Journal articles on the topic 'Ghrelin levels'
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1
Takahashi, T., K. Sato, S. Kato, T. Yonezawa, Y. Kobayashi, Y. Ohtani, S. Ohwada, et al. "Increased plasma ghrelin suppresses insulin release in wethers fed with a high-protein diet." Journal of Endocrinology 221, no. 3 (March 17, 2014): 371–80. http://dx.doi.org/10.1530/joe-13-0501.
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Ghrelin is a multifunctional peptide that promotes an increase of food intake and stimulates GH secretion. Ghrelin secretion is regulated by nutritional status and nutrients. Although a high-protein (HP) diet increases plasma ghrelin secretion in mammals, the mechanisms and the roles of the elevated ghrelin concentrations due to a HP diet have not been fully established. To clarify the roles of elevated acylated ghrelin upon intake of a HP diet, we investigated the regulation of ghrelin concentrations in plasma and tissues in wethers fed with either the HP diet or the control (CNT) diet for 14 days, and examined the action of the elevated plasma ghrelin by using a ghrelin-receptor antagonist. The HP diet gradually increased the plasma acylated-ghrelin concentrations, but the CNT diet did not. Although the GH concentrations did not vary significantly across the groups, an injection of ghrelin-receptor antagonist enhanced insulin levels in circulation in the HP diet group. In the fundus region of the stomach, the ghrelin levels did not differ between the HP and CNT diet groups, whereas ghrelinO-acyltransferase mRNA levels were higher in the group fed with HP diet than those of the CNT diet group were. These results indicate that the HP diet elevated the plasma ghrelin levels by increasing its synthesis; this elevation strongly suppresses the appearance of insulin in the circulation of wethers, but it is not involved in GH secretion. Overall, our findings indicate a role of endogenous ghrelin action in secretion of insulin, which acts as a regulator after the consumption of a HP diet.
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Wu, Rongqian, Mian Zhou, Padmalaya Das, Weifeng Dong, Youxin Ji, Derek Yang, Michael Miksa, Fangming Zhang, Thanjavur S. Ravikumar, and Ping Wang. "Ghrelin inhibits sympathetic nervous activity in sepsis." American Journal of Physiology-Endocrinology and Metabolism 293, no. 6 (December 2007): E1697—E1702. http://dx.doi.org/10.1152/ajpendo.00098.2007.
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Our previous studies have shown that norepinephrine (NE) upregulates proinflammatory cytokines by activating α2-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-α levels at 2 h after CLP. NE administration partially blocked the inhibitory effect of ghrelin on TNF-α in sepsis. GHSR-la inhibition by the administration of a GHSR-la antagonist, [d-Arg1,d-Phe5, d-Trp7,9,Leu11]substance P, significantly increased both NE and TNF-α 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)/Y1 receptor antagonist. However, ghrelin's downregulatory effect on TNF-α 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-α production in sepsis is partially because of its modulation of the overstimulated sympathetic nerve activation.
3
Delporte, Christine. "Recent Advances in Potential Clinical Application of Ghrelin in Obesity." Journal of Obesity 2012 (2012): 1–8. http://dx.doi.org/10.1155/2012/535624.
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Ghrelin is the natural ligand of the growth hormone secretagogue receptor (GHS-R1a). Ghrelin is a 28 amino acid peptide possessing a unique acylation on the serine in position 3 catalyzed by ghrelinO-acyltransferase (GOAT). Ghrelin stimulates growth hormone secretion, but also appetite, food intake, weight gain, and gastric emptying. Ghrelin is involved in weight regulation, obesity, type 2 diabetes, and metabolic syndrome. Furthermore, a better understanding of ghrelin biology led to the identification of molecular targets modulating ghrelin levels and/or its biological effects: GOAT, ghrelin, and GHS-R1a. Furthermore, a recent discovery, showing the involvement of bitter taste receptor T2R in ghrelin secretion and/or synthesis and food intake, suggested that T2R could represent an additional interesting molecular target. Several classes of ghrelin-related pharmacological tools for the treatment of obesity have been or could be developed to modulate the identified molecular targets.
4
Chuang, Jen-Chieh, and Jeffrey M. Zigman. "Ghrelin's Roles in Stress, Mood, and Anxiety Regulation." International Journal of Peptides 2010 (February 14, 2010): 1–5. http://dx.doi.org/10.1155/2010/460549.
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Several studies suggest that the peptide hormone ghrelin mediates some of the usual behavioral responses to acute and chronic stress. Circulating ghrelin levels have been found to rise following stress. It has been proposed that this elevated ghrelin helps animals cope with stress by generating antidepressant-like behavioral adaptations, although another study suggests that decreasing CNS ghrelin expression has antidepressant-like effects. Ghrelin also seems to have effects on anxiety, although these have been shown to be alternatively anxiogenic or anxiolytic. The current review discusses our current understanding of ghrelin's roles in stress, mood, and anxiety.
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Kellokoski, Eija, Seppo M. Pöykkö, Anna H. Karjalainen, Olavi Ukkola, Jorma Heikkinen, Y. Antero Kesäniemi, and Sohvi Hörkkö. "Estrogen Replacement Therapy Increases Plasma Ghrelin Levels." Journal of Clinical Endocrinology & Metabolism 90, no. 5 (May 1, 2005): 2954–63. http://dx.doi.org/10.1210/jc.2004-2016.
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Ghrelin is a novel peptide hormone that has GH releasing activity and also other endocrine and metabolic functions. The purpose of this study was to investigate the effects of estrogen replacement therapy on plasma active ghrelin levels in 64 hysterectomized postmenopausal women receiving peroral estrogen (PE) or transdermal estrogen therapy for 6 months. Active ghrelin was measured using commercial RIA. Estrogen therapy increased plasma active ghrelin from 479 ± 118 to 521 ± 123 pg/ml (P = 0.002) among all the study subjects. PE therapy increased plasma ghrelin levels from 465 ± 99 to 536 ± 104 pg/ml (P = 0.001). Transdermal estrogen therapy did not increase plasma ghrelin levels significantly (from 491 ± 132 to 509 ± 138 pg/ml; P = 0.332). The relative changes in plasma ghrelin levels were associated with the relative changes in serum estradiol concentrations (r = 0.299; P = 0.017). During the estrogen therapy, negative associations were found between plasma active ghrelin levels and several plasma lipids (total cholesterol, low-density lipoprotein cholesterol, very low-density lipoprotein cholesterol, total triglycerides, and very low-density lipoprotein triglycerides). As a conclusion, estrogen replacement therapy increased active plasma ghrelin levels, particularly PE therapy. Additional studies are needed to determine the possible underlying mechanisms.
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Frazao, Renata, Heather M. Dungan Lemko, Regina P. da Silva, Dhirender V. Ratra, Charlotte E. Lee, Kevin W. Williams, Jeffrey M. Zigman, and Carol F. Elias. "Estradiol modulates Kiss1 neuronal response to ghrelin." American Journal of Physiology-Endocrinology and Metabolism 306, no. 6 (March 15, 2014): E606—E614. http://dx.doi.org/10.1152/ajpendo.00211.2013.
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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.
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Tsubone, Tetsuo, Takayuki Masaki, Isao Katsuragi, Katsuhiro Tanaka, Tetsuya Kakuma, and Hironobu Yoshimatsu. "Leptin downregulates ghrelin levels in streptozotocin-induced diabetic mice." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 289, no. 6 (December 2005): R1703—R1706. http://dx.doi.org/10.1152/ajpregu.00773.2004.
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Ghrelin, an orexigenic peptide produced in the stomach, is increased in streptozotocin (STZ)-induced diabetic (DM) mice. This study clarifies the regulation of ghrelin levels by leptin in STZ-DM mice. STZ-DM mice had higher plasma ghrelin concentrations and greater ghrelin mRNA expression than control mice. Changes in ghrelin levels were dose dependently attenuated by the subcutaneous injection of leptin (0–27 nmol·kg−1·day−1 over 7 days). Leptin treatment also partially reversed the hyperphagia and hyperglycemia observed in STZ-DM mice, but not the hypoinsulinemia, and there was a decrease in plasma ghrelin concentrations and ghrelin mRNA levels compared with STZ-LEP pair-fed mice. These results indicate that leptin treatment partially reverses elevated plasma ghrelin levels in STZ-DM mice independent of food intake and insulin, and suggest that hypoleptinemia in STZ-DM mice upregulates ghrelin.
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Erensoy, Ahmet, Suleyman Aydin, Neslihan Kelestimur, Sevda Kirbag, and Salih Kuk. "The Change of Ghrelin Levels in Intestinal Parasitic Infections." Journal of Medical Biochemistry 29, no. 1 (January 1, 2010): 34–38. http://dx.doi.org/10.2478/v10011-010-0004-0.
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The Change of Ghrelin Levels in Intestinal Parasitic InfectionsThe aim of this work was to examine the relationship between active (acylated ghrelin) and inactive (desacylated ghrelin) ghrelin in the serum and other serum parameters in intestinal parasitic infections and healthy controls. Conventional microscopic methods (saline and iodine solutions, trichrome stain) were used to identify intestinal parasites in stool samples of 29 subjects attending Firat University Hospital. Serum parameters were assessed in a single measurement of serum from 29 parasite subjects, and in 18 healthy controls. Serum acylated ghrelin and desacylated ghrelin levels were measured using a commercial radioimmunoassay (RIA) kit. Paraoxonase and arylesterase were measured by using a spectrophotometer at 405 nm and 270 nm, respectively. Serum concentrations of acylated ghrelin and desacylated ghrelin were more markedly decreased in helminth bearing patients than the control group. Glucose, cholesterol and triglyceride levels were higher in intestinal parasitic infections than in controls. Furthermore, there were no correlations between ghrelin levels and BMI. These results indicate that low ghrelin and PON1/AE level may be important for appetite monitoring in intestinal parasitic infections.
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Holliday, Nicholas D., Birgitte Holst, Elena A. Rodionova, Thue W. Schwartz, and Helen M. Cox. "Importance of Constitutive Activity and Arrestin-Independent Mechanisms for Intracellular Trafficking of the Ghrelin Receptor." Molecular Endocrinology 21, no. 12 (December 1, 2007): 3100–3112. http://dx.doi.org/10.1210/me.2007-0254.
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Abstract The ghrelin receptor (GhrelinR) and its related orphan GPR39 each display constitutive signaling, but only GhrelinRs undergo basal internalization. Here we investigate these differences by considering the roles of the C tail receptor domains for constitutive internalization and activity. Furthermore the interaction between phosphorylated receptors and β-arrestin adaptor proteins has been examined. Replacement of the FLAG-tagged GhrelinR C tail with the equivalent GPR39 domain (GhR-39 chimera) preserved Gq signaling. However in contrast to the GhrelinR, GhR-39 receptors exhibited no basal and substantially decreased agonist-induced internalization in transiently transfected HEK293 cells. Internalized GhrelinR and GhR-39 were predominantly localized to recycling compartments, identified with transferrin and the monomeric G proteins Rab5 and Rab11. Both the inverse agonist [d-Arg1, d-Phe5, d-Trp7,9, Leu11] substance P and a naturally occurring mutant GhrelinR (A204E) with eliminated constitutive activity inhibited basal GhrelinR internalization. Surprisingly, we found that noninternalizing GPR39 was highly phosphorylated and that basal and agonist-induced phosphorylation of the GhR-39 chimera was elevated compared with GhrelinRs. Moreover, basal GhrelinR endocytosis occurred without significant phosphorylation, and it was not prevented by cotransfection of a dominant-negative β-arrestin1(319–418) fragment or by expression in β-arrestin1/2 double-knockout mouse embryonic fibroblasts. In contrast, agonist-stimulated GhrelinRs recruited the clathrin adaptor green fluorescent protein-tagged β-arrestin2 to endosomes, coincident with increased receptor phosphorylation. Thus, GhrelinR internalization to recycling compartments depends on C-terminal motifs and constitutive activity, but the high levels of GPR39 phosphorylation, and of the GhR-39 chimera, are not sufficient to drive endocytosis. In addition, basal GhrelinR internalization occurs independently of β-arrestins.
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Lin, Tsung-Chieh, Yuan-Ming Yeh, Wen-Lang Fan, Yu-Chan Chang, Wei-Ming Lin, Tse-Yen Yang, and Michael Hsiao. "Ghrelin Upregulates Oncogenic Aurora A to Promote Renal Cell Carcinoma Invasion." Cancers 11, no. 3 (March 4, 2019): 303. http://dx.doi.org/10.3390/cancers11030303.
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Ghrelin is a peptide hormone, originally identified from the stomach, that functions as an endogenous ligand of the growth hormone secretagogue receptor (GHSR) and promotes growth hormone (GH) release and food intake. Increasing reports point out ghrelin’s role in cancer progression. We previously characterized ghrelin’s prognostic significance in the clear cell subtype of renal cell carcinoma (ccRCC), and its pro-metastatic ability via Snail-dependent cell migration. However, ghrelin’s activity in promoting cell invasion remains obscure. In this study, an Ingenuity Pathway Analysis (IPA)-based investigation of differentially expressed genes in Cancer Cell Line Encyclopedia (CCLE) dataset indicated the potential association of Aurora A with ghrelin in ccRCC metastasis. In addition, a significant correlation between ghrelin and Aurora A expression level in 15 ccRCC cell line was confirmed by variant probes. ccRCC patients with high ghrelin and Aurora A status were clinically associated with poor outcome. We further observed that ghrelin upregulated Aurora A at the protein and RNA levels and that ghrelin-induced ccRCC in vitro invasion and in vivo metastasis occurred in an Aurora A-dependent manner. Furthermore, MMP1, 2, 9 and 10 expressions are associated with poor outcome. In particular, MMP10 is significantly upregulated and required for the ghrelin-Aurora A axis to promote ccRCC invasion. The results of this study indicated a novel signaling mechanism in ccRCC metastasis.
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Egecioglu, Emil, Mikael Bjursell, Anna Ljungberg, Suzanne L. Dickson, John J. Kopchick, Göran Bergström, Lennart Svensson, Jan Oscarsson, Jan Törnell, and Mohammad Bohlooly-Y. "Growth hormone receptor deficiency results in blunted ghrelin feeding response, obesity, and hypolipidemia in mice." American Journal of Physiology-Endocrinology and Metabolism 290, no. 2 (February 2006): E317—E325. http://dx.doi.org/10.1152/ajpendo.00181.2005.
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We have previously shown that growth hormone (GH) overexpression in the brain increased food intake, accompanied with increased hypothalamic agouti-related protein (AgRP) expression. Ghrelin, which stimulates both appetite and GH secretion, was injected intracerebroventricularly to GHR−/− and littermate control (+/+) mice to determine whether ghrelin's acute effects on appetite are dependent on GHR signaling. GHR−/− mice were also analyzed with respect to serum levels of lipoproteins, apolipoprotein (apo)B, leptin, glucose, and insulin as well as body composition. Central injection of ghrelin into the third dorsal ventricle increased food consumption in +/+ mice, whereas no change was observed in GHR−/− mice. After ghrelin injection, AgRP mRNA expression in the hypothalamus was higher in +/+ littermates than in GHR−/− mice, indicating a possible importance of AgRP in the GHR-mediated effect of ghrelin. Compared with controls, GHR−/− mice had increased food intake, leptin levels, and total and intra-abdominal fat mass per body weight and deceased lean mass. Moreover, serum levels of triglycerides, LDL and HDL cholesterol, and apoB, as well as glucose and insulin levels were lower in the GHR−/− mice. In summary, ghrelin's acute central action to increase food intake requires functionally intact GHR signaling. Long-term GHR deficiency in mice is associated with high plasma leptin levels, obesity, and increased food intake but a marked decrease in all lipoprotein fractions.
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Chen, Vicky Ping, Yang Gao, Liyi Geng, Robin J. Parks, Yuan-Ping Pang, and Stephen Brimijoin. "Plasma butyrylcholinesterase regulates ghrelin to control aggression." Proceedings of the National Academy of Sciences 112, no. 7 (February 2, 2015): 2251–56. http://dx.doi.org/10.1073/pnas.1421536112.
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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.
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Dzaja, Andrea, Mira A. Dalal, Hubertus Himmerich, Manfred Uhr, Thomas Pollmächer, and Andreas Schuld. "Sleep enhances nocturnal plasma ghrelin levels in healthy subjects." American Journal of Physiology-Endocrinology and Metabolism 286, no. 6 (June 2004): E963—E967. http://dx.doi.org/10.1152/ajpendo.00527.2003.
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Ghrelin, an endogenous ligand of the growth hormone secretagogue receptor, has been shown to promote slow-wave sleep (SWS, non-REM sleep stages 3 and 4). Plasma levels of ghrelin are dependent on food intake and increase in sleeping subjects during the early part of the night. It is unknown whether sleep itself affects ghrelin levels or whether circadian networks are involved. Therefore, we studied the effect of sleep deprivation on nocturnal ghrelin secretion. In healthy male volunteers, plasma levels of ghrelin, cortisol, and human growth hormone (hGH) were measured during two experimental sessions of 24 h each: once when the subjects were allowed to sleep between 2300 and 0700 and once when they were kept awake throughout the night. During sleep, ghrelin levels increased during the early part of the night and decreased in the morning. This nocturnal increase was blunted during sleep deprivation, and ghrelin levels increased only slightly until the early morning. Ghrelin secretion during the first hours of sleep correlated positively with peak hGH concentrations. We conclude that the nocturnal increase in ghrelin levels is more likely to be caused by sleep-associated processes than by circadian influences. During the first hours of sleep, ghrelin might promote sleep-associated hGH secretion and contribute to the promotion of SWS.
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Rak, Agnieszka, and Ewa Gregoraszczuk. "Ghrelin levels in prepubertal pig ovarian follicles." Acta Veterinaria Hungarica 57, no. 1 (March 1, 2009): 109–13. http://dx.doi.org/10.1556/avet.57.2009.1.11.
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Ghrelin is a novel growth hormone-releasing peptide originally identified in the rat stomach as an endogenous ligand of the growth hormone (GH) secretagogue receptor. Recent work suggests that ghrelin plays an important role in reproductive function. In this study, prepubertal pig ovaries were used to examine ghrelin levels in the ovarian follicles. Ghrelin levels in the follicular fluid, follicular wall and culture medium were measured using an enzyme immunoassay (EIA). The ghrelin level in the follicular fluid (18 pg/ml) was the sum of the amounts found in the follicular wall (13.7 pg/ml) and the culture medium (4.6 pg/ml). In conclusion, the data presented in this paper suggest local production of this hormone in ovarian follicles.
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Aygen, B., A. Dogukan, FE Dursun, S. Aydin, N. Kilic, F. Sahpaz, and H. Celiker. "Ghrelin and Obestatin Levels in End-stage Renal Disease." Journal of International Medical Research 37, no. 3 (May 2009): 757–65. http://dx.doi.org/10.1177/147323000903700319.
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Malnutrition is fairly common in end-stage renal disease (ESRD) patients, persistent lack of appetite being a major symptom. Ghrelin and obestatin are two hormones that are involved in appetite and energy homeostasis. The present study examined ghrelin and obestatin levels in 24 ESRD patients undergoing haemodialysis and 24 age-matched healthy controls. Serum and saliva ghrelin and obestatin levels in the ESRD patients were significantly higher compared with controls, while saliva ghrelin and obestatin levels in all study participants were significantly higher than serum levels. Saliva ghrelin correlated with serum ghrelin and saliva obestatin correlated with serum obestatin in all study participants, although there was no correlation between ghrelin and obestatin levels. In conclusion, the results suggest that the kidneys may have a role in the metabolism and/or clearance of obestatin, as they do for ghrelin. Further studies are needed to determine if elevated levels of these hormones in ESRD patients contribute to the malnutrition that is common in these patients.
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ASADI, Asadollah, Hamid FARAHANI, Touraj MAHMOUDI, Seidamir Pasha TABAEIAN, Gholamreza REZAMAND, Abolfazl MOHAMMADBEIGI, Reza DABIRI, Hossein NOBAKHT, Sajad REZVAN, and Fatemeh MOHAMMADI. "CIRCULATING GHRELIN LEVELS AND SUSCEPTIBILITY TO COLORECTAL CÂNCER." Arquivos de Gastroenterologia 58, no. 3 (September 2021): 316–21. http://dx.doi.org/10.1590/s0004-2803.202100000-54.
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ABSTRACT BACKGROUND AND OBJECTIVE: Considering the association between colorectal cancer (CRC) and both insulin resistance and obesity, and the prominent role of ghrelin in these metabolic disorders, we explored whether plasma levels of ghrelin were associated with CRC. Moreover, in the patients with CRC the possible correlations between ghrelin and insulin, insulin resistance, and body mass index (BMI) as an indicator of obesity were examined. METHODS: A total of 170 subjects, including 82 cases with CRC and 88 controls were enrolled in this study. Plasma levels of ghrelin, insulin, and glucose were measured in all the subjects using ELISA and glucose oxidase methods. Furthermore, insulin resistance was assessed by calculating HOMA-IR index. RESULTS: The cases with CRC had decreased ghrelin levels (P<0.001) and a higher HOMA-IR index (P<0.001) than controls. Interestingly, when CRC patients were stratified based on tumor site, lower ghrelin levels and a higher HOMA-IR index were observed in the patients with either colon or rectal cancer vs. controls too. Additionally, there were an age and BMI-independent negative correlation between ghrelin levels and HOMA-IR (r=-0.365, P<0.05), and an age-independent negative correlation between ghrelin levels and BMI (r=-0.335, P<0.05) in the rectal subgroup. CONCLUSION: Our findings support a role for ghrelin in connection with insulin resistance and obesity in CRC susceptibility; however, it needs to be corroborated by further studies.
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Nonogaki, Katsunori, and Marina Suzuki. "Liraglutide Suppresses the Plasma Levels of Active and Des-Acyl Ghrelin Independently of Active Glucagon-Like Peptide-1 Levels in Mice." ISRN Endocrinology 2013 (August 13, 2013): 1–5. http://dx.doi.org/10.1155/2013/184753.
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Glucagon-like peptide-1 (GLP-1), an insulinotropic gastrointestinal peptide that is primarily produced by intestinal endocrine L-cells, stimulates satiety. Ghrelin, a hormone that is produced predominantly by the stomach stimulates hunger. There are two forms of ghrelin: active ghrelin and inactive des-acyl ghrelin. After depriving mice of food for 24 h, we demonstrated that the systemic administration of liraglutide (100 μg/kg), a human GLP-1 analog that binds to the GLP-1 receptor, increased (1.4-fold) the plasma levels of active GLP-1 and suppressed the plasma levels of active and des-acyl ghrelin after 1 h. Despite the elevated plasma levels of active GLP-1 (11-fold), liraglutide had no effect on the plasma levels of active or des-acyl ghrelin after 12 h. These findings demonstrated that liraglutide suppresses the plasma levels of active and des-acyl ghrelin independently of active GLP-1 levels in fasted mice, suggesting a novel in vivo biological effect of liraglutide beyond regulating plasma GLP-1.
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Sato, Takahiro, Yoshihiko Fukue, Hitoshi Teranishi, Yayoi Yoshida, and Masayasu Kojima. "Molecular Forms of Hypothalamic Ghrelin and Its Regulation by Fasting and 2-Deoxy-d-Glucose Administration." Endocrinology 146, no. 6 (June 1, 2005): 2510–16. http://dx.doi.org/10.1210/en.2005-0174.
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Abstract Ghrelin, an endogenous ligand for the GH secretagogue receptor, is a hormone expressed in stomach and other tissues, such as hypothalamus, testis, and placenta. This hormone acts at a central level to stimulate GH secretion and food intake. Little is known, however, about the molecular forms and physiological roles of ghrelin within the hypothalamus. In this report, we detail the molecular forms, mRNA expression patterns, and peptide contents of ghrelin within the rat hypothalamus. Using the combination of reverse-phase HPLC and ghrelin-specific RIA, we determined that the rat hypothalamus contains both n-octanoyl-modified and des-acyl ghrelins. Fasting for 24 and 48 h significantly decreased ghrelin mRNA expression in the hypothalamus to 24% and 28% of control values, respectively. Both n-octanoyl-modified and des-acyl ghrelin content in the hypothalamus decreased after 24 and 48 h of fasting. These results contrast the changes in gastric ghrelin after fasting, which decreased in content despite increased mRNA expression. Two hours after injection of 2-deoxy-d-glucose (2-DG), a selective blocker of carbohydrate metabolism, ghrelin peptide levels also decreased. Thus, induction of glucoprivic states, such as fasting and 2-DG treatment, decreased ghrelin gene expression and peptide content within the hypothalamus.
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Vicennati, Valentina, Silvia Genghini, Rosaria De Iasio, Francesca Pasqui, Uberto Pagotto, and Renato Pasquali. "Circulating obestatin levels and the ghrelin/obestatin ratio in obese women." European Journal of Endocrinology 157, no. 3 (September 2007): 295–301. http://dx.doi.org/10.1530/eje-07-0059.
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Objective: We measured blood levels of obestatin, total ghrelin, and the ghrelin/obestatin ratio and their relationship with anthropometric and metabolic parameters, adiponectin and insulin resistance, in overweight/obese and normal-weight women. Design: Outpatients Unit of Endocrinology of the S Orsola-Malpighi Hospital of Bologna, Italy. Methods: Fasting obestatin, ghrelin, adiponectin and lipid levels, fasting and glucose-stimulated oral glucose tolerance test insulin, and glucose levels were measured in 20 overweight/obese and 12 controls. The fasting ghrelin/obestatin ratio was calculated; the homeostasis model assessment-IR (HOMA-IR) and insulin sensitivity index (ISIcomposite) were calculated as indices of insulin resistance. Results: Obese women had higher obestatin and lower ghrelin blood levels, and a lower ghrelin/obestatin ratio compared with controls. In all subjects, obestatin was significantly and positively correlated with total cholesterol and triglycerides, but not with ghrelin, anthropometric, and metabolic parameters. In the obese women, however, obestatin and ghrelin concentrations were positively correlated. By contrast, the ghrelin/obestatin ratio was significantly and negatively correlated with body mass index, waist, waist-to-hip ratio, fasting insulin, and HOMA-IR, and positively with ISIcomposite but not with adiponectin. None of these parameters were correlated with the ghrelin/obestatin ratio in the obese. Conclusions: Increased obestatin, decreased ghrelin levels, and a decreased ghrelin/obestatin ratio characterize obesity in women. This supports the hypothesis that the imbalance of ghrelin and obestatin may have a role in the pathophysiology of obesity. On the other hand, some relevant differences between our data on circulating levels of obestatin and the ghrelin/obestatin ratio in obese subjects and those reported in the few studies published so far imply that further research is needed.
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Aly, Gamal S., Nayera E. Hassan, Ghada M. Anwar, Hanaa H. Ahmed, Sahar A. El-Masry, Rokia A. El-Banna, Nihad H. Ahmed, Ayat N. Kamal, and Reham S. Tarkan. "Ghrelin, obestatin and the ghrelin/obestatin ratio as potential mediators for food intake among obese children: a case control study." Journal of Pediatric Endocrinology and Metabolism 33, no. 2 (February 25, 2020): 199–204. http://dx.doi.org/10.1515/jpem-2019-0286.
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AbstractBackgroundGhrelin and obestatin are two gastric hormones encoded by the same preproghrelin gene that convey information concerning nutritional status to the central nervous system. Ghrelin has been considered as an appetite stimulating peptide that has a role in the regulation of energy homeostasis. Obestatin has been described for its appetite suppressing effects opposing ghrelin’s effect on food intake. The study aimed to evaluate ghrelin, obestatin and the ghrelin/obestatin ratio in obese children compared to non-obese and correlate them to food macronutrients intake.MethodsThis study is a cross-sectional case control study comprising 60 obese children, in addition to 31 age- and sex-matched controls. All children were subjected to clinical examination, anthropometric assessment, and a 3-day 24-h dietary recall. Fasting serum ghrelin and obestatin levels were evaluated, the ghrelin/obestatin ratio was calculated and they were correlated to macronutrients intake.ResultsObese children had significantly lower serum fasting levels of ghrelin, obestatin and the ghrelin/obestatin ratio than the control group. The mean intake of total energy and macronutrients was significantly higher in obese children. Ghrelin showed positive correlation with total energy and fat intake in the obese group. Obestatin had positive correlations with total energy and fat intake while the ghrelin/obestatin ratio had a negative correlation with the total energy intake in the control group.ConclusionsGhrelin, obestatin and the ghrelin/obestatin ratio were significantly lower in obese children and significantly associated with their total energy intake. Disturbed ghrelin to obestatin balance may have a role in the etiology and pathophysiology of obesity.
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Rahimi, Somayeh, Faranak Kazerouni, Mehdi Hedayati, Mehr Ali Rahimi, Ali Rahimipour, Marjan Zarif Yeganeh, and Mehrnoosh Shanaki. "Association of plasma ghrelin levels with diabetic nephropathy." LaboratoriumsMedizin 42, no. 1-2 (April 25, 2018): 39–44. http://dx.doi.org/10.1515/labmed-2017-0050.
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AbstractBackground:Ghrelin is a 28-amino acid peptide hormone which is produced in various tissues such as the kidney. It is proposed that this hormone exerts a broad spectrum of biological functions throughout the body. Ghrelin carries out endocrine and/or paracrine functions in the kidney, which seems to be one of the target tissues of this hormone. Results regarding circulating ghrelin levels in chronic kidney disease (CKD) and diabetic nephropathy (DN) patients are conflicting. We aimed to investigate the plasma ghrelin levels in type 2 diabetic patients with and without nephropathy.Methods:A total of 45 patients with DN and 45 patients with diabetes without diabetic nephropathy (NDN) were recruited for this study. Plasma ghrelin levels were determined using the enzyme-linked immunosorbent assay (ELISA) method. The association of plasma ghrelin with concentrations of fasting glucose (FBS), creatinine (Cr), blood urea nitrogen (BUN), low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), triglycerides (TG) and anthropometric parameters was analyzed.Results:Plasma ghrelin concentration in the DN group was 1.16 (1.01–1.38) ng/mL and in the NDN group was 1.16 (0.92–1.41) ng/mL, so there were no significant differences between the two groups (p=0.467). In the NDN group, ghrelin showed an inverse correlation with TG (r=−0.467, p=0.001) and a direct correlation with HDL (r=0.562, p=0.000) but in the DN group these correlations were not found.Conclusions:Our findings implicated no relationship between the plasma ghrelin level and renal dysfunction in type 2 diabetic patients. Therefore, plasma ghrelin level may not be a probable indicator of kidney insufficiency in patients with type 2 diabetes mellitus (T2DM). Furthermore, we also found a positive correlation between ghrelin and HDL and an inverse correlation with TG levels.
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Akamizu, T., T. Murayama, S. Teramukai, K. Miura, I. Bando, T. Irako, H. Iwakura, et al. "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." Journal of Endocrinology 188, no. 2 (February 2006): 333–44. http://dx.doi.org/10.1677/joe.1.06442.
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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 ≥ 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.
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KIZILIRMAK, Deniz, Bülent BOZKURT, and Harun KARAMANLI. "Relationship between ghrelin and obestatin levels and ghrelin/obestatin ratio in patients with asthma." Tuberk Toraks 68, no. 1 (March 30, 2020): 9–16. http://dx.doi.org/10.5578/tt.68815.
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Emanuel, Alan J., and Sue Ritter. "Hindbrain Catecholamine Neurons Modulate the Growth Hormone But Not the Feeding Response to Ghrelin." Endocrinology 151, no. 7 (May 12, 2010): 3237–46. http://dx.doi.org/10.1210/en.2010-0219.
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The gastrointestinal peptide, ghrelin, elicits feeding and secretion when administered systemically or centrally. Previous studies have suggested that hypothalamic projections of hindbrain catecholamine neurons are involved in both of these actions of ghrelin. The purpose of this study was to further assess the role of hindbrain catecholamine neurons in ghrelin-induced feeding and GH secretion and to determine the anatomical distribution of the catecholamine neurons involved. We lesioned noradrenergic and adrenergic neurons that innervate the medial hypothalamus by microinjecting the retrogradely transported immunotoxin, saporin (SAP) conjugated to antidopamine-β-hydroxylase (DSAP) into the paraventricular nucleus of the hypothalamus. Controls were injected with unconjugated SAP. We found that the DSAP lesion did not impair the feeding response to central or peripheral ghrelin administration, indicating that these neurons are not required for ghrelin’s orexigenic effect. However, the GH response to ghrelin was prolonged significantly in DSAP-lesioned rats. We also found that expression of Fos, an indicator of neuronal activation, was significantly enhanced over baseline levels in A1, A1/C1, C1, and A5 cell groups after ghrelin treatment and in A1, A1/C1, and A5 cell groups after GH treatment. The similar pattern of Fos expression in catecholamine cell groups after GH and ghrelin and the prolonged GH secretion in response to ghrelin in DSAP rats together suggest that activation of hindbrain catecholamine neurons by ghrelin or GH could be a component of a negative feedback response controlling GH levels.
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Montazerifar, Farzaneh, Mansour Karajibani, Farnia Gorgij, and Ommolbanin Akbari. "Malnutrition Markers and Serum Ghrelin Levels in Hemodialysis Patients." International Scholarly Research Notices 2014 (October 30, 2014): 1–5. http://dx.doi.org/10.1155/2014/765895.
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Objective. The aim of study was to investigate the changes levels of serum ghrelin in HD patients and its relationship to some malnutrition markers compared with healthy controls. Methods. Forty-five patients on hemodialysis and forty healthy controls were studied. Biochemical parameters and serum ghrelin levels were measured. Both daily dietary intakes and body mass index (BMI) assessments were performed for evaluation of nutritional status. Results. Ghrelin concentrations were significantly reduced in patients undergoing hemodialysis when compared to healthy controls (5±0.68 (1.1–18.5) pg/mL versus 7.8±0.84 (2.4–18.3) pg/mL; P=0.004). BMI and serum albumin in HD patients were markedly reduced compared to controls. The patients with an insufficient intake of energy and protein demonstrated slightly lower levels of serum ghrelin. A negative correlation between serum ghrelin concentration with age (r=-0.34, P=0.02), BUN (r=-0.26, P<0.01), and serum creatinine (r=-0.27, P<0.01) was observed in HD patients. Conclusions. The findings suggest that decreased ghrelin levels in HD patients might be associated with anorexia. Further studies are needed to determine changes in serum ghrelin levels during dialysis and to clarify whether the decrease in ghrelin levels contributes to the malnutrition that is common in these patients.
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Foster-Schubert, Karen E., Anne McTiernan, R. Scott Frayo, Robert S. Schwartz, Kumar B. Rajan, Yutaka Yasui, Shelley S. Tworoger, and David E. Cummings. "Human Plasma Ghrelin Levels Increase during a One-Year Exercise Program." Journal of Clinical Endocrinology & Metabolism 90, no. 2 (February 1, 2005): 820–25. http://dx.doi.org/10.1210/jc.2004-2081.
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Weight loss resulting from decreased caloric intake raises levels of the orexigenic hormone, ghrelin. Because ingested nutrients suppress ghrelin, increased ghrelin levels in hypophagic weight loss may result from decreased inhibitory input by ingested food, rather than from lost weight. We assessed whether ghrelin levels increase in response to exercise-induced weight loss without decreased caloric intake. We randomized 173 sedentary, overweight, postmenopausal women to an aerobic exercise intervention or stretching control group. At baseline, 3 months, and 12 months, we measured body weight and composition, food intake, cardiopulmonary fitness (maximal oxygen consumption), leptin, insulin, and ghrelin. Complete data were available for 168 women (97%) at 12 months. Exercisers lost 1.4 ± 0.4 kg (P < 0.05 compared with baseline; P = 0.01 compared with stretchers) and manifested a significant, progressive increase in ghrelin levels, whereas neither measure changed among stretchers. Ghrelin increased 18% in exercisers who lost more than 3 kg (P < 0.001). There was no change in caloric intake in either group and no effect on ghrelin of exercise per se independent of its impact on body weight. In summary, ghrelin levels increase with weight loss achieved without reduced food intake, consistent with a role for ghrelin in the adaptive response constraining weight loss and, thus, in long-term body weight regulation.
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Myriam Sfar, Houda Ben Jemaa, Amani Kallel, Kamel Ben-Mahrez, Moncef Feki, and Fethi Ben Slama. "Plasma levels of obestatin and ghrelin and obestatin/ghrelin ratio in obese patients." World Journal of Advanced Research and Reviews 14, no. 1 (April 30, 2022): 336–41. http://dx.doi.org/10.30574/wjarr.2022.14.1.0320.
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Background: Obestatin and ghrelin are two gastric hormones that have a potential role in dietary intake regulation. Obestatin/ghrelin ratio has been proposed as activity markers in obesity. The study aimed to evaluate ghrelin, obestatin and the ghrelin/obestatin ratio in obese compared to control subjects and to determine their relationship with anthropometric and metabolic parameters. Methods: Fasting obestatin and ghrelin levels were measured using enzyme-linked immunosorbent assay ELISA in 28 obese and 24 healthy subjects. The fasting ghrelin/obestatin ratio was calculated. Anthropometric and metabolic parameters were also assessed. Results: Obese patients had significantly lower obestatin and ghrelin blood levels compared with controls. The Ghrelin/Obestatin ratio was significantly lower in obese group 0.813±0.0417 ng/ml than in the control group 0.896±0.049 ng/ml, (p<0.001). In obese patients, obestatin and ghrelin were significantly and negatively correlated with BMI and positively correlated with HDL-C. Conclusion: Circulating preprandial ghrelin to obestatin ratio is decreased obese subjects. We suggest that low preprandial ghrelin to obestatin ratio may be involved in the etiology and pathophysiology of obesity.
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Sahin, Hamilcikan, Tugba Erener, Ethem Erginoz, Mehmet Vural, Barbaros Ilikkan, Sultan Kavuncuoglu, Hayrettin Yildiz, and Yildiz Perk. "The relationship of active ghrelin levels and intrauterine growth in preterm infants." European Journal of Endocrinology 166, no. 3 (March 2012): 399–405. http://dx.doi.org/10.1530/eje-11-0607.
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ObjectiveWe examined the association of active ghrelin levels with birth weight, sex, and gestational age (GA) in small for GA (SGA) and appropriate for GA (AGA) preterm infants.MethodsActive ghrelin levels were measured by ELISA method during the first five postnatal days in 38 preterm SGA infants and 32 preterm AGA controls.ResultsActive ghrelin levels were significantly higher in preterm SGA infants than in preterm AGA controls (P<0.01). Active ghrelin levels in preterms with birth weight <1500 g were statistically higher than those over 1500 g. Active ghrelin levels in preterms ≤34 gestational weeks were similar to those over 34 weeks. A negative correlation was detected between active ghrelin levels and birth weight (r=−0.561, P<0.0001) as well as GA (r=−0.449, P<0.0001).ConclusionWe found significantly higher active ghrelin levels in SGA preterms than those in AGA preterms and demonstrated a negative correlation between active ghrelin levels and birth weight in preterm infants. This was the first study showing a negative correlation between active ghrelin levels and birth weight in preterm infants.
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Lotfi, A., H. Aghdam-Shahryar, J. Ghiasi-Ghalehkandi, H. Kaiya, and N. Maheri-Sis. "Effect of in ovo ghrelin administration on subsequent serum insulin and glucose levels in newly-hatched chicks." Czech Journal of Animal Science 56, No. 8 (August 18, 2011): 377–80. http://dx.doi.org/10.17221/2396-cjas.
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Ghrelin is a regulatory peptide in glucose homeostasis in animal species. Its effect in the avian embryo is unclear. The aim of this study was to investigate the effects of in ovo ghrelin administration on serum glucose and insulin levels of hatched chicks. A total of 250 fertilized eggs were divided into 5 groups; group T1 as control (without injection), group T2 (in ovo injected with 50 ng/egg ghrelin on day 5), group T3 (in ovo injected with 100 ng/egg ghrelin on day 5), group T4 (in ovo injected with 50 ng/egg ghrelin on day 10) and group T5 (in ovo injected with 100 ng/egg ghrelin on day 10). After hatching, serum insulin and glucose concentrations were determined. Group T4 and T5 showed significantly higher serum insulin levels (0.43 and 0.60 ng/ml, respectively) compared with T1, T2 and T3 (0.09, 0.10, and 0.23 ng/ml, respectively) in hatched chicks. Glucose concentrations have not been affected by in ovo administered ghrelin in all injected groups. It seems that embryonic β-cells were stimulated to secrete a considerable level of insulin in response to in ovo ghrelin in the late embryonic life. The observed stability of glucose rate suggests the incidence of insulin resistance at hatching time or in newly hatched chicks from in ovo ghrelin administered eggs on day 10.
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St-Pierre, David H., Rémi Rabasa-Lhoret, Marie-Ève Lavoie, Antony D. Karelis, Irene Strychar, Eric Doucet, and Lise Coderre. "Fiber intake predicts ghrelin levels in overweight and obese postmenopausal women." European Journal of Endocrinology 161, no. 1 (July 2009): 65–72. http://dx.doi.org/10.1530/eje-09-0018.
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BackgroundGhrelin levels are decreased upon food intake, but the impact of specific diet-derived macronutrients on its regulation remains unclear. In addition, because of ghrelin's association with body weight regulation, it is important to understand the mechanisms regulating its levels in obese individuals.ObjectiveTo examine the effect of specific macronutrients on ghrelin levels in overweight and obese postmenopausal women.MethodsThirty-five subjects underwent a euglycemic/hyperinsulinemic clamp (EHC) to examine glucose disposal and total ghrelin (TotG) and acylated ghrelin (AG) levels. Macronutrient intake was evaluated with a 3-day food questionnaire.ResultsUnder fasting conditions, positive associations were observed between fiber intake and TotG and AG levels. Fasting AG also correlated positively with the intake of total energy, as well as monounsaturated and polyunsaturated lipids. Importantly, fiber consumption explained up to 26 and 23% of the variation in TotG and AG respectively. During the EHC, TotG levels were significantly reduced at all times, while AG was decreased at 60 min only. TotG area under the curve (AUC) values were positively associated with fiber and polyunsaturated lipid intake, while AG AUC values correlated positively with fiber, total energy, carbohydrate, and lipid intake. Interestingly, fiber intake explained up to 21% of the variation in TotG AUC, while total energy intake predicted up to 21% of the variation in the AG AUC.ConclusionThe present study suggests that fiber intake is an important regulator of ghrelin levels both in fasting and in hyperinsulinemic conditions. Overall, these results reinforce the importance of the intimate association between eating habits and gastrointestinal hormonal regulation.
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Nakahara, Keiko, Rieko Okame, Tetsuro Katayama, Mikiya Miyazato, Kenji Kangawa, and Noboru Murakami. "Nutritional and environmental factors affecting plasma ghrelin and leptin levels in rats." Journal of Endocrinology 207, no. 1 (July 14, 2010): 95–103. http://dx.doi.org/10.1677/joe-10-0062.
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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.
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Luque, Raul M., Manuel D. Gahete, Ute Hochgeschwender, and Rhonda D. Kineman. "Evidence that endogenous SST inhibits ACTH and ghrelin expression by independent pathways." American Journal of Physiology-Endocrinology and Metabolism 291, no. 2 (August 2006): E395—E403. http://dx.doi.org/10.1152/ajpendo.00038.2006.
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Corticosterone and total ghrelin levels are increased in somatostatin (SST) knockout mice ( Sst −/−) compared with SST-intact controls ( Sst +/+). Because exogenous ghrelin can increase glucocorticoids, the question arises whether elevated levels of ghrelin contribute to elevated corticosterone levels in Sst −/− mice. We report that Sst −/− mice had elevated mRNA levels for pituitary proopiomelanocortin (POMC), the precursor of adrenocorticotropic hormone (ACTH), whereas mRNA levels for hypothalamic corticotropin-releasing hormone (CRH) did not differ from Sst +/+ mice. Furthermore, SST suppressed pituitary POMC mRNA levels and ACTH release in vitro independently of CRH actions. In contrast, it has been reported that ghrelin increases glucocorticoids via a central effect on CRH secretion and that n-octanoyl ghrelin is the form of ghrelin that activates the GHS-R1a and modulates CRH neuronal activity. Consistent with elevations in total ghrelin levels, Sst −/− mice displayed an increase in stomach ghrelin mRNA levels, whereas hypothalamic and pituitary expression of ghrelin was not altered. Despite the increase in total ghrelin levels, circulating levels of n-octanoyl ghrelin were not altered in Sst −/− mice. Because glucocorticoids and ghrelin increase in response to fasting, we examined the impact of fasting on the adrenal axis and ghrelin in Sst +/+ and Sst −/− mice and found that endogenous SST does not significantly contribute to this adaptive response. We conclude that endogenous SST inhibits basal ghrelin gene expression in a tissue specific manner and independently and directly inhibits pituitary ACTH synthesis and release. Thus endogenous SST exerts an inhibitory effect on ghrelin synthesis and on the adrenal axis through independent pathways.
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Kanumakala, S., R. Greaves, C. C. Pedreira, S. Donath, G. L. Warne, M. R. Zacharin, and M. Harris. "Fasting Ghrelin Levels Are Not Elevated in Children with Hypothalamic Obesity." Journal of Clinical Endocrinology & Metabolism 90, no. 5 (May 1, 2005): 2691–95. http://dx.doi.org/10.1210/jc.2004-2175.
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Morbid obesity is a common problem after damage to the hypothalamus. Hypothalamic dysfunction is also thought to underlie the obesity that is typical of Prader-Willi syndrome. Elevated fasting levels of the appetite-stimulating hormone ghrelin have been reported in Prader-Willi syndrome. The aim of this study was to determine whether fasting ghrelin levels are increased in children with hypothalamic obesity. Fasting total ghrelin levels were compared in three groups: normal-weight controls (n = 16), obese controls (n = 16), and patients with hypothalamic obesity (n = 16). Obese children had lower fasting total ghrelin levels than normal controls, but there was no difference between the fasting total ghrelin level in obese controls and children with hypothalamic obesity (P = 0.88). These data suggest that it is unlikely that an elevation in fasting total ghrelin is responsible for the obesity that occurs after hypothalamic damage. Therapeutic interventions aimed at reducing fasting total ghrelin may prove ineffective in controlling weight gain in this group.
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Fittipaldi, Antonela S., Julieta Hernández, Daniel Castrogiovanni, Daniela Lufrano, Pablo N. De Francesco, Verónica Garrido, Patrick Vitaux, et al. "Plasma levels of ghrelin, des-acyl ghrelin and LEAP2 in children with obesity: correlation with age and insulin resistance." European Journal of Endocrinology 182, no. 2 (February 2020): 165–75. http://dx.doi.org/10.1530/eje-19-0684.
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Objective The octanoylated peptide hormone ghrelin regulates appetite and glycaemic control. Des-acyl ghrelin abolishes some effects of ghrelin, but does not bind to ghrelin receptor. LEAP2 is a novel ligand for ghrelin receptor that blocks the effects of ghrelin. Some evidences show that plasma levels of these peptides are altered in adults with obesity, but their levels in childhood obesity remain poorly studied. Therefore, the objective of this study was to assess fasting plasma levels of ghrelin, des-acyl ghrelin and LEAP2 in children with normoweight, overweight/obesity and their association with different anthropometric and metabolic variables. Design A total of 42 females and 40 males, ages 3–12 years old were enrolled as a cross-sectional cohort. Results Plasma levels of des-acyl ghrelin and LEAP2 (but not ghrelin) were lower and ghrelin/des-acyl ghrelin ratio was higher in children with overweight/obesity. Des-acyl ghrelin negatively correlated with age, BMI z-score, insulin and HOMA index, and the correlations were stronger in children with overweight/obesity. LEAP2 levels negatively correlated with BMI z-score. No gender differences were found. Conclusions Our findings suggest that ghrelin tone is increased in childhood obesity, due to a decrease on plasma levels of des-acyl ghrelin and LEAP2, and that des-acyl ghrelin is associated to insulin resistance, particularly in children with overweight/obesity.
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De Vriese, Carine, Françoise Grégoire, Philippe De Neef, Patrick Robberecht, and Christine Delporte. "Ghrelin Is Produced by the Human Erythroleukemic HEL Cell Line and Involved in an Autocrine Pathway Leading to Cell Proliferation." Endocrinology 146, no. 3 (March 1, 2005): 1514–22. http://dx.doi.org/10.1210/en.2004-0964.
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Ghrelin, a ligand of the GH secretagogue receptor (GHS-R 1a), is a 28-amino acid peptide with an unusual octanoyl group on Ser3, crucial for its biological activity. For the first time, ghrelin and GHS-R 1b, a truncated variant of the receptor resulting from alternative splicing, but not GHS-R 1a, mRNAs were detected in the human erythroleukemic cell line HEL. Two antibodies, used for RIA, were directed against octanoylated and total (octanoylated and desoctanoylated) ghrelin, and the recognized epitopes were characterized. Using reverse phase HPLC analysis followed by RIA, we demonstrated that octanoylated and desoctanoylated ghrelins were present in HEL cells and their culture medium, of which more than 90% was octanoylated. The ghrelin levels were not affected after 24 h treatment with sodium butyrate, phorbol 12-myristate 13-acetate, or forskolin, but a significant 3-fold increase in desoctanoylated ghrelin was detected in the culture medium after 48 h treatment with sodium butyrate. The antighrelin SB801 and SB969 antisera inhibited HEL cell proliferation by 24% and 39%, respectively, after 72 h. Taken together, these data suggested that endogenous ghrelin stimulated HEL cell proliferation by an autocrine pathway involving an unidentified receptor, distinct from GHS-R1a, and that the HEL cell line represents a unique model to study the octanoylation of ghrelin.
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Vestergaard, Esben Thyssen, Troels Krarup Hansen, Lars Christian Gormsen, Preben Jakobsen, Niels Moller, Jens Sandahl Christiansen, and Jens Otto Lunde Jorgensen. "Constant intravenous ghrelin infusion in healthy young men: clinical pharmacokinetics and metabolic effects." American Journal of Physiology-Endocrinology and Metabolism 292, no. 6 (June 2007): E1829—E1836. http://dx.doi.org/10.1152/ajpendo.00682.2006.
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Ghrelin levels fluctuate rapidly and dynamically with surges before meal times and postprandial troughs, and ghrelin increases appetite and food intake. Circulating ghrelin correlates negatively with body mass index (BMI), but obese individuals have a reduced postprandial decrease in ghrelin levels. Whether this reflects changes in secretion or clearance of ghrelin is uncertain. We therefore studied the pharmacokinetics of ghrelin in relation to anthropometric and biochemical measures. We also studied the effects of ghrelin on hormones and metabolites. In fasting humans, we used a constant infusion rate of ghrelin lasting 180 min at 5 pmol·kg body wt−1·min−1 in a randomized, double-blind, placebo-controlled crossover study. Serum ghrelin (s-ghrelin; total levels) was distributed and eliminated according to a two-compartment model. s-Ghrelin initial half-life was 24 ± 2 min and terminal half-life 146 ± 36 min, respectively. Mean residence time (MRT) of ghrelin was 93 ± 16 min. MRT correlated positively with both BMI ( r = 0.51, P < 0.001) and high-density cholesterol (HDL) levels ( r = 0.75, P < 0.001). Serum insulin levels remained constant during ghrelin infusion, whereas plasma glucose increased 0.3 ± 0.1 mmol/l ( P < 0.01) and free fatty acid levels more than doubled (to 1.03 ± 0.08 mmol/l, P < 0.001), translating into a significant reduction of insulin sensitivity ( P < 0.001). In conclusion, 1) we describe novel pharmacokinetics of ghrelin that are useful when tailoring ghrelin infusion rates in clinical experiments, 2) BMI and HDL correlate positively with MRT of infused ghrelin, and 3) supraphysiological ghrelin levels impair insulin sensitivity.
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Angeloni, Stephen V., Nicole Glynn, Grazia Ambrosini, Michael J. Garant, J. Dee Higley, Stephen Suomi, and Barbara C. Hansen. "Characterization of the Rhesus Monkey Ghrelin Gene and Factors Influencing Ghrelin Gene Expression and Fasting Plasma Levels." Endocrinology 145, no. 5 (May 1, 2004): 2197–205. http://dx.doi.org/10.1210/en.2003-1103.
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Abstract Ghrelin stimulates release of GH from the pituitary, stimulates appetite, and may influence metabolic processes in other tissues expressing the GH secretagogue receptor. Ghrelin can thus influence behaviors and endocrine pathways contributing to weight gain. In this study we characterized the ghrelin gene from the rhesus monkey and analyzed the association of plasma ghrelin levels with metabolic and endocrine markers. Rhesus ghrelin is 97, 91, and 96% homologous to the human cDNA, gene, and peptide, respectively. Ghrelin expression was highest in the stomach with lower levels found in muscle and duodenum. In these tissues, ghrelin expression in calorie-restricted and obese animals was about 40–99% lower than in lean animals. In addition, ghrelin expression in muscle was fairly high and may allow this tissue to contribute significantly to plasma levels. Fasting plasma ghrelin concentrations were also inversely correlated with body mass index and exhibited a nonlinear association with age with increased levels in younger and older monkeys and lower levels in middle-aged monkeys. Although a significant inverse correlation between fasting plasma ghrelin and fasting insulin levels were found, iv glucose and insulin administration did not significantly alter ghrelin levels. These studies demonstrate that ghrelin levels are influenced by age-related factors and adiposity in the rhesus monkey. These similarities between the rhesus monkey and human ghrelin genes and plasma ghrelin responses suggest a unique opportunity to study the mechanisms regulating ghrelin secretion and gene expression in different tissues in normal and disease states using this model system.
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Marchiò, Maddalena, Laura Roli, Carmela Giordano, Elisa Caramaschi, Azzurra Guerra, Tommaso Trenti, and Giuseppe Biagini. "High plasma levels of ghrelin and des-acyl ghrelin in responders to antiepileptic drugs." Neurology 91, no. 1 (May 25, 2018): e62-e66. http://dx.doi.org/10.1212/wnl.0000000000005741.
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ObjectiveTo reconsider ghrelin and des-acyl ghrelin plasma levels in children with epilepsy in order to establish a possible relation with response to antiepileptic drugs (AEDs).MethodsWe designed an observational study in which 114 patients with epilepsy were classified as responders (77) or nonresponders (37) and compared to 59 controls. In these patients, we measured ghrelin and des-acyl ghrelin by immunoassays in blood samples obtained after overnight fast.ResultsGhrelin plasma levels were higher (+94%; p < 0.001, Dunn test) in responders compared to controls. Des-acyl ghrelin plasma levels were also higher in the same group (+55%; p < 0.001). In addition, both hormones were unmodified in nonresponders compared to controls. By comparing responders to nonresponders, ghrelin and des-acyl ghrelin, respectively, were +126% (p < 0.001) and +29% (p < 0.001) in patients with a positive response to AEDs.ConclusionsThese results indicate that ghrelin and des-acyl ghrelin plasma levels are especially high in patients with epilepsy who positively respond to AEDs. In view of the anticonvulsant properties of ghrelin and des-acyl ghrelin, we propose that their higher levels could play a role in modulating the response to AEDs. Moreover, these peptides could be promising markers of response to AEDs.
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Yalniz, Mehmet, Ibrahim Halil Bahcecioglu, Huseyin Ataseven, Bilal Ustundag, Fulya Ilhan, Orhan K. Poyrazoglu, and Ahmet Erensoy. "Serum Adipokine and Ghrelin Levels in Nonalcoholic Steatohepatitis." Mediators of Inflammation 2006 (2006): 1–5. http://dx.doi.org/10.1155/mi/2006/34295.
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Adipokines and ghrelin play role in insulin resistance, the key pathophysiological abnormality in patients with nonalcoholic fatty liver diseases. In the present study, relationship between nonalcoholic steatohepatitis (NASH) and serum adipokine and ghrelin levels was investigated. Thirty seven patients with biopsy-proven NASH and 25 age- and sex-matched controls were enrolled. Ten of NASH patients (27%) had diabetes mellitus (n=5) or impaired glucose tolerance (n=5). Body mass index (BMI) was less than 30 kg/m2in67.6%of patients, while in the remaining32.4%it was more than 30 kg/m2. Serum adiponectin, leptin, TNF-α, and ghrelin were determined. Serum leptin (15.49±4.84vs10.31±2.53) and TNF-α(12.1±2.7vs10.31±2.56) levels were significantly higher in the NASH group compared to in the control group (P<.001for each). Nevertheless, adiponectin (11.1±2.1vs17.3±2.8) and ghrelin (6.46±1.1vs7.8±1.1) levels were lower in the NASH group than in the control group (P<.001for each). Serum levels of the adipokines and ghrelin, however, were comparable in the subgroups of patients regardless of whether BMI was<30or>30or glucose tolerance was impaired or not (P>.05). Additionally, neither adipokines nor ghrelin was correlated with histopathological grade and stage (P>.05). In conclusion; there is a significant relationship between NASH and adipokines and ghrelin independent from BMI and status of the glucose metabolism. These cytokines that appear to have role in the pathogenesis of NASH, however, do not have any effect upon the severity of the histopathology.
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Iqbal, Javed, Yohei Kurose, Benedict Canny, and Iain J. Clarke. "Effects of Central Infusion of Ghrelin on Food Intake and Plasma Levels of Growth Hormone, Luteinizing Hormone, Prolactin, and Cortisol Secretion in Sheep." Endocrinology 147, no. 1 (January 1, 2006): 510–19. http://dx.doi.org/10.1210/en.2005-1048.
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Ghrelin is an endogenous ligand for the GH secretagogue/ghrelin receptor (GHS-R) and stimulates feeding behavior and GH levels in rodents and humans. A preprandial increase in plasma ghrelin levels is seen in sheep on programmed feeding, followed by a postprandial rise in plasma GH levels, but effects on food intake and endocrine function are not defined in this ruminant species. We administered ghrelin to female sheep in various modes and measured effects on voluntary food intake (VFI) and plasma levels of GH, LH, prolactin, and cortisol. Whether administered intracerebroventricularly or iv, ghrelin consistently failed to stimulate VFI. On the other hand, ghrelin invariably increased plasma GH levels and α,β-diaminopropanoic acid-octanoyl3 human ghrelin was more potent than ovine ghrelin. Bolus injection of ghrelin into the third cerebral ventricle reduced plasma LH levels but did not affect levels of prolactin or cortisol. These findings suggested that the preprandial rise in plasma ghrelin that is seen in sheep on programmed feeding does not influence VFI but is likely to be important in the postprandial rise in GH levels. Thus, ghrelin does not appear to be a significant regulator of ingestive behavior in this species of ruminant but acts centrally to indirectly regulate GH and LH secretion.
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Ariyasu, Hiroyuki, Kazuhiko Takaya, Tetsuya Tagami, Yoshihiro Ogawa, Kiminori Hosoda, Takashi Akamizu, Michio Suda, et al. "Stomach Is a Major Source of Circulating Ghrelin, and Feeding State Determines Plasma Ghrelin-Like Immunoreactivity Levels in Humans." Journal of Clinical Endocrinology & Metabolism 86, no. 10 (October 1, 2001): 4753–58. http://dx.doi.org/10.1210/jcem.86.10.7885.
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Ghrelin, an endogenous ligand for the GH secretagogue receptor, was isolated from rat stomach and is involved in a novel system for regulating GH release. Although previous studies in rodents suggest that ghrelin is also involved in energy homeostasis and that ghrelin secretion is influenced by feeding, little is known about plasma ghrelin in humans. To address this issue, we studied plasma ghrelin-like immunoreactivity levels and elucidated the source of circulating ghrelin and the effects of feeding state on plasma ghrelin-like immunoreactivity levels in humans. The plasma ghrelin-like immunoreactivity concentration in normal humans measured by a specific RIA was 166.0 ± 10.1 fmol/ml. Northern blot analysis of various human tissues identified ghrelin mRNA found most abundantly in the stomach and plasma ghrelin-like immunoreactivity levels in totally gastrectomized patients were reduced to 35% of those in normal controls. Plasma ghrelin-like immunoreactivity levels were increased by 31% after 12-h fasting and reduced by 22% immediately after habitual feeding. In patients with anorexia nervosa, plasma ghrelin-like immunoreactivity levels were markedly elevated compared with those in normal controls (401.2 ± 58.4 vs. 192.8 ± 19.4 fmol/ml) and were negatively correlated with body mass indexes. We conclude that the stomach is a major source of circulating ghrelin and that plasma ghrelin-like immunoreactivity levels reflect acute and chronic feeding states in humans.
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Akamizu, Takashi, Nobuo Sakura, Yosuke Shigematsu, Go Tajima, Akira Ohtake, Hiroshi Hosoda, Hiroshi Iwakura, Hiroyuki Ariyasu, and Kenji Kangawa. "Analysis of plasma ghrelin in patients with medium-chain acyl-CoA dehydrogenase deficiency and glutaric aciduria type II." European Journal of Endocrinology 166, no. 2 (February 2012): 235–40. http://dx.doi.org/10.1530/eje-11-0785.
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ObjectiveGhrelin requires a fatty acid modification for binding to the GH secretagogue receptor. Acylation of the Ser3 residue of ghrelin is essential for its biological activities. We hypothesized that acyl-CoA is the fatty acid substrate for ghrelin acylation. Because serum octanoyl-CoA levels are altered by fatty acid oxidation disorders, we examined circulating ghrelin levels in affected patients.Materials and methodsBlood levels of acyl (A) and des-acyl (D) forms of ghrelin and acylcarnitine of patients with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency and glutaric aciduria type II (GA2) were measured.ResultsPlasma acyl ghrelin levels and A/D ratios increased in patients with MCAD deficiency or GA2 when compared with normal subjects. Reverse-phase HPLC confirmed that n-octanoylated ghrelin levels were elevated in these patients.ConclusionChanging serum medium-chain acylcarnitine levels may affect circulating acyl ghrelin levels, suggesting that acyl-CoA is the substrate for ghrelin acylation.
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Wang, Lixin, Nicole R. Basa, Almaas Shaikh, Andrew Luckey, David Heber, David H. St-Pierre, and Yvette Taché. "LPS inhibits fasted plasma ghrelin levels in rats: role of IL-1 and PGs and functional implications." American Journal of Physiology-Gastrointestinal and Liver Physiology 291, no. 4 (October 2006): G611—G620. http://dx.doi.org/10.1152/ajpgi.00533.2005.
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LPS injected intraperitoneally decreases fasted plasma levels of ghrelin at 3 h postinjection in rats. We characterized the inhibitory action of LPS on plasma ghrelin and whether exogenous ghrelin restores LPS-induced suppression of food intake and gastric emptying in fasted rats. Plasma ghrelin and insulin and blood glucose were measured after intraperitoneal injection of LPS, intravenous injection of IL-1β and urocortin 1, and in response to LPS under conditions of blockade of IL-1 or CRF receptors by subcutaneous injection of IL-1 receptor antagonist (IL-1Ra) or astressin B, respectively, and prostaglandin (PG) synthesis by intraperitoneal indomethacin. Food intake and gastric emptying were measured after intravenous injection of ghrelin at 5 h postintraperitoneal LPS injection. LPS inhibited the elevated fasted plasma ghrelin levels by 47.6 ± 4.9%, 58.9 ± 3.3%, 74.4 ± 2.7%, and 48.9 ± 8.7% at 2, 3, 5, and 7 h postinjection, respectively, and values returned to preinjection levels at 24 h. Insulin levels were negatively correlated to those of ghrelin, whereas there was no significant correlation between glucose and ghrelin. IL-1Ra and indomethacin prevented the first 3-h decline in ghrelin levels induced by LPS, whereas astressin B did not. IL-1β inhibited plasma ghrelin levels, whereas urocortin 1 had no influence. Ghrelin injected intravenously prevented an LPS-induced 87% reduction of gastric emptying and 61% reduction of food intake. These data showed that IL-1 and PG pathways are part of the early mechanisms by which LPS suppresses fasted plasma ghrelin and that exogenous ghrelin can normalize LPS-induced-altered digestive functions.
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V., Harikrishnan, Rakesh Kumar, Naresh Sachdeva, and Devi Dayal. "Low plasma ghrelin levels in children with severe protein energy malnutrition." International Journal of Contemporary Pediatrics 5, no. 4 (June 22, 2018): 1527. http://dx.doi.org/10.18203/2349-3291.ijcp20182558.
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Background: Children with primary protein energy malnutrition (PEM) have significant loss of appetite which makes their nutritional rehabilitation difficult. Trials in patients with anorexia nervosa and cancer cachexia have shown short term efficacy of supplementing ghrelin to increase appetite. However, literature on ghrelin hormone status in children with PEM is scarce. We planned to study plasma ghrelin hormone levels in children with PEM and difference in plasma ghrelin levels among children having PEM of different grades.Methods: Cross-sectional observational study was conducted over one year period. All hospitalised children during the study period and fulfilling the inclusion criteria for primary PEM (WHO criteria for malnutrition) were enrolled as cases. The cases (59 children) were divided into 2 groups – (Group 1 -severe PEM, group 2 - mild to moderate PEM) and were compared with 19 healthy children as controls (Group 3). Plasma fasting ghrelin levels were measured using enzyme immunoassay. The results were analysed using Mann-Whitney U Test.Results: Median plasma ghrelin level among severe PEM group was 1.942ng/ml (interquartile range (IQR): 0.064, 9.506), mild to moderate PEM - 17.662 ng/ml (IQR: 1.658, 40.129) and controls - 17.525 ng/ml (IQR: 0.626, 27.361). Median ghrelin value was significantly lower in severe PEM group as compared to mild to moderate PEM (p value- 0.027).Conclusions: Plasma ghrelin levels are significantly reduced in children with severe PEM as compared with mild to moderate PEM and healthy controls.
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Heldsinger, Andrea, Gintautas Grabauskas, Xiaoyin Wu, ShiYi Zhou, Yuanxu Lu, Il Song, and Chung Owyang. "Ghrelin Induces Leptin Resistance by Activation of Suppressor of Cytokine Signaling 3 Expression in Male Rats: Implications in Satiety Regulation." Endocrinology 155, no. 10 (October 1, 2014): 3956–69. http://dx.doi.org/10.1210/en.2013-2095.
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Abstract The anorexigenic adipocyte-derived hormone leptin and the orexigenic hormone ghrelin act in opposition to regulate feeding behavior via the vagal afferent pathways. The mechanisms by which ghrelin exerts its inhibitory effects on leptin are unknown. We hypothesized that ghrelin activates the exchange protein activated by cAMP (Epac), inducing increased SOCS3 expression, which negatively affects leptin signal transduction and neuronal firing in nodose ganglia (NG) neurons. We showed that 91 ± 3% of leptin receptor (LRb) –bearing neurons contained ghrelin receptors (GHS-R1a) and that ghrelin significantly inhibited leptin-stimulated STAT3 phosphorylation in rat NG neurons. Studies of the signaling cascades used by ghrelin showed that ghrelin caused a significant increase in Epac and suppressor of cytokine signaling 3 (SOCS3) expression in cultured rat NG neurons. Transient transfection of cultured NG neurons to silence SOCS3 and Epac genes reversed the inhibitory effects of ghrelin on leptin-stimulated STAT3 phosphorylation. Patch-clamp studies and recordings of single neuronal discharges of vagal primary afferent neurons showed that ghrelin markedly inhibited leptin-stimulated neuronal firing, an action abolished by silencing SOCS3 expression in NG. Plasma ghrelin levels increased significantly during fasting. This was accompanied by enhanced SOCS3 expression in the NG and prevented by treatment with a ghrelin antagonist. Feeding studies showed that silencing SOCS3 expression in the NG reduced food intake evoked by endogenous leptin. We conclude that ghrelin exerts its inhibitory effects on leptin-stimulated neuronal firing by increasing SOCS3 expression. The SOCS3 signaling pathway plays a pivotal role in ghrelin's inhibitory effect on STAT3 phosphorylation, neuronal firing, and feeding behavior.
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Yokoyama, Masayuki, Keiko Nakahara, Masayasu Kojima, Hiroshi Hosoda, Kenji Kangawa, and Noboru Murakami. "Influencing the between-feeding and endocrine responses of plasma ghrelin in healthy dogs." European Journal of Endocrinology 152, no. 1 (January 2005): 155–60. http://dx.doi.org/10.1530/eje.1.01818.
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Objectives: Ghrelin has recently been isolated from rat and human stomach as an endogenous ligand for the growth hormone (GH) secretagog receptor. Using beagle dogs, we investigated the distribution of ghrelin in the stomach and its possible role. Methods: We examined: (i) GH release in response to ghrelin injection (0.5 or 5 μg/kg, i.v.), (ii) gastric localization of ghrelin-immunostained cells, (iii) changes in daily food consumption after ghrelin injection (3, 10, and 20 μg/kg, i.v.), (iv) plasma ghrelin levels under regular, but restricted feeding conditions, and (v) variations in plasma ghrelin levels in relatively lean, normal and obese dogs. Results: Administration of ghrelin to dogs promptly increased circulating GH concentrations, although this effect was transitory and was maintained for only 20 min. Ghrelin was localized in the stomach fundus and body, but none was detected in either the pylorus or cardia. Administration of ghrelin at a dose of 20 μg/kg increased the daily food intake of beagle dogs. Plasma ghrelin levels peaked just before meal times, and then returned to basal levels. Obese dogs had higher plasma ghrelin levels than did normal and lean dogs. Conclusions: These results indicate that ghrelin is a potent GH secretagog in dogs. The distribution of ghrelin-immunoreactive cells in the canine stomach resembles that of both the murine and human stomach. Ghrelin participates in the control of feeding behavior and energy homeostasis in dogs and may, therefore, be involved in the development of obesity.
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Tassone, F., F. Broglio, S. Destefanis, S. Rovere, A. Benso, C. Gottero, F. Prodam, et al. "Neuroendocrine and Metabolic Effects of Acute Ghrelin Administration in Human Obesity." Journal of Clinical Endocrinology & Metabolism 88, no. 11 (November 1, 2003): 5478–83. http://dx.doi.org/10.1210/jc.2003-030564.
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Abstract Ghrelin stimulates appetite and plays a role in the neuroendocrine response to energy balance variations. Ghrelin levels are inversely associated with body mass index (BMI), increased by fasting and decreased by food intake, glucose load, insulin, and somatostatin. Ghrelin levels are reduced in obesity, a condition of hyperinsulinism, reduced GH secretion, and hypothalamus-pituitary-adrenal axis hyperactivity. We studied the endocrine and metabolic response to acute ghrelin administration (1.0 μg/kg iv) in nine obese women [OB; BMI (mean ± sd) 36.3 ± 2.3 kg/m2] and seven normal women (NW; BMI 20.3 ± 1.7 kg/m2). Basal ghrelin levels in NW were higher than in OB (P < 0.05). In NW, ghrelin increased (P < 0.05) GH, prolactin (PRL), ACTH, cortisol, and glucose levels but did not modify insulin. In OB, ghrelin increased (P < 0.01) GH, PRL, ACTH, and cortisol levels. The GH response to ghrelin in OB was 55% lower (P < 0.02) than in NW, whereas the PRL, ACTH, and cortisol responses were similar. In OB, ghrelin increased glucose and reduced insulin (P < 0.05). Thus, obesity shows remarkable reduction of the somatotroph responsiveness to ghrelin, suggesting that ghrelin hyposecretion unlikely explains the impairment of somatotroph function in obesity. On the other hand, in obesity ghrelin shows preserved influence on PRL, ACTH, and insulin secretion as well as in glucose levels.
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Huang, Lei, Bin Qiu, Lin Yuan, Lili Zheng, Qiang Li, and Shigong Zhu. "Influence of fasting, insulin and glucose on ghrelin in the dorsal vagal complex in rats." Journal of Endocrinology 211, no. 3 (September 19, 2011): 257–62. http://dx.doi.org/10.1530/joe-11-0147.
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The dorsal vagal complex (DVC) is an important site in which ghrelin plays an orexigenic role. However, the relationship between ghrelin expression in DVC and the energy status of the organism is unclear, as well as the role of the vagus nerve in this process. In this study, ghrelin expression in DVC neurons of rats was detected, then levels of ghrelin expression were observed under the conditions of regular diet, fasting, high blood glucose, low blood glucose, and following subdiaphragmatic vagotomy and vagus nerve electrostimulation. The results showed the following: 1) there was positive staining of ghrelin neurons in DVC; 2) ghrelin protein and mRNA levels in DVC increased under fasting condition; 3) Hyperglycemia, induced by glucose production, decreased DVC ghrelin levels and levels did not increase under hypoglycemia induced by insulin injection; 4) the dorsal trunk of the subdiaphragmatic vagus transmits a stimulatory signal to increase DVC ghrelin levels, whereas the ventral trunk transmits inhibitory information; and 5) DVC ghrelin levels decreased with 20 Hz stimulation on the ventral or dorsal trunk of subdiaphragmatic vagus nerves but increased with 1 Hz stimulation on the dorsal trunk. These results indicate that endogenous ghrelin is synthesized in DVC neurons. Conditions such as fasting, hyperglycemia, and hypoglycemia result in changes in DVC ghrelin levels in which the dorsal and ventral trunks of subdiaphragmatic vagus play different modulation roles.
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Gong, Zhi, Makoto Yoshimura, Sayaka Aizawa, Reiko Kurotani, Jeffrey M. Zigman, Takafumi Sakai, and Ichiro Sakata. "G protein-coupled receptor 120 signaling regulates ghrelin secretion in vivo and in vitro." American Journal of Physiology-Endocrinology and Metabolism 306, no. 1 (January 1, 2014): E28—E35. http://dx.doi.org/10.1152/ajpendo.00306.2013.
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Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor, is produced predominantly in the stomach. It has been reported that endogenous ghrelin levels are increased by fasting and decreased immediately after feeding and that fasting-induced ghrelin release is controlled by the sympathetic nervous system. However, the mechanisms of plasma ghrelin decrement after feeding are poorly understood. Here, we studied the control of ghrelin secretion using ghrelin-producing cell lines and found that these cells express high levels of mRNA encoding G-protein coupled receptor 120 (GPR120). Addition of GW-9508 (a GPR120 chemical agonist) and α-linolenic acid (a natural ligand for GPR120) inhibited the secretion of ghrelin by ∼50 and 70%, respectively. However, the expression levels of preproghrelin and ghrelin O-acyltransferase (GOAT) mRNAs were not influenced by GW-9508. In contrast, the expression levels of prohormone convertase 1 were decreased significantly by GW-9508 incubation. Moreover, we observed that the inhibitory effect of GW-9508 on ghrelin secretion was blocked by a small interfering RNA (siRNA) targeting the sequence of GPR120. Furthermore, pretreatment with GW-9508 blocked the effect of the norepinephrine (NE)-induced ghrelin elevation in ghrelin cell lines. In addition, we showed that GW-9508 inhibited ghrelin secretion via extracellular signal-regulated kinase activity in ghrelin cell lines. Finally, we found that GW-9508 decreased plasma ghrelin levels in mice. These results suggest that the decrease of ghrelin secretion after feeding is induced partially by long-chain fatty acids that act directly on gastric GPR120-expressing ghrelin cells.
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Bando, Mika, Hiroshi Iwakura, Hiroyuki Ariyasu, Hiroshi Hosoda, Go Yamada, Kiminori Hosoda, Souichi Adachi, Kazuwa Nakao, Kenji Kangawa, and Takashi Akamizu. "Transgenic overexpression of intraislet ghrelin does not affect insulin secretion or glucose metabolism in vivo." American Journal of Physiology-Endocrinology and Metabolism 302, no. 4 (February 15, 2012): E403—E408. http://dx.doi.org/10.1152/ajpendo.00341.2011.
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Whereas ghrelin is produced primarily in the stomach, a small amount of it is produced in pancreatic islets. Although exogenous administration of ghrelin suppresses insulin secretion in vitro or in vivo, the role of intraislet ghrelin in the regulation of insulin secretion in vivo remains unclear. To understand the physiological role of intraislet ghrelin in insulin secretion and glucose metabolism, we developed a transgenic (Tg) mouse model, rat insulin II promoter ghrelin-internal ribosomal entry site-ghrelin O-acyl transferase (RIP-GG) Tg mice, in which mouse ghrelin cDNA and ghrelin O-acyltransferase are overexpressed under the control of the rat insulin II promoter. Although pancreatic desacyl ghrelin levels were elevated in RIP-GG Tg mice, pancreatic ghrelin levels were not altered in animals on a standard diet. However, when Tg mice were fed a medium-chain triglyceride-rich diet (MCTD), pancreatic ghrelin levels were elevated to ∼16 times that seen in control animals. It seems likely that the gastric ghrelin cells possess specific machinery to provide the octanoyl acid necessary for ghrelin acylation but that this machinery is absent from pancreatic β-cells. Despite the overexpression of ghrelin, plasma ghrelin levels in the portal veins of RIP-GG Tg mice were unchanged from control levels. Glucose tolerance, insulin secretion, and islet architecture in RIP-GG Tg mice were not significantly different even when the mice were fed a MCTD. These results indicate that intraislet ghrelin does not play a major role in the regulation of insulin secretion in vivo.