an efficient production of MELs, Pseudozyma parantarctica JCM 11752(T), which is a newly identified strain of the genus, was examined for the productivity of MELs at different culture conditions. The yeast strain showed significant cell growth and production of di-acylated MELs even at 36 degrees C. In contrast, on conventional high-level MEL producers including P. rugulosa, the MEL yield considerably decreased with an increase of the cultivation temperature at over 30 degrees C. On P. parantarctica, soybean oil and sodium nitrate were the best carbon and nitrogen sources, respectively. Under the optimal conditions on a shake-flask culture at 34 degrees C, the amount of di-acylated MELs reached over 100 g/L by intermittent feeding of only soybean oil. Interestingly, the yeast strain produced tri-acylated MELs as well as di-acylated ones when grown on the medium containing higher soybean oil concentrations than 8% (vol/vol). The production of tri-acylated MELs was significantly accelerated at between 34 and 36 degrees C. With 20 % (vol/vol) of soybean oil at 34 degrees C, the yield of tri-acylated MELs reached 22.7 g/L. The extracellular lipase activity considerably depended on the culture temperature, and became the maximum at 34 degrees C; this would bring the accelerated production of tri-acylated MELs. Accordingly, the present strain of P. parantarctica provided high efficiency in MEL production at elevated temperatures compared to conventional MEL producers, and would thus be highly advantageous for the commercial production of the promising biosurfactants. PMID:18781056

  17. Acyl-acyl carrier protein as a source of fatty acids for bacterial bioluminescence

    SciTech Connect

    Byers, D.M.; Meighen, E.A.

    1985-09-01

    Pulse-chase experiments with (/sup 3/H)tetradecanoic acid and ATP showed that the bioluminescence-related 32-kDa acyltransferase from Vibrio harveyi can specifically catalyze the deacylation of a /sup 3/H-labeled 18-kDa protein observed in extracts of this bacterium. The 18-kDa protein has been partially purified and its physical and chemical properties strongly indicate that it is fatty acyl-acyl carrier protein (acyl-ACP). Both this V. harveyi (/sup 3/H)acylprotein and (/sup 3/H)palmitoyl-ACP from Escherichia coli were substrates in vitro for either the V. harveyi 32-kDa acyltransferase or the analogous enzyme (34K) from Photobacterium phosphoreum. TLC analysis indicated that the hexane-soluble product of the reaction is fatty acid. No significant cleavage of either E. coli or V. harveyi tetradecanoyl-ACP was observed in extracts of these bacteria unless the 32-kDa or 34K acyltransferase was present. Since these enzymes are believed to be responsible for the supply of fatty acids for reduction to form the aldehyde substrate of luciferase, the above results suggest that long-chain acyl-ACP is the source of fatty acids for bioluminescence.

  18. Sequence, genomic organization and expression of ghrelin receptor in grass carp, Ctenopharyngodon idellus.

    PubMed

    Cai, Wen-jing; Yuan, Xiao-chen; Yuan, Yong-chao; Xie, Shou-qi; Gong, Yuan; Su, Hang; Qiao, Yang

    2015-01-01

    The growth hormone secretagogue-receptor (GHS-R) is an endogenous receptor for the gut hormone ghrelin. Here we report the identification and characterization of GHS-R1a in grass carp, Ctenopharyngodon idellus. The full-length GHS-R1a cDNA contained a 1803-bp coding domain sequence which encoded a peptide of 360 amino acid residues. Comparison analysis revealed that the amino acid sequences of GHS-R1a were highly conserved in vertebrates and shared 97% amino acid identity with zebrafish (Danio rerio), 96% with jian carp (Cyprinus carpio var. Jian) and 93% with goldfish (Carassius auratus). The GHS-R1a showed the highest level of mRNA expression in the pituitary, followed by the brain and liver, and the lowest expression was observed in the hindgut. Intraperitoneally injected with grass carp ghrelin (50, 100 and 150ng/g body weight (BW)), grass carp showed greater mRNA expression of GHS-R1a in the pituitary compared with saline injected at 0.5h postinjection. It was observed that food deprivation could promote the expression of ghrelin and GHS-R1a in the pituitary, demonstrating that nutritional status can influence the expression of both ghrelin and GHS-R1a in the pituitary. After a 2- or 4-week fast, plasma growth hormone (GH) increased, was positively correlated with ghrelin and GHS-R1a mRNA expression levels in the pituitary. These results suggested that the involvement of ghrelin/GHS-R1a systems in mediating the effects of nutritional status and ghrelin on growth processes in grass carp.

  19. Effects of ghrelin on the apoptosis of human neutrophils in vitro.

    PubMed

    Li, Bin; Zeng, Mian; Zheng, Haichong; Huang, Chunrong; He, Wanmei; Lu, Guifang; Li, Xia; Chen, Yanzhu; Xie, Ruijie

    2016-09-01

    Acute respiratory distress syndrome (ARDS) is characterized by lung inflammation and the diffuse infiltration of neutrophils into the alveolar space. Neutrophils are abundant, short-lived leukocytes that play a key role in immune defense against microbial infections. These cells die via apoptosis following the activation and uptake of microbes, and will also enter apoptosis spontaneously at the end of their lifespan if they do not encounter pathogens. Apoptosis is essential for the removal of neutrophils from inflamed tissues and for the timely resolution of neutrophilic inflammation. Ghrelin is an endogenous ligand for the growth hormone (GH) secretagogue receptor, produced and secreted mainly from the stomach. Previous studies have reported that ghrelin exerts anti-inflammatory effects in lung injury through the regulation of the apoptosis of different cell types; however, the ability of ghrelin to regulate alveolar neutrophil apoptosis remains largely undefined. We hypothesized that ghrelin may have the ability to modulate neutrophil apoptosis. In this study, to examine this hypothesis, we investigated the effects of ghrelin on freshly isolated neutrophils in vitro. Our findings demonstrated a decrease in the apoptotic ratio (as shown by flow cytometry), as well as in the percentage of cells with decreased mitochondrial membrane potential (ΔΨm) and in the terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick‑end labeling-positive rate, accompanied by an increased B-cell lymphoma 2/Bax ratio and the downregulation of cleaved caspase-3 in neutrophils following exposure to lipopolysaccharide (100 ng/ml). However, pre-treatment with ghrelin at a physiological level (100 nM) did not have a notable influence on the neutrophils in all the aforementioned tests. Our findings suggest that ghrelin may not possess the ability to modulate the neutrophil lifespan in vitro. PMID:27431014

  20. Ghrelin relieves cancer cachexia associated with the development of lung adenocarcinoma in mice.

    PubMed

    Tsubouchi, Hironobu; Yanagi, Shigehisa; Miura, Ayako; Matsumoto, Nobuhiro; Kangawa, Kenji; Nakazato, Masamitsu

    2014-11-15

    Cancer cachexia is a multifactorial, critical illness syndrome characterized by an ongoing loss of skeletal muscle and adipose tissue. The reductions in body weight and skeletal muscle mass are important prognostic indicators for cancer patients that are refractory to current therapies. Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor, is produced in the stomach, stimulates food intake and growth hormone secretion, suppresses inflammation, and prevents muscle catabolism. We investigated the pharmacological potential of ghrelin in the treatment of cancer cachexia by using urethane-treated, bronchioalveolar epithelium-specific Pten-deficient mice that developed lung adenocarcinomas. Ghrelin or phosphate-buffered saline was given to mice daily for four weeks beginning at five months after urethane injection, which corresponded to the time point of lung adenocarcinoma formation. Ghrelin inhibited the inductions of C-reactive protein, tumor necrosis factor-α, interleukin-1β, and interleukin-6, mitigated the reduction of food intake and fat mass, and consequently ameliorated body weight loss in the mouse model of lung adenocarcinoma. We also demonstrated that skeletal muscle mass and muscle contraction force in both fast-twitch muscle and slow-twitch muscle were retained in ghrelin-treated mice in conjunction with an upregulation of local insulin-like growth factor 1/Akt signaling. In addition, ghrelin administration reduced the expressions of phosphorylated-p38 mitogen-activated protein kinase, phosphorylated-nuclear factor-kappa B, Forkhead box protein O1, muscle RING-finger protein-1, and F-Box protein 32 in the lysates of skeletal muscle in the tumor-bearing state. Our results indicate that ghrelin administration exerts a protective effect against cancer cachexia by ameliorating skeletal muscle wasting and regulating systemic inflammation.

  1. Effects of ghrelin on the apoptosis of human neutrophils in vitro

    PubMed Central

    Li, Bin; Zeng, Mian; Zheng, Haichong; Huang, Chunrong; He, Wanmei; Lu, Guifang; Li, Xia; Chen, Yanzhu; Xie, Ruijie

    2016-01-01

    Acute respiratory distress syndrome (ARDS) is characterized by lung inflammation and the diffuse infiltration of neutrophils into the alveolar space. Neutrophils are abundant, short-lived leukocytes that play a key role in immune defense against microbial infections. These cells die via apoptosis following the activation and uptake of microbes, and will also enter apoptosis spontaneously at the end of their lifespan if they do not encounter pathogens. Apoptosis is essential for the removal of neutrophils from inflamed tissues and for the timely resolution of neutrophilic inflammation. Ghrelin is an endogenous ligand for the growth hormone (GH) secretagogue receptor, produced and secreted mainly from the stomach. Previous studies have reported that ghrelin exerts anti-inflammatory effects in lung injury through the regulation of the apoptosis of different cell types; however, the ability of ghrelin to regulate alveolar neutrophil apoptosis remains largely undefined. We hypothesized that ghrelin may have the ability to modulate neutrophil apoptosis. In this study, to examine this hypothesis, we investigated the effects of ghrelin on freshly isolated neutrophils in vitro. Our findings demonstrated a decrease in the apoptotic ratio (as shown by flow cytometry), as well as in the percentage of cells with decreased mitochondrial membrane potential (ΔΨm) and in the terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick-end labeling-positive rate, accompanied by an increased B-cell lymphoma 2/Bax ratio and the downregulation of cleaved caspase-3 in neutrophils following exposure to lipopolysaccharide (100 ng/ml). However, pre-treatment with ghrelin at a physiological level (100 nM) did not have a notable influence on the neutrophils in all the aforementioned tests. Our findings suggest that ghrelin may not possess the ability to modulate the neutrophil lifespan in vitro. PMID:27431014

  2. 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

  3. Silencing of ghrelin receptor expression inhibits endometrial cancer cell growth in vitro and in vivo.

    PubMed

    Fung, Jenny N T; Jeffery, Penny L; Lee, John D; Seim, Inge; Roche, Deborah; Obermair, Andreas; Chopin, Lisa K; Chen, Chen

    2013-07-15

    Ghrelin is a 28-amino acid peptide hormone produced predominantly in the stomach but also in a range of normal cell types and tumors, where it has endocrine, paracrine, and autocrine roles. Previously, we have demonstrated that ghrelin has proliferative and antiapoptotic effects in endometrial cancer cell lines, suggesting a potential role in promoting tumor growth. In the present study, we investigated the effect of ghrelin receptor, GHSR, and gene silencing in vitro and in vivo and characterized ghrelin and GHSR1a protein expression in human endometrial tumors. GHSR gene silencing was achieved in the Ishikawa and KLE endometrial cancer cell lines, using a lentiviral short-hairpin RNA targeting GHSR. The effects of GHSR1a knockdown were further analyzed in vivo using the Ishikawa cell line in a NOD/SCID xenograft model. Cell proliferation was reduced in cultured GHSR1a knockdown Ishikawa and KLE cells compared with scrambled controls in the absence of exogenously applied ghrelin and in response to exogenous ghrelin (1,000 nM). The tumor volumes were reduced significantly in GHSR1a knockdown Ishikawa mouse xenograft tumors compared with scrambled control tumours. Using immunohistochemistry, we demonstrated that ghrelin and GHSR1a are expressed in benign and cancerous glands in human endometrial tissue specimens, although there was no correlation between the intensity of staining and cancer grade. These data indicate that downregulation of GHSR expression significantly inhibits endometrial cancer cell line and mouse xenograft tumour growth. This is the first preclinical evidence that downregulation of GHSR may be therapeutic in endometrial cancer.

  4. Acylated iridoids with cytotoxicity from Valeriana jatamansi.

    PubMed

    Lin, Sheng; Shen, Yun-Heng; Li, Hui-Liang; Yang, Xian-Wen; Chen, Tao; Lu, Long-Hai; Huang, Zheng-Sheng; Liu, Run-Hui; Xu, Xi-Ke; Zhang, Wei-Dong; Wang, Hui

    2009-04-01

    Thirteen new acylated iridoids, jatamanvaltrates A-M (1-13), together with nine known valepotriates (14-22), were isolated from the whole plants of Valeriana jatamansi (syn. Valeriana wallichii). The structures of these new compounds were assigned by detailed interpretation of spectroscopic data. Jatamanvaltrates D (4) and H (9) are the first examples of naturally occurring valepotriates containing an o-hydroxybenzoyloxy moiety at C-10. All isolated compounds were tested for their cytotoxicity against lung adenocarcinoma (A549), metastatic prostate cancer (PC-3M), colon cancer (HCT-8), and hepatoma (Bel7402) cell lines.

  5. Weight loss during oligofructose supplementation is associated with decreased ghrelin and increased peptide YY in overweight and obese adults2

    PubMed Central

    Parnell, Jill A; Reimer, Raylene A

    2013-01-01

    Background Rodent studies show that oligofructose promotes weight loss, stimulates satiety hormone secretion, reduces energy intake, and improves lipid profiles. Objective Our objective was to examine the effects of oligofructose supplementation on body weight and satiety hormone concentrations in overweight and obese adults. Design This study was a randomized, double-blind, placebo-controlled trial. Forty-eight otherwise healthy adults with a body mass index (in kg/m2) > 25 were randomly assigned to receive 21 g oligo-fructose/d or a placebo (maltodextrin) for 12 wk. Body composition (by dual-energy X-ray absorptiometry); meal tolerance tests, including satiety hormone response; food intake; and subjective appetite ratings were determined. Results There was a reduction in body weight of 1.03 ±0.43 kg with oligofructose supplementation, whereas the control group experienced an increase in body weight of 0.45 ± 0.31 kg over 12 wk (P = 0.01). A lower area under the curve (AUC) for ghrelin (P = 0.004) and a higher AUC for peptide YY (PYY) with oligofructose (P = 0.03) coincided with a reduction in self-reported caloric intake (P ≤ 0.05). Glucose decreased in the oligofructose group and increased in the control group between initial and final tests (P ≤ 0.05). Insulin concentrations mirrored this pattern (P ≤ 0.05). Oligofructose supplementation did not affect plasma active glucagon-like peptide 1 secretion. According to a visual analog scale designed to assess side effects, oligofructose was well tolerated. Conclusions Independent of other lifestyle changes, oligofructose supplementation has the potential to promote weight loss and improve glucose regulation in overweight adults. Suppressed ghrelin and enhanced PYY may contribute in part to the reduction in energy intake. The trial was registered at clinicaltrials.gov as NCT00522353. PMID:19386741

  6. Reaction of /alpha/,/beta/-unsaturated acyl isothiocyanates with salts of dithiocarbamic acids

    SciTech Connect

    Krus, K.; Masias, A.; Beletskaya, I.P.

    1989-01-10

    The reaction of unsaturated isothiocyanates with the sodium and calcium salts of N-alkyl- and N,N-dialkyldithiocarbamic acids was studied. Depending on the structure of the dithiocarbamate, the reaction products are thiazines or acyl dithiocarbamates. For the salts of methyldithiocarbamic acid the effect of the concentration and the nature of the metal on the relative yields of 6-phenyl-3-methylpropiorhodanine and 6-phenylpropiorhodanine was studied. A method is proposed for the synthesis of 3-substituted propiorhodanines.

  7. The Association of Polymorphisms in Leptin/Leptin Receptor Genes and Ghrelin/Ghrelin Receptor Genes With Overweight/Obesity and the Related Metabolic Disturbances: A Review

    PubMed Central

    Ghalandari, Hamid; Hosseini-Esfahani, Firoozeh; Mirmiran, Parvin

    2015-01-01

    Context: Leptin and ghrelin are two important appetite and energy balance-regulating peptides. Common polymorphisms in the genes coding these peptides and their related receptors are shown to be associated with body weight, different markers of obesity and metabolic abnormalities. This review article aims to investigate the association of common polymorphisms of these genes with overweight/obesity and the metabolic disturbances related to it. Evidence Acquisition: The keywords leptin, ghrelin, polymorphism, single-nucleotide polymorphism (SNP), obesity, overweight, Body Mass Index, metabolic syndrome, and type 2 diabetes mellitus (T2DM) (MeSH headings) were used to search in the following databases: Pubmed, Sciencedirect (Elsevier), and Google scholar. Overall, 24 case-control studies, relevant to our topic, met the criteria and were included in the review. Results: The most prevalent leptin/leptin receptor genes (LEP/LEPR) and ghrelin/ghrelin receptor genes (GHRL/GHSR) single nucleotide polymorphisms studied were LEP G-2548A, LEPR Q223R, and Leu72Met, respectively. Nine studies of the 17 studies on LEP/LEPR, and three studies of the seven studies on GHRL/GHSR showed significant relationships. Conclusions: In general, our study suggests that the association between LEP/LEPR and GHRL/GHSR with overweight/obesity and the related metabolic disturbances is inconclusive. These results may be due to unidentified gene-environment interactions. More investigations are needed to further clarify this association. PMID:26425125

  8. Seasonal response of ghrelin, growth hormone, and insulin-like growth factor I in the free-ranging Florida manatee (Trichechus manatus latirostris)

    USGS Publications Warehouse

    Tighe, Rachel L; Bonde, Robert K.; Avery, Julie P.

    2016-01-01

    Seasonal changes in light, temperature, and food availability stimulate a physiological response in an animal. Seasonal adaptations are well studied in Arctic, Sub-Arctic, and hibernating mammals; however, limited studies have been conducted in sub-tropical species. The Florida manatee (Trichechus manatus latirostris), a sub-tropical marine mammal, forages less during colder temperatures and may rely on adipose stores for maintenance energy requirements. Metabolic hormones, growth hormone (GH), insulin-like growth factor (IGF)-I, and ghrelin influence growth rate, accretion of lean and adipose tissue. They have been shown to regulate seasonal changes in body composition. The objective of this research was to investigate manatee metabolic hormones in two seasons to determine if manatees exhibit seasonality and if these hormones are associated with seasonal changes in body composition. In addition, age related differences in these metabolic hormones were assessed in multiple age classes. Concentrations of GH, IGF-I, and ghrelin were quantified in adult manatee serum using heterologous radioimmunoassays. Samples were compared between short (winter) and long (summer) photoperiods (n = 22 male, 20 female) and by age class (adult, juvenile, and calf) in long photoperiods (n = 37). Short photoperiods tended to have reduced GH (p = 0.08), greater IGF-I (p = 0.01), and greater blubber depth (p = 0.03) compared with long photoperiods. No differences were observed in ghrelin (p = 0.66). Surprisingly, no age related differences were observed in IGF-I or ghrelin concentrations (p > 0.05). However, serum concentrations of GH tended (p = 0.07) to be greater in calves and juveniles compared with adults. Increased IGF-I, greater blubber thickness, and reduced GH during short photoperiod suggest a prioritization for adipose deposition. Whereas, increased GH, reduced blubber thickness, and decreased IGF-I in long photoperiod suggest prioritization of lean tissue

  9. 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.

  10. 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...

  11. Ghrelin inhibits high glucose-induced 16HBE cells apoptosis by regulating Wnt/β-catenin pathway.

    PubMed

    Liu, Xiaoyan; Chen, Dilong; Wu, Zhongjun; Li, Jing; Li, Jianqiang; Zhao, Hui; Liu, Tanzhen

    2016-09-01

    Ghrelin has a protective effect on diabetes and its complications. To expound its probable molecular mechanisms, we investigated the effects of ghrelin on high glucose (HG)-induced cell apoptosis and intracellular signaling pathways in cultured human bronchial epithelial cells (16HBE). In this study, we firstly came to conclusion that HG-induced 16HBE apoptosis was significantly inhibited by co-treatment of ghrelin. The molecular mechanism of ghrelin-induced protective effects for lungs is still not understood. We reported here for the first time that ghrelin can not only eliminate apoptosis of 16HBE, but also regulate the disordered cell cycle caused by HG. We speculated here that ghrelin inhibits the apoptosis of 16HBE by regulating the abnormal cell cycle to some extent. The mechanism may be that ghrelin up-regulates the expression of cyclin D1 via regulating Wnt/β-catenin pathway, which has an intimate relationship with lung diseases. These results suggested the possible role of ghrelin in treating diabetic lung diseases, especially in view of its low toxicity in humans. PMID:27378423

  12. The CB1 receptor mediates the peripheral effects of ghrelin on AMPK activity but not on growth hormone release.

    PubMed

    Kola, Blerina; Wittman, Gábor; Bodnár, Ibolya; Amin, Faisal; Lim, Chung Thong; Oláh, Márk; Christ-Crain, Mirjam; Lolli, Francesca; van Thuijl, Hinke; Leontiou, Chrysanthia A; Füzesi, Tamás; Dalino, Paolo; Isidori, Andrea M; Harvey-White, Judith; Kunos, George; Nagy, György M; Grossman, Ashley B; Fekete, Csaba; Korbonits, Márta

    2013-12-01

    This study aimed to investigate whether the growth hormone release and metabolic effects of ghrelin on AMPK activity of peripheral tissues are mediated by cannabinoid receptor type 1 (CB1) and the central nervous system. CB1-knockout (KO) and/or wild-type mice were injected peripherally or intracerebroventricularly with ghrelin and CB1 antagonist rimonabant to study tissue AMPK activity and gene expression (transcription factors SREBP1c, transmembrane protein FAS, enzyme PEPCK, and protein HSL). Growth hormone levels were studied both in vivo and in vitro. Peripherally administered ghrelin in liver, heart, and adipose tissue AMPK activity cannot be observed in CB1-KO or CB1 antagonist-treated mice. Intracerebroventricular ghrelin treatment can influence peripheral AMPK activity. This effect is abolished in CB1-KO mice and by intracerebroventricular rimonabant treatment, suggesting that central CB1 receptors also participate in the signaling pathway that mediates the effects of ghrelin on peripheral tissues. Interestingly, in vivo or in vitro growth hormone release is intact in response to ghrelin in CB1-KO animals. Our data suggest that the metabolic effects of ghrelin on AMPK in peripheral tissues are abolished by the lack of functional CB1 receptor via direct peripheral effect and partially through the central nervous system, thus supporting the existence of a possible ghrelin-cannabinoid-CB1-AMPK pathway.

  13. 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.

  14. Mechanism of Cytosolic Phospholipase A(2) Activation in Ghrelin Protection of Salivary Gland Acinar Cells against Ethanol Cytotoxicity.

    PubMed

    Slomiany, Bronislaw L; Slomiany, Amalia

    2010-01-01

    Ghrelin, a peptide hormone, newly identified in oral mucosal tissues, has emerged recently as an important mediator of the processes of mucosal defense. Here, we report on the mechanism of ghrelin protection against ethanol cytotoxicity in rat sublingual salivary gland cells. The protective effect of ghrelin was associated with the increase in NO and PGE2, and upregulation in cytosolic phospholipase A(2) (cPLA(2)) activity and arachidonic acid (AA) release. The loss in countering effect of ghrelin occurred with cNOS inhibitor, L-NAME, as well as indomethacin and COX-1 inhibitor, SC-560, while COX-2 inhibitor, NS-398, and iNOS inhibitor, 1400W, had no effect. The effect of L-NAME was reflected in the inhibition of ghrelin-induced cell capacity for NO production, cPLA(2) activation and PGE2 generation, whereas indomethacin caused only the inhibition in PGE2. Moreover, the ghrelin-induced up-regulation in AA release was reflected in the cPLA(2) phosphorylation and S-nitrosylation. Inhibition in ghrelin-induced S-nitrosylation was attained with L-NAME, whereas the ERK inhibitor, PD98059, caused the blockage in cPLA(2) protein phosphorylation as well as S-nitrosylation. Thus, ghrelin protection of salivary gland cells against ethanol involves cNOS-derived NO induction of cPLA(2) activation through S-nitrosylation for the increase in AA release at the site of COX-1 action for PGE2 synthesis.

  15. Acyl-ACP Substrate Recognition in Burkholderia mallei BmaI1 Acyl-Homoserine Lactone Synthase

    PubMed Central

    2015-01-01

    The acyl-homoserine lactone (AHL) autoinducer mediated quorum sensing regulates virulence in several pathogenic bacteria. The hallmark of an efficient quorum sensing system relies on the tight specificity in the signal generated by each bacterium. Since AHL signal specificity is derived from the acyl-chain of the acyl-ACP (ACP = acyl carrier protein) substrate, AHL synthase enzymes must recognize and react with the native acyl-ACP with high catalytic efficiency while keeping reaction rates with non-native acyl-ACPs low. The mechanism of acyl-ACP substrate recognition in these enzymes, however, remains elusive. In this study, we investigated differences in catalytic efficiencies for shorter and longer chain acyl-ACP substrates reacting with an octanoyl-homoserine lactone synthase Burkholderia mallei BmaI1. With the exception of two-carbon shorter hexanoyl-ACP, the catalytic efficiencies of butyryl-ACP, decanoyl-ACP, and octanoyl-CoA reacting with BmaI1 decreased by greater than 20-fold compared to the native octanoyl-ACP substrate. Furthermore, we also noticed kinetic cooperativity when BmaI1 reacted with non-native acyl-donor substrates. Our kinetic data suggest that non-native acyl-ACP substrates are unable to form a stable and productive BmaI1·acyl-ACP·SAM ternary complex and are thus effectively discriminated by the enzyme. These results offer insights into the molecular basis of substrate recognition for the BmaI1 enzyme. PMID:25215658

  16. Emulsifying properties of acylated rapeseed (Brassica napus L.) peptides.

    PubMed

    Sánchez-Vioque, Raúl; Bagger, Christian L; Larré, Colette; Guéguen, Jacques

    2004-03-01

    A peptide fraction having an average size of 5.6 amino acids has been purified from a rapeseed hydrolyzate, acylated using C(10)-C(14) acyl chlorides, and the surface tension values at the air-water interface and emulsifying properties studied. As compared with standard surface-active proteins, such as bovine serum albumin (BSA), and with detergents such as sodium dodecyl sulfate (SDS), acylated peptides exhibited particular surface characteristics. The surface tension at air-water interface of acylated peptides ranged from 29.1 to 37.8 mN/m at equilibrium; these values were considerably lower than those for BSA and closer those for SDS, suggesting that acylated peptides pack at the air-water interface more like detergents than like proteins. The adsorption of acylated peptides to the oil-water interface was slower than for SDS or BSA, as deduced from the rather large size of oil droplets in emulsions (31-17 microm). Consequently, these emulsions creamed extensively during aging. Nevertheless, emulsions generated from acylated peptides were in general more stable to phase separation than those prepared from SDS. The C(14) acylated peptides were more effective for generating emulsions than the C(10) and C(12) derivatives, especially concerning the stability of emulsions against coalescence and phase separation, which was better than SDS and close to BSA.

  17. Understanding Acyl Chain and Glycerolipid Metabolism in Plants

    SciTech Connect

    Ohlrogge, John B.

    2013-11-05

    Progress is reported in these areas: acyl-editing in initial eukaryotic lipid assembly in soybean seeds; identification and characterization of two Arabidopsis thaliana lysophosphatidyl acyltransferases with preference for lysophosphatidylethanolamine; and characterization and subcellular distribution of lysolipid acyl transferase activity of pea leaves.

  18. Characterization of the "Escherichia Coli" Acyl Carrier Protein Phosphodiesterase

    ERIC Educational Resources Information Center

    Thomas, Jacob

    2009-01-01

    Acyl carrier protein (ACP) is a small essential protein that functions as a carrier of the acyl intermediates of fatty acid synthesis. ACP requires the posttranslational attachment of a 4'phosphopantetheine functional group, derived from CoA, in order to perform its metabolic function. A Mn[superscript 2+] dependent enzymatic activity that removes…

  19. Are There Acyl-Homoserine Lactones within Mammalian Intestines?

    PubMed Central

    Swearingen, Matthew C.; Sabag-Daigle, Anice

    2013-01-01

    Many Proteobacteria are capable of quorum sensing using N-acyl-homoserine lactone (acyl-HSL) signaling molecules that are synthesized by LuxI or LuxM homologs and detected by transcription factors of the LuxR family. Most quorum-sensing species have at least one LuxR and one LuxI homolog. However, members of the Escherichia, Salmonella, Klebsiella, and Enterobacter genera possess only a single LuxR homolog, SdiA, and no acyl-HSL synthase. The most obvious hypothesis is that these organisms are eavesdropping on acyl-HSL production within the complex microbial communities of the mammalian intestinal tract. However, there is currently no evidence of acyl-HSLs being produced within normal intestinal communities. A few intestinal pathogens, including Yersinia enterocolitica, do produce acyl-HSLs, and Salmonella can detect them during infection. Therefore, a more refined hypothesis is that SdiA orthologs are used for eavesdropping on other quorum-sensing pathogens in the host. However, the lack of acyl-HSL signaling among the normal intestinal residents is a surprising finding given the complexity of intestinal communities. In this review, we examine the evidence for and against the possibility of acyl-HSL signaling molecules in the mammalian intestine and discuss the possibility that related signaling molecules might be present and awaiting discovery. PMID:23144246

  20. Acyl-homoserine lactone binding to and stability of the orphan Pseudomonas aeruginosa quorum-sensing signal receptor QscR.

    PubMed

    Oinuma, Ken-Ichi; Greenberg, E Peter

    2011-01-01

    The Pseudomonas aeruginosa transcription factor QscR responds