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Journal articles on the topic 'Ghrelin'
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1
Schwandt, Sara E., Sarath C. Peddu, and Larry G. Riley. "Differential Roles for Octanoylated and Decanoylated Ghrelins in Regulating Appetite and Metabolism." International Journal of Peptides 2010 (March 17, 2010): 1–6. http://dx.doi.org/10.1155/2010/275804.
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Since its identification in 1999, ghrelin has been identified in all vertebrate groups. The “active core” of ghrelin is highly conserved among vertebrates, suggesting its biological activity to be also conserved. In fish, both acylated forms of ghrelin have been identified; however, the ratio of the ghrelin-C8 to ghrelin-C10 is not as great as observed in mammals. In the tilapia (Oreochromis mossambicus), ghrelin-C10 is the major form of ghrelin. Since fish are known to inhabit every ecological niche on earth, studies on fish have provided valuable insight into vertebrate physiology in general; it is likely that understanding the role of both acylated forms of ghrelin, in more detail, in fish will result into novel insights in the biology of ghrelin within vertebrates. In this paper we discuss ghrelin's role in regulating appetite and metabolism in fish, in general, and provide evidence that the two tilapia ghrelins exhibit different biological roles.
2
De Vriese, Carine, and Christine Delporte. "Autocrine proliferative effect of ghrelin on leukemic HL-60 and THP-1 cells." Journal of Endocrinology 192, no. 1 (January 2007): 199–205. http://dx.doi.org/10.1677/joe.1.06881.
Full textAbstract:
Ghrelin is a 28 amino acid peptide hormone that is mainly produced by the stomach, but also by several tissues and tumors. Ghrelin is octanoylated on the Ser3, but is also detected as a des-acylated form. Only the acylated ghrelin activates the GH secretagogue receptor (GHS-R) type 1a to stimulate GH release, and regulate food intake and energy metabolism. For the first time, we report that ghrelin and des-acyl ghrelin are present in human promyelocytic HL-60, monocytic THP-1 and lymphoblastic SupT1 cell lines. The human leukemic cell lines did not express the functional GHS-R 1a, whereas they expressed GHS-R 1b, a truncated variant of the receptor. Leukemic cell proliferation was not modified by the addition of octanoylated or des-acyl ghrelins. However, THP-1 and HL-60 cell proliferations were inhibited by SB801, an antibody directed against the N-terminal octanoylated portion of ghrelin, suggesting that octanoylated ghrelin stimulates cell proliferation via an autocrine pathway involving an as yet unidentified ghrelin receptor. Both octanoylated and des-acyl ghrelins did not alter the basal adenylate cyclase activity. Treatments of THP-1 and SupT1 cells by both octanoylated and des-acyl ghrelins did not modify the adenylate cyclase activity in response to vasoactive intestinal peptide, suggesting that ghrelin is unlikely to modulate the anti-inflammatory and differentiating properties of vasoactive intestinal peptide.
3
Heppner, Kristy M., and Jenny Tong. "MECHANISMS IN ENDOCRINOLOGY: Regulation of glucose metabolism by the ghrelin system: multiple players and multiple actions." European Journal of Endocrinology 171, no. 1 (July 2014): R21—R32. http://dx.doi.org/10.1530/eje-14-0183.
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Ghrelin is a 28-amino acid peptide secreted mainly from the X/A-like cells of the stomach. Ghrelin is found in circulation in both des-acyl (dAG) and acyl forms (AG). Acylation is catalyzed by the enzyme ghrelinO-acyltransferase (GOAT). AG acts on the GH secretagogue receptor (GHSR) in the CNS to promote feeding and adiposity and also acts on GHSR in the pancreas to inhibit glucose-stimulated insulin secretion. These well-described actions of AG have made it a popular target for obesity and type 2 diabetes mellitus pharmacotherapies. However, despite the lack of a cognate receptor, dAG appears to have gluco-regulatory action, which adds an additional layer of complexity to ghrelin's regulation of glucose metabolism. This review discusses the current literature on the gluco-regulatory action of the ghrelin system (dAG, AG, GHSR, and GOAT) with specific emphasis aimed toward distinguishing AG vs dAG action.
4
Delporte, Christine. "Structure and Physiological Actions of Ghrelin." Scientifica 2013 (2013): 1–25. http://dx.doi.org/10.1155/2013/518909.
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Ghrelin is a gastric peptide hormone, discovered as being the endogenous ligand of growth hormone secretagogue receptor. Ghrelin is a 28 amino acid peptide presenting a uniquen-octanoylation modification on its serine in position 3, catalyzed by ghrelinO-acyl transferase. Ghrelin is mainly produced by a subset of stomach cells and also by the hypothalamus, the pituitary, and other tissues. Transcriptional, translational, and posttranslational processes generate ghrelin and ghrelin-related peptides. Homo- and heterodimers of growth hormone secretagogue receptor, and as yet unidentified receptors, are assumed to mediate the biological effects of acyl ghrelin and desacyl ghrelin, respectively. Ghrelin exerts wide physiological actions throughout the body, including growth hormone secretion, appetite and food intake, gastric secretion and gastrointestinal motility, glucose homeostasis, cardiovascular functions, anti-inflammatory functions, reproductive functions, and bone formation. This review focuses on presenting the current understanding of ghrelin and growth hormone secretagogue receptor biology, as well as the main physiological effects of ghrelin.
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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.
6
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.
7
Gupta, Deepali, Salil Varshney, Kripa Shankar, Sherri Osborne-Lawrence, Nathan P. Metzger, and Jeffrey Marc Zigman. "Role of Growth Hormone in Ghrelin’s Metabolic Actions." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A553. http://dx.doi.org/10.1210/jendso/bvab048.1127.
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Abstract Objective: Ghrelin regulates eating, body weight, and blood glucose. Upon binding to its receptor (growth hormone secretagogue receptor; GHSR), administered ghrelin increases food intake, body weight, and blood glucose. In contrast, blocking ghrelin lowers body weight and food intake. Also, mice that lack ghrelin or GHSR develop life-threatening hypoglycemia when submitted to a prolonged caloric restriction protocol providing only 40% of usual daily calories. Although GHSR was first identified in the pituitary, ghrelin was first defined by its ability to stimulate GH secretion via GHSRs, GH replacement prevents hypoglycemia in ghrelin-KO mice undergoing prolonged caloric restriction, and GH is known to modulate body composition, relatively little attention has been devoted to the role of GH-secreting pituitary somatotrophs (“GH cells”) in ghrelin action. The objective here was to determine the requirement for GHSR-expressing GH cells in mediating ghrelin’s metabolic actions. Methods: Mice with GH cell-selective GHSR deletion were generated by crossing novel GH-IRES-Cre mice to novel floxed-GHSR mice. GH cell-selective GHSR knockout mice and three control littermate groups were studied. Plasma GH, food intake, and blood glucose were measured after ip or sc ghrelin administration. Blood glucose and plasma GH were measured over the course of a 15-d calorie restriction protocol providing only 40% of usual daily calories. Results: In mice with GH cell-selective GHSR deletion, ghrelin-induced GH secretion and food intake were attenuated (by 84.1% at 15 min and by 35.3% at 45 min, respectively) as compared to controls; ghrelin-induced blood glucose elevation was unchanged. Mice with GH cell-selective GHSR deletion exhibited an attenuated GH rise (by 76.8%) over the 15-d calorie restriction period, yet they nonetheless resisted life-threatening hypoglycemia which is observed in similarly-treated ghrelin-KO mice, GHSR-null mice, and mice with hepatocyte-selective GH receptor deletion. Conclusions: These results suggest that GH cell-expressed GHSRs are required for ghrelin’s acute orexigenic and GH secretory actions but are dispensable for ghrelin’s glucoregulatory actions, at least in the settings assessed here. Although GH cell-expressed GHSRs are required for the progressive GH elevations associated with prolonged calorie restriction, they are not required for ghrelin’s overall protective effects to block prolonged calorie restriction-associated hypoglycemia.
8
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.
9
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.
10
Wu, Wei, Lei Zhu, Zhimin Dou, Qiliang Hou, Sen Wang, Ziqian Yuan, and Bin Li. "Ghrelin in Focus: Dissecting Its Critical Roles in Gastrointestinal Pathologies and Therapies." Current Issues in Molecular Biology 46, no. 1 (January 22, 2024): 948–64. http://dx.doi.org/10.3390/cimb46010061.
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This review elucidates the critical role of ghrelin, a peptide hormone mainly synthesized in the stomach in various gastrointestinal (GI) diseases. Ghrelin participates in diverse biological functions ranging from appetite regulation to impacting autophagy and apoptosis. In sepsis, it reduces intestinal barrier damage by inhibiting inflammatory responses, enhancing GI blood flow, and modulating cellular processes like autophagy and apoptosis. Notably, in inflammatory bowel disease (IBD), serum ghrelin levels serve as markers for distinguishing between active and remission phases, underscoring its potential in IBD treatment. In gastric cancer, ghrelin acts as an early risk marker, and due to its significant role in increasing the proliferation and migration of gastric cancer cells, the ghrelin–GHS-R axis is poised to become a target for gastric cancer treatment. The role of ghrelin in colorectal cancer (CRC) remains controversial; however, ghrelin analogs have demonstrated substantial benefits in treating cachexia associated with CRC, highlighting the therapeutic potential of ghrelin. Nonetheless, the complex interplay between ghrelin’s protective and potential tumorigenic effects necessitates a cautious approach to its therapeutic application. In post-GI surgery scenarios, ghrelin and its analogs could be instrumental in enhancing recovery and reducing complications. This article accentuates ghrelin’s multifunctionality, shedding light on its influence on disease mechanisms, including inflammatory responses and cancer progression, and examines its therapeutic potential in GI surgeries and disorders, advocating for continued research in this evolving field.
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Kok, Petra, Remberto C. Paulo, Mihaela Cosma, Kristi L. Mielke, John M. Miles, Cyril Y. Bowers, and Johannes D. Veldhuis. "Estrogen Supplementation Selectively Enhances Hypothalamo-Pituitary Sensitivity to Ghrelin in Postmenopausal Women." Journal of Clinical Endocrinology & Metabolism 93, no. 10 (October 1, 2008): 4020–26. http://dx.doi.org/10.1210/jc.2008-0522.
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Context: Sex-steroid hormones amplify pulsatile GH secretion by unknown mechanisms. Ghrelin is the most potent natural GH secretagogue discovered to date. A plausible unifying postulate is that estradiol (E2) enhances hypothalamo-pituitary sensitivity to ghrelin (a physiological effect). The hypothesis is relevant to understanding the basis of hyposomatotropism in aging and other relatively hypogonadal states. Objective: Our objective was to test the hypothesis that E2 supplementation potentiates ghrelin’s stimulation of pulsatile GH secretion. Setting: The study was conducted at an academic medical center. Subjects: Healthy postmenopausal women (n = 20) were included in the study. Interventions: Separate-day iv infusions of saline vs. five graded doses of ghrelin were performed in volunteers prospectively randomly assigned to receive (n = 8) or not receive (n = 12) transdermal E2 for 21 d were performed. Measures: GH secretion was estimated by deconvolution analysis and abdominal visceral fat mass determined by computerized axial tomography were calculated. Results: E2 supplementation augmented ghrelin’s stimulation of basal (nonpulsatile) GH secretion by 3.6-fold (P = 0.022), increased GH responses to low-dose ghrelin by 2.9-fold (P = 0.035), did not alter ghrelin efficacy, and elicited more regular patterns of acylated ghrelin concentrations during saline infusion (P = 0.033). Abdominal visceral fat negatively determined responses to ghrelin (R = −0.346; P < 0.005). Conclusions: Transdermal E2 supplementation potentiates GH secretion stimulated by physiological but not pharmacological concentrations of acylated ghrelin, and concomitantly regularizes patterns of bioactive ghrelin secretion in postmenopausal women. Accordingly, the estrogen milieu appears to control sensitivity of the hypothalamopituitary unit to acylated ghrelin.
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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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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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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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Hougland, James L. "Ghrelin octanoylation by ghrelin O-acyltransferase: Unique protein biochemistry underlying metabolic signaling." Biochemical Society Transactions 47, no. 1 (January 9, 2019): 169–78. http://dx.doi.org/10.1042/bst20180436.
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Abstract Ghrelin is a small peptide hormone that requires a unique post-translational modification, serine octanoylation, to bind and activate the GHS-R1a receptor. Ghrelin signaling is implicated in a variety of neurological and physiological processes, but is most well known for its roles in controlling hunger and metabolic regulation. Ghrelin octanoylation is catalyzed by ghrelin O-acyltransferase (GOAT), a member of the membrane-bound O-acyltransferase (MBOAT) enzyme family. From the status of ghrelin as the only substrate for GOAT in the human genome to the source and requirement for the octanoyl acyl donor, the ghrelin–GOAT system is defined by multiple unique aspects within both protein biochemistry and endocrinology. In this review, we examine recent advances in our understanding of the interactions and mechanisms leading to ghrelin modification by GOAT, discuss the potential sources for the octanoyl acyl donor required for ghrelin's activation, and summarize the current landscape of molecules targeting ghrelin octanoylation through GOAT inhibition.
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Sun, Yuxiang, Saira Ahmed, and Roy G. Smith. "Deletion of Ghrelin Impairs neither Growth nor Appetite." Molecular and Cellular Biology 23, no. 22 (November 15, 2003): 7973–81. http://dx.doi.org/10.1128/mcb.23.22.7973-7981.2003.
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ABSTRACT Pharmacological studies show that ghrelin stimulates growth hormone release, appetite, and fat deposition, but ghrelin's physiological role in energy homeostasis has not been established. Ghrelin was also proposed to regulate leptin and insulin release and to be important for the normal function of stomach, heart, kidney, lung, testis, and placenta. To help determine a definable physiological role for ghrelin, we generated ghrelin-null mice. In contrast to predictions made from the pharmacology of ghrelin, ghrelin-null mice are not anorexic dwarfs; their size, growth rate, food intake, body composition, reproduction, gross behavior, and tissue pathology are indistinguishable from wild-type littermates. Fasting produces identical decreases in serum leptin and insulin in null and wild-type mice. Ghrelin-null mice display normal responses to starvation and diet-induced obesity. As in wild-type mice, the administration of exogenous ghrelin stimulates appetite in null mice. Our data show that ghrelin is not critically required for viability, fertility, growth, appetite, bone density, and fat deposition and not likely to be a direct regulator of leptin and insulin. Therefore, antagonists of ghrelin are unlikely to have broad utility as antiobesity agents.
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Sassi, Martina, Alwena H. Morgan, and Jeffrey S. Davies. "Ghrelin Acylation—A Post-Translational Tuning Mechanism Regulating Adult Hippocampal Neurogenesis." Cells 11, no. 5 (February 22, 2022): 765. http://dx.doi.org/10.3390/cells11050765.
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Adult hippocampal neurogenesis—the generation of new functional neurones in the adult brain—is impaired in aging and many neurodegenerative disorders. We recently showed that the acylated version of the gut hormone ghrelin (acyl-ghrelin) stimulates adult hippocampal neurogenesis while the unacylated form of ghrelin inhibits it, thus demonstrating a previously unknown function of unacyl-ghrelin in modulating hippocampal plasticity. Analysis of plasma samples from Parkinson’s disease patients with dementia demonstrated a reduced acyl-ghrelin:unacyl-ghrelin ratio compared to both healthy controls and cognitively intact Parkinson’s disease patients. These data, from mouse and human studies, suggest that restoring acyl-ghrelin signalling may promote the activation of pathways to support memory function. In this short review, we discuss the evidence for ghrelin’s role in regulating adult hippocampal neurogenesis and the enzymes involved in ghrelin acylation and de-acylation as targets to treat mood-related disorders and dementia.
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Skibicka, Karolina P., Rozita H. Shirazi, Caroline Hansson, and Suzanne L. Dickson. "Ghrelin Interacts with Neuropeptide Y Y1 and Opioid Receptors to Increase Food Reward." Endocrinology 153, no. 3 (March 1, 2012): 1194–205. http://dx.doi.org/10.1210/en.2011-1606.
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Ghrelin, a stomach-derived hormone, is an orexigenic peptide that was recently shown to potently increase food reward behavior. The neurochemical circuitry that links ghrelin to the mesolimbic system and food reward behavior remains unclear. Here we examined the contribution of neuropeptide Y (NPY) and opioids to ghrelin's effects on food motivation and intake. Both systems have well-established links to the mesolimbic ventral tegmental area (VTA) and reward/motivation control. NPY mediates the effect of ghrelin on food intake via activation of NPY-Y1 receptor (NPY-Y1R); their connection with respect to motivated behavior is unexplored. The role of opioids in any aspect of ghrelin's action on food-oriented behaviors is unknown. Rats were trained in a progressive ratio sucrose-induced operant schedule to measure food reward/motivation behavior. Chow intake was measured immediately after the operant test. In separate experiments, we explored the suppressive effects of a selective NPY-Y1R antagonist or opioid receptor antagonist naltrexone, injected either intracerebroventricularly or intra-VTA, on ghrelin-induced food reward behavior. The ventricular ghrelin-induced increase in sucrose-motivated behavior and chow intake were completely blocked by intracerebroventricular pretreatment with either an NPY-Y1R antagonist or naltrexone. The intra-VTA ghrelin-induced sucrose-motivated behavior was blocked only by intra-VTA naltrexone. In contrast, the intra-VTA ghrelin-stimulated chow intake was attenuated only by intra-VTA NPY-Y1 blockade. Finally, ghrelin infusion was associated with an elevated VTA μ-opioid receptor expression. Thus, we identify central NPY and opioid signaling as the necessary mediators of food intake and reward effects of ghrelin and localize these interactions to the mesolimbic VTA.
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YILDIRIM YAROĞLU, Hatice, Buğra ÖZKAN, Senay BALCI, Zeynep Nil ÜNAL, Sema ERDEN ERTÜRK, Dilek çiçek DİLEK ÇİÇEK, and Lülüfer TAMER. "Koroner arter hastalığında ghrelin ve ghrelin leu72met polimorfizmi arasındaki ilişki." Cukurova Medical Journal 48, no. 2 (June 30, 2023): 637–43. http://dx.doi.org/10.17826/cumj.1243029.
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Purpose: Ghrelin represents a hormone, which is defined as an endogenous ligand bound to the growth hormone-releasing hormone receptor (GHS-R1a). However, the mechanisms that underlie ghrelin’s impacts on cardiovascular diseases have not been completely detected. For this reason, we aimed to research the relationship between serum ghrelin and ghrelin gene polymorphism in coronary artery disease (CAD).
Materials and Methods: The study group consisted of 88 patients diagnosed with a minimum of one coronary artery stenosis over 70%, and the control group comprised 81 individuals without coronary artery lesions. An autoanalyzer was used to analyze fasting blood glucose (FBG) and lipid parameter levels. Ghrelin levels were examined with an enzyme-linked immunosorbent assay (ELISA) kit.
Results: Ghrelin levels were found to be 2.2 ng/ml in the control group and 2.1 ng/ml in the CAD group. No statistical relation in ghrelin Leu72Met genotypes were detected between the control and patient groups.
Conclusion: Serum ghrelin levels were higher in the control group than in the CAD group. Whether ghrelin levels and Leu72Met polymorphism have protective effects in CAD must be revealed in an extensive study group with other polymorphisms and ghrelin expression in the ghrelin gene.
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Sakata, Ichiro, Jing Yang, Charlotte E. Lee, Sherri Osborne-Lawrence, Sherry A. Rovinsky, Joel K. Elmquist, and Jeffrey M. Zigman. "Colocalization of ghrelin O-acyltransferase and ghrelin in gastric mucosal cells." American Journal of Physiology-Endocrinology and Metabolism 297, no. 1 (July 2009): E134—E141. http://dx.doi.org/10.1152/ajpendo.90859.2008.
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Ghrelin is a peptide hormone with many known functions, including orexigenic, blood glucose-regulatory, and antidepressant actions, among others. Mature ghrelin is unique in that it is the only known naturally occurring peptide to be posttranslationally modified by O-acylation with octanoate. This acylation is required for many of ghrelin's actions, including its effects on promoting increases in food intake and body weight. GOAT (ghrelin O-acyltransferase), one of 16 members of the MBOAT family of membrane-bound O-acyltransferases, has recently been identified as the enzyme responsible for catalyzing the addition of the octanoyl group to ghrelin. Although the initial reports of GOAT have localized its encoding mRNA to tissues known to contain ghrelin, it is as yet unclear whether the octanoylation occurs within ghrelin-producing cells or in neighboring cells. Here, we have performed dual-label histochemical analysis on mouse stomach sections and quantitative PCR on mRNAs from highly enriched pools of mouse gastric ghrelin cells to demonstrate a high degree of GOAT mRNA expression within ghrelin-producing cells of the gastric oxyntic mucosa. We also demonstrate that GOAT is the only member of the MBOAT family whose expression is highly enriched within gastric ghrelin cells and whose whole body distribution mirrors that of ghrelin.
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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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Peiu, Sorin Nicolae, Diana Gabriela Iosep, Mihai Danciu, Veronica Scripcaru, Victor Ianole, and Veronica Mocanu. "Ghrelin Expression in Atherosclerotic Plaques and Perivascular Adipose Tissue: Implications for Vascular Inflammation in Peripheral Artery Disease." Journal of Clinical Medicine 13, no. 13 (June 26, 2024): 3737. http://dx.doi.org/10.3390/jcm13133737.
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Atherosclerosis, a leading cause of peripheral artery disease (PAD), is driven by lipid accumulation and chronic inflammation within arterial walls. Objectives: This study investigates the expression of ghrelin, an anti-inflammatory peptide hormone, in plaque morphology and inflammation in patients with PAD, highlighting its potential role in age-related vascular diseases and metabolic syndrome. Methods: The analysis specifically focused on the immunohistochemical expression of ghrelin in atherosclerotic plaques and perivascular adipose tissue (PVAT) from 28 PAD patients. Detailed immunohistochemical staining was performed to identify ghrelin within these tissues, comparing its presence in various plaque types and assessing its association with markers of inflammation and macrophage polarization. Results: Significant results showed a higher prevalence of calcification in fibro-lipid plaques (63.1%) compared to fibrous plaques, with a notable difference in inflammatory infiltration between the two plaque types (p = 0.027). Complicated plaques exhibited increased ghrelin expression, suggesting a modulatory effect on inflammatory processes, although this did not reach statistical significance. The correlation between ghrelin levels and macrophage presence, especially the pro-inflammatory M1 phenotype, indicates ghrelin’s involvement in the inflammatory dynamics of atherosclerosis. Conclusions: The findings propose that ghrelin may influence plaque stability and vascular inflammation, pointing to its therapeutic potential in managing atherosclerosis. The study underlines the necessity for further research to clarify ghrelin’s impact on vascular health, particularly in the context of metabolic syndrome and age-related vascular alterations.
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Fernández-Fernández, Rafael, Manuel Tena-Sempere, Juan Roa, Juan Manuel Castellano, Víctor M. Navarro, Enrique Aguilar, and Leonor Pinilla. "Direct stimulatory effect of ghrelin on pituitary release of LH through a nitric oxide-dependent mechanism that is modulated by estrogen." Reproduction 133, no. 6 (June 2007): 1223–32. http://dx.doi.org/10.1530/rep-06-0227.
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Ghrelin, a gut peptide with key actions on food intake and GH secretion, has been recently recognized as potential regulator of reproductive function. Thus, in adult female rats, ghrelin has been proven to modulate GnRH/LH secretion, with predominant inhibitory effectsin vivo. We analyze herein potential direct pituitary effects of ghrelin on basal and GnRH-stimulated gonadotropin secretion in prepubertal female rats, and its interplay with ovarian inputs, nitric oxide (NO), and hypothalamic differentiation. In the experimental setting, pituitaries from intact and ovariectomized prepubertal female rats were challenged with ghrelinin vitroand LH secretion was monitored. Our results demonstrate that 1) ghrelin consistently stimulatedin vitropituitary LH secretion under different experimental conditions; 2) the sensitivity to ghrelin, expressed either as the minimal effective dose or the amplitude of the LH response, was modulated by ovarian inputs; 3) the blockade of estrogen action significantly augmented the stimulatory effect of ghrelin; 4) the stimulatory effect of ghrelin on LH secretion required proper NO synthesis; and 5) the ability of ghrelin to elicit LH secretionin vitrowas preserved after alteration (masculinization) of brain sexual differentiation. Overall, our present data reinforce the concept that ghrelin participates in the control of LH secretion, with potential stimulatory actions at the pituitary level that require the presence of NO and are modulated by ovarian signals.
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Rauh, Manfred, Michael Gröschl, and Wolfgang Rascher. "Simultaneous Quantification of Ghrelin and Desacyl-Ghrelin by Liquid Chromatography–Tandem Mass Spectrometry in Plasma, Serum, and Cell Supernatants." Clinical Chemistry 53, no. 5 (May 1, 2007): 902–10. http://dx.doi.org/10.1373/clinchem.2006.078956.
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Abstract Background: A sensitive method specific for ghrelins is needed for investigations of this gastrointestinal peptide. Our aim was to develop and validate a quantitative mass spectrometry (MS) method to measure ghrelin and desacyl-ghrelin simultaneously. Methods: After deproteinization by precipitation, we performed reversed-phase separation with a rapid 2-column online extraction design coupled to a quadrupole mass spectrometer for electrospray ionization MS detection. Chromatography was performed on a C18 monolithic column, with ammonium acetate buffer/methanol as the mobile phase and a chromatographic run time of 6 min/sample. The 4-fold–charged ions were used for multiple reaction monitoring experiments. Results: The method was linear with injections of 0.01–10 ng. Limits of detection and quantification were 0.02 and 0.07 μg/L for ghrelin, respectively, and 0.03 and 0.35 μg/L for desacyl-ghrelin. Intra- and interday imprecision (CVs) were 9%–4% and 12%–6% at concentrations of 0.33–5.93 μg/L for ghrelin, respectively, and 16%–6% and 15%–8% at concentrations of 1.12–10.02 μg/L for desacyl-ghrelin. The mean (SD) recoveries in plasma of added ghrelin and desacyl-ghrelin were 95.8% (12%) and 101% (1.2%), respectively. Using kinetic modeling, we determined the mean (SD) periods of half-change (t1/2) of ghrelin to be 156 (16) min in EDTA plasma and 49 (1) min in Li-heparin plasma. Bland–Altman analysis showed that the median differences between EIA and liquid chromatography–tandem mass spectrometry (MS/MS) for desacyl-ghrelin were −40% for plasma/serum samples and 85% for cell supernatants and for ghrelin were 6% for enriched plasma samples and 44% for cell supernatants. Conclusion: Our HPLC-MS/MS procedure has excellent selectivity and sufficient limit of quantification to allow the monitoring of concentration–time profiles in biological matrices.
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II, William H. Walker, Brittany D. Elliott, Claire O. Kisamore, Randy J. Nelson, and A. Courtney DeVries. "Abstract A072: Ghrelin deletion reduces mammary tumor growth and enhances response to immunotherapy." Molecular Cancer Therapeutics 22, no. 12_Supplement (December 1, 2023): A072. http://dx.doi.org/10.1158/1535-7163.targ-23-a072.
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Abstract Ghrelin is a peptide hormone, primarily produced in the stomach, best known for its role as a regulator of nutrient sensing, appetite, and meal initiation. However, increasing evidence supports a more complex and nuanced role for ghrelin in a diverse array of biological processes, including cancer. Ghrelin’s effects on breast cancer development and progression are not clear, as the literature detailing its effects is conflicting. Several studies in breast cancer survivors have concluded that higher expression of ghrelin is correlated with better recurrence-free and breast cancer-specific survival. However, additional clinical and foundational science studies have suggested greater complexity for ghrelin’s role in breast cancer development as a splice variant of ghrelin, namely In1-ghrelin, is associated with increased tumor proliferation and reduced disease-free survival of breast cancer patients. Thus, the current study sought to determine the effects of ghrelin deletion within mammary tumor cells (67NR) on subsequent tumor growth. Specifically, we hypothesized that ghrelin deletion would significantly alter tumor growth. Adult female mice received bilateral orthotopic injections of the nonmetastatic murine breast carcinoma cell line 67NR or one of two CRISPR generated ghrelin deleted cell lines 1G9 or 2G2 (derived from the 67NR cell line). Ghrelin deletion significantly reduced tumor volume and tumor mass by ~60% and ~55%, respectively. Additionally, ghrelin deletion significantly increased median survival duration by ~30%. When examining changes within the tumor microenvironment we observed a significant increase in macrophage colonization in ghrelin knockouts relative to the parental 67NR tumors. Notably, the percent F4/80 staining within the tumor positively correlated with length of survival. To determine the role of these F4/80 cells on tumor progression, we ablated these macrophages by feeding chow containing the colony stimulating factor receptor 1 inhibitor, PLX5622, for the entirety of the study. Ablating macrophages significantly increased tumor volume and tumor mass and rendered the previous beneficial effects of ghrelin deletion null, suggesting that the positive effects of ghrelin deletion may be due to actions on macrophages. Lastly, because of the increased macrophage infiltration within ghrelin knockout tumors, we sought to determine their repose to an immunotherapy targeting macrophages, namely anti-CD47. Notably, ghrelin deleted tumors displayed a positive response to the immunotherapy and further reduction in tumor growth (~80% reduction in tumor volume compared to 67NR tumors). Whereas, 67NR tumors were unresponsive to the immunotherapy. These data add to the literature detailing the complex effects of ghrelin on tumor growth and suggest that ghrelin may be a druggable target to slow tumor development. Citation Format: William H Walker II, Brittany D Elliott, Claire O Kisamore, Randy J Nelson, A. Courtney DeVries. Ghrelin deletion reduces mammary tumor growth and enhances response to immunotherapy [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A072.
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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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Veldhuis, Johannes D., Daniel M. Keenan, Ali Iranmanesh, Kristi Mielke, John M. Miles, and Cyril Y. Bowers. "Estradiol Potentiates Ghrelin-Stimulated Pulsatile Growth Hormone Secretion in Postmenopausal Women." Journal of Clinical Endocrinology & Metabolism 91, no. 9 (September 1, 2006): 3559–65. http://dx.doi.org/10.1210/jc.2006-0948.
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Abstract Context: Ghrelin and an estrogen-rich milieu individually amplify pulsatile GH secretion by increasing the amount of hormone released per burst. However, how these distinct agonists interact in controlling pulsatile GH output is not known. Objective: The objective of the study was to test the hypothesis that elevated estradiol (E2) concentrations potentiate hypothalamo-pituitary responses to a near-physiological ghrelin stimulus. Design: This was a double-blind, placebo-controlled, prospectively randomized, parallel-cohort study. Setting: The study was conducted at an academic medical center. Subjects: Twenty-one postmenopausal women participated in the study. Interventions: Eleven subjects received placebo (Pl) and 10 others E2 transdermally in escalating doses over 3 wk to mimic late follicular-phase E2 concentrations. Saline or a submaximally stimulatory amount of ghrelin (0.3 μg/kg) was infused iv on separate randomly ordered mornings fasting after 17–21 d of Pl or E2 administration. Outcomes: Outcomes included serum concentrations of E2, ghrelin, GH, IGF-I, IGF binding protein (IGFBP)-1 and IGFBP-3, and the estimated mass and waveform of stimulated GH secretory bursts. Results: Administration of E2 yielded late follicular-phase E2 concentrations. Compared with Pl, E2 did not alter ghrelin concentrations but reduced IGF-I and IGFBP-3 and elevated IGFBP-1 concentrations. Compared with saline, ghrelin infusion amplified pulsatile GH secretion by 7.1-fold (P < 0.01). The effect of E2 alone was 2.0-fold placebo and that of combined ghrelin/E2 10.4-fold (P < 0.01). Ghrelin and E2 accelerated initial GH release individually but nonadditively by more than 2-fold (P < 0.01). Conclusions: Estrogen augments ghrelin’s near-physiological stimulation of pulsatile GH secretion and mimics ghrelin’s acceleration of initial GH release. Thus, we hypothesize that estrogen and a GH secretagogue act via independent as well as convergent mechanisms.
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Delhanty, P. J. D., B. C. J. van der Eerden, M. van der Velde, C. Gauna, H. A. P. Pols, H. Jahr, H. Chiba, A. J. van der Lely, and J. P. T. M. van Leeuwen. "Ghrelin and unacylated ghrelin stimulate human osteoblast growth via mitogen-activated protein kinase (MAPK)/phosphoinositide 3-kinase (PI3K) pathways in the absence of GHS-R1a." Journal of Endocrinology 188, no. 1 (January 2006): 37–47. http://dx.doi.org/10.1677/joe.1.06404.
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Recent studies demonstrate widespread expression of ghrelin among tissues and have uncovered its pleiotropic nature. We have examined gene expression of ghrelin and its two receptor splice variants, growth hormone secretagogue receptors (GHS-R) 1a and 1b, in human bone biopsies and in the human pre-osteoblastic SV-HFO cell line during differentiation. Additionally, we examined proliferative effects of ghrelin and unacylated ghrelin (UAG) in differentiating and non-differentiating cells. We detected GHS-R1b mRNA in human bone and osteoblasts but not ghrelin’s cognate receptor GHS-R1a, using two different real-time PCR assays and both total RNA and mRNA. In osteoblasts GHS-R1b mRNA expression remained low during the first 14 days of culture, but increased 300% in differentiating cells by day 21. Both human bone biopsies and osteoblasts expressed ghrelin mRNA, and osteoblasts were found to secrete ghrelin. Overall, ghrelin gene expression was greater in differentiating than non-differentiating osteoblasts, but was not increased during culture in either group. Ghrelin and UAG induced thymidine uptake dose-dependently, peaking at 1 and 10 nM respectively, at day 6 of culture in both non-differentiating and differentiating osteoblasts. The proliferative response to ghrelin and UAG declined with culture time and state of differentiation. The proliferative effects of ghrelin and UAG were suppressed by inhibitors of extracellular-signal-regulated kinase (ERK) and phosphoinositide-3 kinase, and both peptides rapidly induced ERK phosphorylation. Overall, our data suggest new roles for ghrelin and UAG in modulating human osteoblast proliferation via a novel signal transduction pathway.
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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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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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Katare, Rajesh, Shruti Rawal, Pujika Emani Munasinghe, Hirotsugu Tsuchimochi, Tadakatsu Inagaki, Yutaka Fujii, Parul Dixit, et al. "Ghrelin Promotes Functional Angiogenesis in a Mouse Model of Critical Limb Ischemia Through Activation of Proangiogenic MicroRNAs." Endocrinology 157, no. 2 (December 16, 2015): 432–45. http://dx.doi.org/10.1210/en.2015-1799.
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Abstract Current therapeutic strategies for the treatment of critical limb ischemia (CLI) have only limited success. Recent in vitro evidence in the literature, using cell lines, proposes that the peptide hormone ghrelin may have angiogenic properties. In this study, we aim to investigate if ghrelin could promote postischemic angiogenesis in a mouse model of CLI and, further, identify the mechanistic pathway(s) that underpin ghrelin's proangiogenic properties. CLI was induced in male CD1 mice by femoral artery ligation. Animals were then randomized to receive either vehicle or acylated ghrelin (150 μg/kg sc) for 14 consecutive days. Subsequently, synchrotron radiation microangiography was used to assess hindlimb perfusion. Subsequent tissue samples were collected for molecular and histological analysis. Ghrelin treatment markedly improved limb perfusion by promoting the generation of new capillaries and arterioles (internal diameter less than 50 μm) within the ischemic hindlimb that were both structurally and functionally normal; evident by robust endothelium-dependent vasodilatory responses to acetylcholine. Molecular analysis revealed that ghrelin's angiogenic properties were linked to activation of prosurvival Akt/vascular endothelial growth factor/Bcl-2 signaling cascade, thus reducing the apoptotic cell death and subsequent fibrosis. Further, ghrelin treatment activated proangiogenic (miR-126 and miR-132) and antifibrotic (miR-30a) microRNAs (miRs) while inhibiting antiangiogenic (miR-92a and miR-206) miRs. Importantly, in vitro knockdown of key proangiogenic miRs (miR-126 and miR-132) inhibited the angiogenic potential of ghrelin. These results therefore suggest that clinical use of ghrelin for the early treatment of CLI may be a promising and potent inducer of reparative vascularization through modulation of key molecular factors.
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Matuszyk, Aleksandra, Dagmara Ceranowicz, Zygmunt Warzecha, Piotr Ceranowicz, Krzysztof Fyderek, Krystyna Gałązka, Jakub Cieszkowski, et al. "The Influence of Ghrelin on the Development of Dextran Sodium Sulfate-Induced Colitis in Rats." BioMed Research International 2015 (2015): 1–9. http://dx.doi.org/10.1155/2015/718314.
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Ghrelin has protective and therapeutic effects in the gut. The aim of present studies was to investigate the effect of treatment with ghrelin on the development of colitis evoked by dextran sodium sulfate (DSS). Methods. Studies have been performed on rats. Colitis was induced by adding 5% DSS to the drinking water for 5 days. During this period animals were treated intraperitoneally twice a day with saline or ghrelin given at the dose of 8 nmol/kg/dose. On the sixth day, animals were anesthetized and the severity of colitis was assessed. Results. Treatment with ghrelin during administration of DSS reduced the development of colitis. Morphological features of colonic mucosa exhibited a reduction in the area and deep of mucosal damage. Ghrelin reversed the colitis-induced decrease in blood flow, DNA synthesis, and superoxide dismutase activity in colonic mucosa. These effects were accompanied by a decrease in the colitis-evoked increase in mucosal concentration of interleukin-1β and malondialdehyde. Treatment with ghrelin reversed the DSS-induced reduction in body weight gain. Conclusions. Administration of ghrelin exhibits the preventive effect against the development of DSS-induced colitis. This effect seems to be related to ghrelin’s anti-inflammatory and antioxidative properties.
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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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Page, Amanda J., James A. Slattery, Catherine Milte, Rhianna Laker, Tracey O'Donnell, Camilla Dorian, Stuart M. Brierley, and L. Ashley Blackshaw. "Ghrelin selectively reduces mechanosensitivity of upper gastrointestinal vagal afferents." American Journal of Physiology-Gastrointestinal and Liver Physiology 292, no. 5 (May 2007): G1376—G1384. http://dx.doi.org/10.1152/ajpgi.00536.2006.
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Ghrelin is a peptide released from gastric endocrine cells that has an orexigenic effect via a vagal pathway. Here we determine the effect of ghrelin on mechanosensitivity of upper-intestinal vagal afferent fibers in ferret and mouse. The responses of gastroesophageal vagal afferents to graded mechanical stimulation were determined in vitro before and during application of ghrelin to their peripheral endings. Three types of vagal afferent were tested: tension receptors responding to circumferential tension, mucosal receptors responding only to mucosal stroking, and tension/mucosal (TM) receptors in ferret esophagus that responded to both stimuli. In the mouse, ghrelin did not significantly affect the response of mucosal receptors to mucosal stroking with calibrated von Frey hairs. However, it significantly reduced responses of tension receptors to circumferential tension ( P < 0.005; two-way ANOVA) by up to 40%. This inhibition was reversed by the ghrelin receptor antagonist [d-Lys-3]-growth hormone-releasing peptide (GHRP)-6. In the ferret, ghrelin significantly reduced the response of mucosal and TM receptors to mucosal stroking with calibrated von Frey hairs. Surprisingly, ghrelin did not significantly alter the response to circumferential tension in either tension or TM receptors. RT-PCR analysis indicated that both ghrelin and its receptor are expressed in vagal afferent cell bodies in mouse nodose ganglia. In conclusion, ghrelin selectively inhibits subpopulations of mechanically sensitive gastroesophageal vagal afferents; there is also potential for ghrelin release from vagal afferents. However, the subpopulation of afferents inhibited differs between species. These data have broad implications for ghrelin's role in food intake regulation and reflex control of gastrointestinal function.
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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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Kang, Ki Sung, Satowa Yahashi, and Kouhei Matsuda. "The Effects of Ghrelin on Energy Balance and Psychomotor Activity in a Goldfish Model: An Overview." International Journal of Peptides 2011 (May 24, 2011): 1–9. http://dx.doi.org/10.1155/2011/171034.
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The goldfish (Carassius auratus) has a number of merits as a laboratory animal, and we have extensively identified the mechanisms by which ghrelin regulates food intake in this species. For the first time, we have purified and characterized 11 molecular variants of ghrelin that are present in goldfish intestine and shown that 17-residue ghrelin, the predominant form with n-octanoyl modification, is biologically active and implicated in the regulation of food intake as an endogenous orexigenic factor. Ghrelin and its receptor system are present not only in peripheral tissues such as stomach and intestine, but also in the central nervous system. Recent studies have also revealed that a number of neuropeptides are widely distributed in the brain in key areas of emotional regulation, and their role as modulators of behavioral states is being increasingly recognized. Interestingly, administration of ghrelin induces an orexigenic effect and also modifies locomotor activity, suggesting the involvement of ghrelin in feeding control and regulation of energy balance. Information derived from studies of ghrelin has been increasing, and important results have been obtained from both fish and mammals. Here, we present an overview of the effects of ghrelin on energy balance and psychomotor activity in the goldfish as an animal model. The available data provide an insight into evolutionary background of ghrelin's multiple actions on energy homeostasis in vertebrates.
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Kojima, Masayasu, and Kenji Kangawa. "Ghrelin: Structure and Function." Physiological Reviews 85, no. 2 (April 2005): 495–522. http://dx.doi.org/10.1152/physrev.00012.2004.
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Small synthetic molecules called growth hormone secretagogues (GHSs) stimulate the release of growth hormone (GH) from the pituitary. They act through the GHS-R, a G protein-coupled receptor whose ligand has only been discovered recently. Using a reverse pharmacology paradigm with a stable cell line expressing GHS-R, we purified an endogenous ligand for GHS-R from rat stomach and named it “ghrelin,” after a word root (“ghre”) in Proto-Indo-European languages meaning “grow.” Ghrelin is a peptide hormone in which the third amino acid, usually a serine but in some species a threonine, is modified by a fatty acid; this modification is essential for ghrelin's activity. The discovery of ghrelin indicates that the release of GH from the pituitary might be regulated not only by hypothalamic GH-releasing hormone, but also by ghrelin derived from the stomach. In addition, ghrelin stimulates appetite by acting on the hypothalamic arcuate nucleus, a region known to control food intake. Ghrelin is orexigenic; it is secreted from the stomach and circulates in the bloodstream under fasting conditions, indicating that it transmits a hunger signal from the periphery to the central nervous system. Taking into account all these activities, ghrelin plays important roles for maintaining GH release and energy homeostasis in vertebrates.
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Szentirmai, Éva, Levente Kapás, and James M. Krueger. "Ghrelin microinjection into forebrain sites induces wakefulness and feeding in rats." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 292, no. 1 (January 2007): R575—R585. http://dx.doi.org/10.1152/ajpregu.00448.2006.
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Ghrelin, a gut-brain peptide, is best known for its role in the stimulation of feeding and growth hormone release. In the brain, orexin, neuropeptide Y (NPY), and ghrelin are parts of a food intake regulatory circuit. Orexin and NPY are also implicated in maintaining wakefulness. Previous experiments in our laboratory revealed that intracerebroventricular injections of ghrelin induce wakefulness in rats. To further elucidate the possible role of ghrelin in the regulation of arousal, we studied the effects of microinjections of ghrelin into hypothalamic sites, which are implicated in the regulation of feeding and sleep, such as the lateral hypothalamus (LH), medial preoptic area (MPA), and paraventricular nucleus (PVN) on sleep in rats. Sleep responses, motor activity, and food intake after central administration of 0.04, 0.2, or 1 μg (12, 60, or 300 pmol) ghrelin were recorded. Microinjections of ghrelin into the LH had strong wakefulness-promoting effects lasting for 2 h. Wakefulness was also stimulated by ghrelin injection into the MPA and PVN; the effects were confined to the first hour after the injection. Ghrelin's non-rapid-eye-movement sleep-suppressive effect was accompanied by attenuation in the electroencephalographic (EEG) slow-wave activity and changes in the EEG power spectrum. Food consumption was significantly stimulated after microinjections of ghrelin into each hypothalamic site. Together, these results are consistent with the hypothesis that forebrain ghrelinergic mechanisms play a role in the regulation of vigilance, possibly through activating the components of the food intake- and arousal-promoting network formed by orexin and NPY.
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Shirai, Mikiyasu, Natalie Joe, Hirotsugu Tsuchimochi, Takashi Sonobe, and Daryl O. Schwenke. "Ghrelin Supresses Sympathetic Hyperexcitation in Acute Heart Failure in Male Rats: Assessing Centrally and Peripherally Mediated Pathways." Endocrinology 156, no. 9 (June 29, 2015): 3309–16. http://dx.doi.org/10.1210/en.2015-1333.
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The hormone ghrelin prevents a dangerous increase in cardiac sympathetic nerve activity (SNA) after acute myocardial infarction (MI), although the underlying mechanisms remain unknown. This study aimed to determine whether ghrelin's sympathoinhibitory properties stem either from directly within the central nervous system, or via modulation of specific cardiac vagal inhibitory afferents. Cardiac SNA was recorded in urethane-anesthetized rats for 3 hours after the ligation of the left anterior descending coronary artery (ie, MI). Rats received ghrelin either sc (150 μg/kg) or intracerebroventricularly (5 μg/kg) immediately after the MI. In another two groups, the cervical vagi were denervated prior to the MI, followed by sc injection of either ghrelin or placebo. Acute MI induced a 188% increase in cardiac SNA, which was significantly attenuated in ghrelin-treated rats for both sc or intracerebroventricularly administration (36% and 76% increase, respectively). Consequently, mortality (47%) and the incidence of arrhythmic episodes (12 per 2 h) were improved with both routes of ghrelin administration (<13% and less than five per 2 h, respectively). Bilateral vagotomy significantly attenuated the cardiac SNA response to acute MI (99% increase). Ghrelin further attenuated the sympathetic response to MI in vagotomized rats so that the SNA response was comparable between vagotomized and vagal-intact MI rats treated with ghrelin. These results suggest that ghrelin may act primarily via a central pathway within the brain to suppress SNA after MI, although peripheral vagal afferent pathways may also contribute in part. The exact region(s) within the central nervous system whereby ghrelin inhibits SNA remains to be fully elucidated.
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Huda, M. S. B., T. M. Dovey, S. P. Wong, P. J. English, J. C. G. Halford, P. McCulloch, J. Cleator, et al. "Ghrelin does not orchestrate the metabolic changes seen in fasting but has significant effects on lipid mobilisation and substrate utilisation." European Journal of Endocrinology 165, no. 1 (July 2011): 45–55. http://dx.doi.org/10.1530/eje-10-1122.
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ObjectiveShort-term fasting is associated with increased GH pulsatility and mobilisation of fats, but underlying mechanisms are unclear. We studied ghrelin's role during fasting and the effects of exogenous ghrelin on lipid mobilisation.DesignRandomised placebo-controlled study.MethodsIn this study, ten controls (body mass index (BMI) 23.3±3.2), ten morbidly obese subjects (BMI 50.1±10.6) and six post-gastrectomy subjects (BMI 25.2±1.0) were fasted for 36 h undergoing regular blood sampling. On a separate occasion, subjects were infused with either i.v. ghrelin (5 pmol/kg per min) or saline over 270 min.ResultsObese and post-gastrectomy subjects had lower ghrelin compared with controls (ANOVA, P=0.02) during the fast. Controls and gastrectomy subjects showed a similar increase in GH pulsatility, circulating non-esterified fatty acids (NEFA) and 3β-hydroxybutyrate (3 HB). Obese subjects had an impaired GH response (P<0.001), reduced excursions of 3 HB (P=0.01) but no change in NEFA excursions (P=0.09) compared with controls. Ghrelin infusion increased GH, NEFA and ketone bodies (ANOVA, P<0.0001) in all the three groups, but GH response was impaired in the obese subjects (P=0.001). Ghrelin also induced a significant (ANOVA, P=0.004) biphasic NEFA response to meals in all the subjects.ConclusionsDespite low circulating ghrelin, gastrectomy subjects maintain a normal metabolic response to fasting, implying that ghrelin plays a minimal role. In contrast, infused ghrelin has significant effects on lipid mobilisation and induces a marked biphasic NEFA response to meals. Hence, ghrelin may play a significant role in meal-related substrate utilisation and metabolic flexibility.
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Ma, Xiaojun, Yuezhen Lin, Ligen Lin, Guijun Qin, Fred A. Pereira, Morey W. Haymond, Nancy F. Butte, and Yuxiang Sun. "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." American Journal of Physiology-Endocrinology and Metabolism 303, no. 3 (August 1, 2012): E422—E431. http://dx.doi.org/10.1152/ajpendo.00576.2011.
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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 hormone secretagogue receptor (GHS-R), and GHS-R antagonists are thought to be an effective strategy for treating diabetes. However, since some of ghrelin's effects are independent of GHS-R, we have utilized genetic approaches to determine whether ghrelin's effect on insulin secretion is mediated through GHS-R and whether GHS-R antagonism indeed inhibits insulin secretion. We investigated the effects of GHS-R on glucose homeostasis in Ghsr-ablated ob/ ob mice ( Ghsr−/−: ob/ ob). Ghsr ablation did not rescue the hyperphagia, obesity, or insulin resistance of ob/ ob mice. Surprisingly, Ghsr ablation worsened the hyperglycemia, decreased insulin, and impaired glucose tolerance. Consistently, Ghsr ablation in ob/ ob mice upregulated negative β-cell regulators (such as UCP-2, SREBP-1c, ChREBP, and MIF-1) and downregulated positive β-cell regulators (such as HIF-1α, FGF-21, and PDX-1) in whole pancreas; this suggests that Ghsr ablation impairs pancreatic β-cell function in leptin deficiency. Of note, Ghsr ablation in ob/ ob mice did not affect the islet size; the average islet size of Ghsr−/−: ob/ ob mice is similar to that of ob/ ob mice. In summary, because Ghsr ablation in leptin deficiency impairs insulin secretion and worsens hyperglycemia, this suggests that GHS-R antagonists may actually aggravate diabetes under certain conditions. The paradoxical effects of ghrelin ablation and Ghsr ablation in ob/ob mice highlight the complexity of the ghrelin-signaling pathway.
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Hosoda, Hiroshi. "Effect of Ghrelin on the Cardiovascular System." Biology 11, no. 8 (August 8, 2022): 1190. http://dx.doi.org/10.3390/biology11081190.
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Ghrelin, an n-octanoyl-modified 28-amino-acid-peptide, was first discovered in the human and rat stomach as an endogenous ligand for the growth hormone secretagogue receptor (GHS-R). Ghrelin-GHS-R1a signaling regulates feeding behavior and energy balance, promotes vascular activity and angiogenesis, improves arrhythmia and heart failure, and also protects against cardiovascular disease by suppressing cardiac remodeling after myocardial infarction. Ghrelin’s cardiovascular protective effects are mediated by the suppression of sympathetic activity; activation of parasympathetic activity; alleviation of vascular endothelial dysfunction; and regulation of inflammation, apoptosis, and autophagy. The physiological functions of ghrelin should be clarified to determine its pharmacological potential as a cardiovascular medication.
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Holst, Birgitte, Erik Brandt, Anders Bach, Anders Heding, and Thue W. Schwartz. "Nonpeptide and Peptide Growth Hormone Secretagogues Act Both as Ghrelin Receptor Agonist and as Positive or Negative Allosteric Modulators of Ghrelin Signaling." Molecular Endocrinology 19, no. 9 (September 1, 2005): 2400–2411. http://dx.doi.org/10.1210/me.2005-0059.
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Abstract Two nonpeptide (L692,429 and MK-677) and two peptide [GH-releasing peptide (GHRP)-6 and ghrelin] agonists were compared in binding and in signal transduction assays: calcium mobilization, inositol phosphate turnover, cAMP-responsive element (CRE), and serum-responsive element (SRE) controlled transcription, as well as arrestin mobilization. MK-677 acted as a simple agonist having an affinity of 6.5 nm and activated all signal transduction systems with similar high potency (0.2–1.4 nm). L-692,429 also displayed a very similar potency in all signaling assays (25–60 nm) but competed with a 1000-fold lower apparent affinity for ghrelin binding and surprisingly acted as a positive allosteric receptor modulator by increasing ghrelin’s potency 4- to 10-fold. In contrast, the potency of GHRP-6 varied 600-fold (0.1–61 nm) depending on the signal transduction assay, and it acted as a negative allosteric modulator of ghrelin signaling. Unexpectedly, the maximal signaling efficacy for ghrelin was increased above what was observed with the hormone itself during coadministration with the nonendogenous agonists. It is concluded that agonists for the ghrelin receptor vary both in respect of their intrinsic agonist properties and in their ability to modulate ghrelin signaling. A receptor model is presented wherein ghrelin normally only activates one receptor subunit in a dimer and where the smaller nonendogenous agonists bind in the other subunit to act both as coagonists and as either neutral (MK-677), positive (L-692,429), or negative (GHRP-6) modulators of ghrelin function. It is suggested that an optimal drug candidate could be an agonist that also is a positive modulator of ghrelin signaling.
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Overduin, Joost, Dianne P. Figlewicz, Jennifer Bennett-Jay, Sepideh Kittleson, and David E. Cummings. "Ghrelin increases the motivation to eat, but does not alter food palatability." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 303, no. 3 (August 1, 2012): R259—R269. http://dx.doi.org/10.1152/ajpregu.00488.2011.
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Homeostatic eating cannot explain overconsumption of food and pathological weight gain. A more likely factor promoting excessive eating is food reward and its representation in the central nervous system (CNS). The anorectic hormones leptin and insulin reduce food reward and inhibit related CNS reward pathways. Conversely, the orexigenic gastrointestinal hormone ghrelin activates both homeostatic and reward-related neurocircuits. The current studies were conducted to identify in rats the effects of intracerebroventricular ghrelin infusions on two distinct aspects of food reward: hedonic valuation (i.e., “liking”) and the motivation to self-administer (i.e., “wanting”) food. To assess hedonic valuation of liquid food, lick motor patterns were recorded using lickometry. Although ghrelin administration increased energy intake, it did not alter the avidity of licking (initial lick rates or lick-cluster size). Several positive-control conditions ruled out lick-rate ceiling effects. Similarly, when the liquid diet was hedonically devalued with quinine supplementation, ghrelin failed to reverse the quinine-associated reduction of energy intake and avidity of licking. The effects of ghrelin on rats' motivation to eat were assessed using lever pressing to self-administer food in a progressive-ratio paradigm. Ghrelin markedly increased motivation to eat, to levels comparable to or greater than those seen following 24 h of food deprivation. Pretreatment with the dopamine D1 receptor antagonist SCH-23390 eliminated ghrelin-induced increases in lever pressing, without compromising generalized licking motor control, indicating a role for D1 signaling in ghrelin's motivational feeding effects. These results indicate that ghrelin increases the motivation to eat via D1 receptor-dependent mechanisms, without affecting perceived food palatability.
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Jiao, Zheng-Tong, and Qi Luo. "Molecular Mechanisms and Health Benefits of Ghrelin: A Narrative Review." Nutrients 14, no. 19 (October 8, 2022): 4191. http://dx.doi.org/10.3390/nu14194191.
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Ghrelin, an endogenous brain–gut peptide, is secreted in large quantities, mainly from the stomach, in humans and rodents. It can perform the biological function of activating the growth hormone secretagogue receptor (GHSR). Since its discovery in 1999, ample research has focused on promoting its effects on the human appetite and pleasure–reward eating. Extensive, in-depth studies have shown that ghrelin is widely secreted and distributed in tissues. Its role in neurohumoral regulation, such as metabolic homeostasis, inflammation, cardiovascular regulation, anxiety and depression, and advanced cancer cachexia, has attracted increasing attention. However, the effects and regulatory mechanisms of ghrelin on obesity, gastrointestinal (GI) inflammation, cardiovascular disease, stress regulation, cachexia treatment, and the prognosis of advanced cancer have not been fully summarized. This review summarizes ghrelin’s numerous effects in participating in a variety of biochemical pathways and the clinical significance of ghrelin in the regulation of the homeostasis of organisms. In addition, potential mechanisms are also introduced.
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Naznin, Farhana, Koji Toshinai, T. M. Zaved Waise, Tadashi Okada, Hideyuki Sakoda, and Masamitsu Nakazato. "Restoration of metabolic inflammation-related ghrelin resistance by weight loss." Journal of Molecular Endocrinology 60, no. 2 (February 2018): 109–18. http://dx.doi.org/10.1530/jme-17-0192.
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High-fat diet (HFD)-induced metabolic inflammation in the central and peripheral organs contributes to the pathogenesis of obesity. Long-term HFD blunts signaling by ghrelin, a gastric-derived orexigenic peptide, in the vagal afferent nerve via a mechanism involving in situ activation of inflammation. This study was undertaken to investigate whether ghrelin resistance is associated with progressive development of metabolic inflammation. In mice, ghrelin’s orexigenic activity was abolished 2–4 weeks after the commencement of HFD (60% of energy from fat), consistent with the timing of accumulation and activation of macrophages and microglia in the nodose ganglion and hypothalamus. Calorie-restricted weight loss after 12-week HFD feeding restored ghrelin responsiveness and alleviated the upregulation of macrophage/microglia activation markers and inflammatory cytokines. HSP72, a chaperone protein, was upregulated in the hypothalamus of HFD-fed mice, potentially contributing to prevention of irreversible neuron damage. These results demonstrate that ghrelin resistance is reversible following reversal of the HFD-induced inflammation and obesity phenotypes.
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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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Howell, Erin, Hannah Baumgartner, Lia Zallar, Joaquín Selva, Liv Engel, and Paul Currie. "Glucagon-Like Peptide-1 (GLP-1) and 5-Hydroxytryptamine 2c (5-HT2c) Receptor Agonists in the Ventral Tegmental Area (VTA) Inhibit Ghrelin-Stimulated Appetitive Reward." International Journal of Molecular Sciences 20, no. 4 (February 19, 2019): 889. http://dx.doi.org/10.3390/ijms20040889.
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Current literature indicates that the orexigenic peptide ghrelin increases appetitive motivation via signaling in the mesolimbic reward system. Another gastric peptide, glucagon-like peptide-1 (GLP-1), and the neurotransmitter 5-hydroxytryptamine (5-HT), are both known to suppress operant responding for food by acting on key mesolimbic nuclei, including the ventral tegmental area (VTA). In order to investigate the interaction effects of ghrelin, GLP-1, and 5-HT within the VTA, we measured operant responding for sucrose pellets after the administration of ghrelin, the GLP-1 receptor agonist exendin-4 (Ex-4), and the 5-HT2c receptor agonist Ro60-0175 in male Sprague-Dawley rats. Following training on a progressive ratio 3 (PR3) schedule, animals were first injected with ghrelin into the VTA at doses of 3 to 300 pmol. In subsequent testing, separate rats were administered intraperitoneal (IP) Ex-4 (0.1–1.0 µg/kg) or VTA Ex-4 (0.01–0.1 µg) paired with 300 pmol ghrelin. In a final group of rats, the 5-HT2c agonist Ro60-0175 was injected IP (0.25–1.0 mg/kg) or into the VTA (1.5–3.0 µg), and under both conditions paired with 300 pmol ghrelin delivered into the VTA. Our results indicated that ghrelin administration increased operant responding for food reward and that this effect was attenuated by IP and VTA Ex-4 pretreatment as well as pre-administration of IP or VTA Ro60-0175. These data provide compelling evidence that mesolimbic GLP-1 and serotonergic circuitry interact with the ghrelinergic system to suppress ghrelin’s effects on the mediation of food reinforcement.
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Benčo, A., A. V. Sirotkin, D. Vašíček, S. Pavlová, J. Zemanová, J. Kotwica, K. Darlak, and F. Valenzuela. "Involvement of the transcription factor STAT1 in the regulation of porcine ovarian granulosa cell functions treated and not treated with ghrelin." REPRODUCTION 138, no. 3 (September 2009): 553–60. http://dx.doi.org/10.1530/rep-08-0313.
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The aim of our in vitro experiments was to study the role of the transcription factor STAT1 and the hormone ghrelin in controlling porcine ovarian function. The effects of treatment with ghrelin (0, 1, 10, 100 ng/ml), transfection-induced overexpression of transcription factor STAT1, and their combination on apoptosis (expression of apoptosis-related peptides caspase-3, BAX and anti-apoptotic peptide BCL2), proliferation (expression of proliferating cell nuclear antigene PCNA, proliferation-associated protein kinase MAPK/ERK1,2) and release of the hormones progesterone (P4), prostaglandin F (PGF) and oxytocin (OXT) in cultured porcine ovarian granulosa cells was evaluated using RIA, immunocytochemistry and SDS-PAGE–western immunoblotting. It was found that ghrelin, when given alone, increased the expression of proliferation-associated PCNA and MAPK/ERK1,2, decreased the accumulation of apoptosis-related substances caspase-3, BAX, BCL2, decreased P4, and increased PGF and OXT release. Ghrelin tended to promote accumulation of STAT1 in both control and transfected cells, although in transfected cells ghrelin at 1 ng/ml decreased STAT1 accumulation. Transfection of porcine granulosa cells by a gene construct encoding STAT1 promoted the expression of STAT1 and apoptosis-related-BAX but the expression of BCL2 did not, and decreased the accumulation of proliferation-associated MAPK/ERK1,2 but not that of PCNA. It also promoted PGF and OXT but not P4 release. Overexpression of STAT1 reversed the effect of ghrelin on STAT1, PCNA, PGF, OXT (from stimulatory to inhibitory), BCL2, P4 (from inhibitory to stimulatory), prevented ghrelin effect on caspase-3 and BAX, but did not affect ghrelin's effect on MAPK/ERK1,2 expression. These results suggest that ghrelin directly affects porcine ovarian cells function – stimulates proliferation, inhibits apoptosis and affects secretory activity. Furthermore, they demonstrated the involvement of the transcription factor STAT1 in controlling these functions, the promotion of some markers of apoptosis (BAX), inhibition of some markers of proliferation (MAPK/ERK1,2) and stimulation of PGF release. Finally, the obtained data failed to demonstrate that STAT1 is involved in mediating the action of ghrelin on ovarian cell functions.
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Gluck, Elizabeth F., Natalie Stephens, and Steven J. Swoap. "Peripheral ghrelin deepens torpor bouts in mice through the arcuate nucleus neuropeptide Y signaling pathway." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 291, no. 5 (November 2006): R1303—R1309. http://dx.doi.org/10.1152/ajpregu.00232.2006.
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Many small mammals have the ability to enter torpor, characterized by a controlled drop in body temperature (Tb). We hypothesized that ghrelin would modulate torpor bouts, because torpor is induced by fasting in mice coincident with elevated circulating ghrelin. Female National Institutes of Health (NIH) Swiss mice were implanted with a Tb telemeter and housed at an ambient temperature (Ta) of 18°C. On fasting, all mice entered a bout of torpor (minimum Tb: 23.8 ± 2.0°C). Peripheral ghrelin administration (100 μg) during fasting significantly deepened the bout of torpor (Tb minimum: 19.4 ± 0.5°C). When the arcuate nucleus (ARC) of the hypothalamus, a ghrelin receptor-rich region of the brain, was chemically ablated with monosodium glutamate (MSG), fasted mice failed to enter torpor (minimum Tb = 31.6 ± 0.6°C). Furthermore, ghrelin administration had no effect on the Tb minimum of ARC-ablated mice (31.8 ± 0.8°C). Two major pathways that regulate food intake reside in the ARC, the anorexigenic α-melanocyte stimulating hormone (α-MSH) pathway and the orexigenic neuropeptide Y (NPY) signaling pathway. Both Ay mice, which have the α-MSH pathway blocked, and Npy −/− mice exhibited shallow, aborted torpor bouts in response to fasting (Tb minimum: 29.1 ± 0.6°C and 29.9 ± 1.2°C, respectively). Ghrelin deepened torpor in Ay mice (Tb minimum: 22.8 ± 1.3°C), but had no effect in Npy −/− mice (Tb minimum: 29.5 ± 0.8°C). Collectively, these data suggest that ghrelin's actions on torpor are mediated via NPY neurons within the ARC.