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Andreas Stengel - One of the best experts on this subject based on the ideXlab platform.
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Pharmacological Modulation of Ghrelin to Induce Weight Loss: Successes and Challenges
Current Diabetes Reports, 2019Co-Authors: Martha A. Schalla, Andreas StengelAbstract:Purpose of Review Obesity is affecting over 600 million adults worldwide and has numerous negative effects on health. Since Ghrelin positively regulates food intake and body weight, targeting its signaling to induce weight loss under conditions of obesity seems promising. Thus, the present work reviews and discusses different possibilities to alter Ghrelin signaling. Recent Findings Ghrelin signaling can be altered by RNA Spiegelmers, GHSR/Fc, Ghrelin- O -acyltransferase inhibitors as well as antagonists, and inverse agonists of the Ghrelin receptor. PF-05190457 is the first inverse agonist of the Ghrelin receptor tested in humans shown to inhibit growth hormone secretion, gastric emptying, and reduce postprandial glucose levels. Effects on body weight were not examined. Summary Although various highly promising agents targeting Ghrelin signaling exist, so far, they were mostly only tested in vitro or in animal models. Further research in humans is thus needed to further assess the effects of Ghrelin antagonism on body weight especially under conditions of obesity.
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Pharmacological Modulation of Ghrelin to Induce Weight Loss: Successes and Challenges.
Current diabetes reports, 2019Co-Authors: Martha A. Schalla, Andreas StengelAbstract:Obesity is affecting over 600 million adults worldwide and has numerous negative effects on health. Since Ghrelin positively regulates food intake and body weight, targeting its signaling to induce weight loss under conditions of obesity seems promising. Thus, the present work reviews and discusses different possibilities to alter Ghrelin signaling. Ghrelin signaling can be altered by RNA Spiegelmers, GHSR/Fc, Ghrelin-O-Acyltransferase inhibitors as well as antagonists, and inverse agonists of the Ghrelin receptor. PF-05190457 is the first inverse agonist of the Ghrelin receptor tested in humans shown to inhibit growth hormone secretion, gastric emptying, and reduce postprandial glucose levels. Effects on body weight were not examined. Although various highly promising agents targeting Ghrelin signaling exist, so far, they were mostly only tested in vitro or in animal models. Further research in humans is thus needed to further assess the effects of Ghrelin antagonism on body weight especially under conditions of obesity.
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Sa2024 Inhibition of Ghrelin-O-Acyltransferase (GOAT) Reduces Food Intake by Increasing Satiety in Rats
Gastroenterology, 2015Co-Authors: Pauline Teuffel, Miriam Goebel-stengel, Tobias Hofmann, Peter Kobelt, Burghard F. Klapp, Lixin Wang, Philip Prinz, Matthias Rose, Joseph R. Reeve, Andreas StengelAbstract:The percentage of the remaining heart rate after electrical stimulation of the cervical vagus nerve with 5 (A) and 20 (B) Hz, 0.5-1-2 ms pulse width and 2.5 mA using the pacing wires, hook, single delta and double delta electrode in a random order. The baseline heart rate was set as 100%. The percentage of remaining heart rate is significantly different from the single delta electrode with P < 0.001 (***) and the double delta electrode differs with the hook electrode with P
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The Ghrelin activating enzyme Ghrelin-O-Acyltransferase (GOAT) is present in human plasma and expressed dependent on body mass index.
Peptides, 2013Co-Authors: Miriam Goebel-stengel, Tobias Hofmann, Ulf Elbelt, Pauline Teuffel, Anne Ahnis, Peter Kobelt, Nils Lambrecht, Burghard F. Klapp, Andreas StengelAbstract:Abstract Ghrelin is the only known peripherally produced and centrally acting peptide hormone stimulating food intake. The acylation of Ghrelin is essential for binding to its receptor. Recently, the Ghrelin activating enzyme Ghrelin-O-Acyltransferase (GOAT) was identified in mice, rats and humans. In addition to gastric mucosal expression, GOAT was also detected in the circulation of rodents and its expression was dependent on metabolic status. We investigated whether GOAT is also present in human plasma and whether expression levels are affected under different conditions of body weight. Normal weight, anorexic and obese subjects with body mass index (BMI) 30–40, 40–50 and >50 were recruited (n = 9/group). In overnight fasted subjects GOAT protein expression was assessed by Western blot and Ghrelin measured by ELISA. GOAT protein was detectable in human plasma. Anorexic patients showed reduced GOAT protein levels (−42%, p 50 had increased concentrations (+34%) compared to normal weight controls. Ghrelin levels were higher in anorexic patients compared to all other groups (+62–78%, p
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Ghrelin - a pleiotropic hormone secreted from endocrine x/a-like cells of the stomach.
Frontiers in neuroscience, 2012Co-Authors: Andreas Stengel, Yvette TachéAbstract:The gastric X/A-like endocrine cell receives growing attention due it its peptide products with Ghrelin being the best characterized. This peptide hormone was identified a decade ago as a stimulator of food intake and to date remains the only known peripherally produced and centrally acting orexigenic hormone. In addition, subsequent studies identified numerous other functions of this peptide including the modulation of gastrointestinal motility, the maintenance of energy homeostasis and an impact on reproduction. Moreover, Ghrelin is also involved in the response to stress and assumed to play a role in coping functions and exert a modulatory action on immune pathways. Our knowledge on the regulation of Ghrelin has markedly advanced during the past years by the identification of the Ghrelin acylating enzyme, Ghrelin-O-Acyltransferase, and by the description of changes in expression, activation and release under different metabolic as well as physically and psychically challenging conditions. However, our insight on regulatory processes of Ghrelin at the cellular and subcellular levels is still very limited and warrants further investigation.
James L. Hougland - One of the best experts on this subject based on the ideXlab platform.
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An overview of Ghrelin O-Acyltransferase inhibitors: a literature and patent review for 2010-2019.
Expert opinion on therapeutic patents, 2020Co-Authors: Jacob E. Moose, John D. Chisholm, Katelyn A. Leets, Nilamber A. Mate, James L. HouglandAbstract:The peptide hormone Ghrelin regulates physiological processes associated with energy homeostasis such as appetite, insulin signaling, glucose metabolism, and adiposity. Ghrelin has also been implic...
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Biochemical assays for Ghrelin acylation and inhibition of Ghrelin O-Acyltransferase
Methods in molecular biology (Clifton N.J.), 2019Co-Authors: Michelle A Sieburg, Elizabeth R. Cleverdon, James L. HouglandAbstract:Ghrelin O-Acyltransferase (GOAT) is an enzyme responsible for octanoylating and activating Ghrelin, a peptide hormone that plays a key role in energy regulation and hunger signaling. Due to its nature as an integral membrane protein, GOAT has yet to be purified in active form which has complicated biochemical and structural studies of GOAT-catalyzed Ghrelin acylation. In this chapter, we describe protocols for efficient expression and enrichment of GOAT in insect cell-derived microsomal fraction, HPLC-based assays for GOAT acylation activity employing fluorescently labeled peptides, and assessment of inhibitor potency against GOAT.
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Ghrelin octanoylation by Ghrelin O-Acyltransferase: Unique protein biochemistry underlying metabolic signaling.
Biochemical Society transactions, 2019Co-Authors: James L. HouglandAbstract: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 Ghrelin9s activation, and summarize the current landscape of molecules targeting Ghrelin octanoylation through GOAT inhibition.
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Functional group and stereochemical requirements for substrate binding by Ghrelin O-Acyltransferase revealed by unnatural amino acid incorporation.
Bioorganic chemistry, 2018Co-Authors: Elizabeth R. Cleverdon, Tasha R Davis, James L. HouglandAbstract:Abstract Ghrelin is a small peptide hormone that undergoes a unique posttranslational modification, serine octanoylation, to play its physiological roles in processes including hunger signaling and glucose metabolism. Ghrelin O -acyltransferase (GOAT) catalyzes this posttranslational modification, which is essential for Ghrelin to bind and activate its cognate GHS-R1a receptor. Inhibition of GOAT offers a potential avenue for modulating Ghrelin signaling for therapeutic effect. Defining the molecular characteristics of Ghrelin that lead to binding and recognition by GOAT will facilitate the development and optimization of GOAT inhibitors. We show that small peptide mimics of Ghrelin substituted with 2,3-diaminopropanoic acid in place of the serine at the site of octanoylation act as submicromolar inhibitors of GOAT. Using these chemically modified analogs of desacyl Ghrelin, we define key functional groups within the N-terminal sequence of Ghrelin essential for binding to GOAT and determine GOAT’s tolerance to backbone methylations and altered amino acid stereochemistry within Ghrelin. Our study provides a structure-activity analysis of Ghrelin binding to GOAT that expands upon activity-based investigations of Ghrelin recognition and establishes a new class of potent substrate-mimetic GOAT inhibitors for further investigation and therapeutic interventions targeting Ghrelin signaling.
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Synthetic Triterpenoid Inhibition of Human Ghrelin O-Acyltransferase: The Involvement of a Functionally Required Cysteine Provides Mechanistic Insight into Ghrelin Acylation
Biochemistry, 2017Co-Authors: Kayleigh R. Mcgovern-gooch, Michelle A Sieburg, Nivedita S. Mahajani, Ariana Garagozzo, Anthony J. Schramm, Lauren G. Hannah, John D. Chisholm, James L. HouglandAbstract:The peptide hormone Ghrelin plays a key role in regulating hunger and energy balance within the body. Ghrelin signaling presents a promising and unexploited target for development of small molecule therapeutics for treatment of obesity, diabetes, and other health conditions. Inhibition of Ghrelin O-Acyltransferase (GOAT), which catalyzes an essential octanoylation step in Ghrelin maturation, offers a potential avenue for controlling Ghrelin signaling. Through screening a small molecule library, we have identified a class of synthetic triterpenoids that efficiently inhibit Ghrelin acylation by the human isoform of GOAT (hGOAT). These compounds function as covalent reversible inhibitors of hGOAT, providing the first evidence of the involvement of a nucleophilic cysteine residue in substrate acylation by a MBOAT family acyltransferase. Surprisingly, the mouse form of GOAT does not exhibit susceptibility to cysteine-modifying electrophiles, revealing an important distinction in the activity and behavior betwe...
Matthias H. Tschöp - One of the best experts on this subject based on the ideXlab platform.
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Effect of Deletion of Ghrelin‐O‐Acyltransferase on the Pulsatile Release of Growth Hormone in Mice
Journal of neuroendocrinology, 2015Co-Authors: T. Y. Xie, Matthias H. Tschöp, Lisa K. Chopin, Shyuan T. Ngo, Johannes D. Veldhuis, Penelope L. Jeffery, Michael J. Waters, Virginie Tolle, Jacques Epelbaum, Chen ChenAbstract:Ghrelin, a gut hormone originating from the post-translational cleavage of preproGhrelin, is the endogenous ligand of growth hormone secretagogue receptor 1a (GHS-R1a). Within the growth hormone (GH) axis, the biological activity of Ghrelin requires octanoylation by Ghrelin-O-Acyltransferase (GOAT), conferring selective binding to the GHS-R1a receptor via acylated Ghrelin. Complete loss of preproGhrelin-derived signalling (through deletion of the Ghrl gene) contributes to a decline in peak GH release; however, the selective contribution of endogenous acyl-Ghrelin to pulsatile GH release remains to be established. We assessed the pulsatile release of GH in ad lib. fed male germline goat(-/-) mice, extending measures to include mRNA for key hypothalamic regulators of GH release, and peripheral factors that are modulated relative to GH release. The amount of GH released was reduced in young goat(-/-) mice compared to age-matched wild-type mice, whereas pulse frequency and irregularity increased. Altered GH release did not coincide with alterations in hypothalamic Ghrh, Srif, Npy or Ghsr mRNA expression, or pituitary GH content, suggesting that loss of Goat does not compromise canonical mechanisms that contribute to pituitary GH production and release. Although loss of Goat resulted in an irregular pattern of GH release (characterised by an increase in the number of GH pulses observed during extended secretory events), this did not contribute to a change in the expression of sexually dimorphic GH-dependent liver genes. Of interest, circulating levels of insulin-like growth factor (IGF)-1 were elevated in goat(-/-) mice. This rise in circulating levels of IGF-1 was correlated with an increase in GH pulse frequency, suggesting that sustained or increased IGF-1 release in goat(-/-) mice may occur in response to altered GH release patterning. Our observations demonstrate that germline loss of Goat alters GH release and patterning. Although the biological relevance of altered GH secretory patterning remains unclear, we propose that this may contribute to sustained IGF-1 release and growth in goat(-/-) mice.
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Effect of deletion of Ghrelin-O-Acyltransferase on the pulsatile release of growth hormone in mice
2015Co-Authors: T. Y. Xie, Matthias H. Tschöp, Lisa K. Chopin, Shyuan T. Ngo, Johannes D. Veldhuis, Penelope L. Jeffery, Michael J. Waters, Virginie Tolle, Jacques Epelbaum, Chen ChenAbstract:Ghrelin, a gut hormone originating from the post-translational cleavage of preproGhrelin, is the endogenous ligand of growth hormone secretagogue receptor 1a (GHS-R1a). Within the growth hormone (GH) axis, the biological activity of Ghrelin requires octanoylation by Ghrelin-O-Acyltransferase (GOAT), conferring selective binding to the GHS-R1a receptor via acylated Ghrelin. Complete loss of preproGhrelin-derived signalling (through deletion of the Ghrl gene) contributes to a decline in peak GH release; however, the selective contribution of endogenous acyl-Ghrelin to pulsatile GH release remains to be established. We assessed the pulsatile release of GH in ad lib. fed male germline goat−/− mice, extending measures to include mRNA for key hypothalamic regulators of GH release, and peripheral factors that are modulated relative to GH release. The amount of GH released was reduced in young goat−/− mice compared to age-matched wild-type mice, whereas pulse frequency and irregularity increased. Altered GH release did not coincide with alterations in hypothalamic Ghrh, Srif, Npy or Ghsr mRNA expression, or pituitary GH content, suggesting that loss of Goat does not compromise canonical mechanisms that contribute to pituitary GH production and release. Although loss of Goat resulted in an irregular pattern of GH release (characterised by an increase in the number of GH pulses observed during extended secretory events), this did not contribute to a change in the expression of sexually dimorphic GH-dependent liver genes. Of interest, circulating levels of insulin-like growth factor (IGF)-1 were elevated in goat−/− mice. This rise in circulating levels of IGF-1 was correlated with an increase in GH pulse frequency, suggesting that sustained or increased IGF-1 release in goat−/− mice may occur in response to altered GH release patterning. Our observations demonstrate that germline loss of Goat alters GH release and patterning. Although the biological relevance of altered GH secretory patterning remains unclear, we propose that this may contribute to sustained IGF-1 release and growth in goat−/− mice.
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Ablation of Ghrelin O-Acyltransferase does not improve glucose intolerance or body adiposity in mice on a leptin-deficient ob/ob background.
PloS one, 2013Co-Authors: Henriette Kirchner, Kristy M. Heppner, Matthias H. Tschöp, Jenna Holland, Dhiraj G. Kabra, Paul T. PflugerAbstract:Type 2 Diabetes is a global health burden and based on current estimates will become an even larger problem in the future. Developing new strategies to prevent and treat diabetes is a scientific challenge of high priority. The stomach hormone Ghrelin has been associated with playing a role in the regulation of glucose homeostasis. However, its precise mechanism and impact on whole glucose metabolism remains to be elucidated. This study aims to clarify the role of the two Ghrelin isoforms acyl- and desacyl Ghrelin in regulating glucose homeostasis. Therefore Ghrelin activating enzyme Ghrelin-O-Acyltransferase (GOAT) was ablated in leptin-deficient ob/ob mice to study whether specific acyl Ghrelin deficiency or desacyl Ghrelin abundance modifies glucose tolerance on a massively obese background. As targeted deletion of acyl Ghrelin does not improve glucose homeostasis in our GOAT-ob/ob mouse model we conclude that neither acyl Ghrelin nor the increased ratio of desacyl/acyl Ghrelin is crucial for controlling glucose homeostasis in the here presented model of massive obesity induced by leptin deficiency.
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The Role of Ghrelin in the Control of Energy Balance
Handbook of experimental pharmacology, 2011Co-Authors: Henriette Kirchner, Kristy M. Heppner, Matthias H. TschöpAbstract:Ghrelin is the only potent orexigenic peptide in circulation. It stimulates food intake and leads to positive energy balance, adipogenesis, and body weight gain. However, the physiological significance of Ghrelin in the regulation of energy homeostasis is controversial, since loss of Ghrelin function in rodents does not necessarily lead to anorexia and weight loss. In this chapter, we discuss the metabolic function of Ghrelin and are highlighting recent findings including the discovery and function of Ghrelin-acylating enzyme Ghrelin O-Acyltransferase (GOAT). Based on available published data, we conclude that Ghrelin is a principally important endogenous regulator of energy balance, which however may affect both food intake and systemic metabolism via independent mechanisms. Importantly, Ghrelin, when acylated by GOAT, might represent a key molecular link between the sensing of consumed calories and the neuroendocrine control of energy homeostasis. Thus, agents antagonizing the action of Ghrelin may have therapeutic potential in the therapy of obesity.
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The Ghrelin O-Acyltransferase-Ghrelin system: a novel regulator of glucose metabolism.
Current opinion in endocrinology diabetes and obesity, 2011Co-Authors: Kristy M. Heppner, Jenny Tong, Henriette Kirchner, Ralf Nass, Matthias H. TschöpAbstract:Ghrelin, an orexigenic hormone secreted from the stomach, exists in the circulation in two isoforms: des-acyl and acyl Ghrelin. Acylation by the enzyme Ghrelin O-acyl-transferase (GOAT) enables Ghrelin to activate the Ghrelin receptor. This review discusses recent findings illustrating the role of acyl Ghrelin, des-acyl Ghrelin and GOAT in regulating glucose homeostasis. Recent publications support a role of Ghrelin in modulating glucose homeostasis. Novel cellular mechanisms have been proposed to explain these effects. Controversy on this topic continues to exist owing to inconsistent observations made in both rodents and humans. Many recent studies are uncovering a role of des-acyl Ghrelin in glucose metabolism specifically in modulating insulin sensitivity and glucose uptake into adipocytes. A novel role of Ghrelin acylation by the enzyme GOAT in regulating glucose metabolism during caloric deprivation has newly been discovered. Ghrelin plays a role in regulating glucose homeostasis through the modulation of insulin secretion and insulin sensitivity. Acyl Ghrelin and des-acyl Ghrelin appear to have opposing glucoregulatory effects and regulation of acylation by the enzyme GOAT appears to play a role in mediating glucose metabolism. Modulation of GOAT or Ghrelin signaling may be a clinically relevant strategy to treat metabolic diseases such as type II diabetes.
Kim D. Janda - One of the best experts on this subject based on the ideXlab platform.
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Oligoclonal Antibody Targeting Ghrelin Increases Energy Expenditure and Reduces Food Intake in Fasted Mice
Molecular pharmaceutics, 2011Co-Authors: Joseph S. Zakhari, Eric P. Zorrilla, Bin Zhou, Alexander V. Mayorov, Kim D. JandaAbstract:Ghrelin, an enteric peptide hormone linked to the pathophysiology of obesity has been a therapeutic target of great interest over the past decade. Many research efforts have focused on the antagonism of Ghrelin’s endogenous receptor GHSR1a, which is found along ascending vagal afferent fibers, as well as in the arcuate nucleus of the hypothalamus. Additionally, peptidic inhibitors of Ghrelin O-Acyltransferase, the enzyme responsible for the paracrine activation of Ghrelin, have recently been studied. Our research has taken an alternative immunological approach, studying both active and passive vaccination as a means to sequester Ghrelin in the periphery, with the original discovery in rat of decreased feed efficiency and adiposity, as well as increased metabolic activity. Using our previous hapten designs as a stepping-stone, three monoclonal antibodies (JG2, JG3, and JG4) were procured against Ghrelin and tested in vivo. While mAb JG4 had the highest affinity for Ghrelin, it failed to attenuate the orexi...
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A Small Molecule Antagonist of Ghrelin O-Acyltransferase (GOAT).
ChemInform, 2011Co-Authors: Amanda L. Garner, Kim D. JandaAbstract:The compounds (I) as antagonists of GOAT are promising anti-obesity and anti-diabetes drug targets.
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A small molecule antagonist of Ghrelin O-Acyltransferase (GOAT)
Chemical communications (Cambridge England), 2011Co-Authors: Amanda L. Garner, Kim D. JandaAbstract:Using our recently disclosed fluorescence-based assay to monitor acyltransferase activity, the first non-peptidic, small molecule antagonists of Ghrelin O-Acyltransferase (GOAT), a potential anti-obesity and anti-diabetes target, have been discovered. Each exhibits micromolar inhibition of the enzyme, and may be useful probes for future study of the Ghrelin-GOAT system.
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Shedding Light on the Ghrelin/GOAT Metabolism Saga
Chembiochem : a European journal of chemical biology, 2011Co-Authors: Amanda L. Garner, Kim D. JandaAbstract:Getting the GOAT: The identification of a Ghrelin O-Acyltransferase (GOAT) inhibitor displaying metabolic modulatory activities has recently been reported. This research might provide a link for answering key questions relating to Ghrelin's role(s) in obesity and diabetes.
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cat-ELCCA: a robust method to monitor the fatty acid acyltransferase activity of Ghrelin O-Acyltransferase (GOAT).
Angewandte Chemie (International ed. in English), 2010Co-Authors: Amanda L. Garner, Kim D. JandaAbstract:Assays armed with catalytic signal amplification have arisen as superior systems for ultrasensitive detection of analytes. Here we describe a conceptually new enzyme assay based on cat-ELISA, catalytic assay using enzyme-linked click chemistry assay (cat-ELCCA), where an enzyme-linked azide is utilized to arm the assay with catalytic fluorescence signal amplification. Using this assay technology, we have developed the first potentially high-throughput screen for the recently disclosed acyltransferase, Ghrelin O-Acyltransferase (GOAT).
Yvette Taché - One of the best experts on this subject based on the ideXlab platform.
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Ghrelin - a pleiotropic hormone secreted from endocrine x/a-like cells of the stomach.
Frontiers in neuroscience, 2012Co-Authors: Andreas Stengel, Yvette TachéAbstract:The gastric X/A-like endocrine cell receives growing attention due it its peptide products with Ghrelin being the best characterized. This peptide hormone was identified a decade ago as a stimulator of food intake and to date remains the only known peripherally produced and centrally acting orexigenic hormone. In addition, subsequent studies identified numerous other functions of this peptide including the modulation of gastrointestinal motility, the maintenance of energy homeostasis and an impact on reproduction. Moreover, Ghrelin is also involved in the response to stress and assumed to play a role in coping functions and exert a modulatory action on immune pathways. Our knowledge on the regulation of Ghrelin has markedly advanced during the past years by the identification of the Ghrelin acylating enzyme, Ghrelin-O-Acyltransferase, and by the description of changes in expression, activation and release under different metabolic as well as physically and psychically challenging conditions. However, our insight on regulatory processes of Ghrelin at the cellular and subcellular levels is still very limited and warrants further investigation.
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Stress-related alterations of acyl and desacyl Ghrelin circulating levels: Mechanisms and functional implications
Peptides, 2011Co-Authors: Andreas Stengel, Lixin Wang, Yvette TachéAbstract:Ghrelin is the only known peripherally produced and centrally acting peptide hormone that stimulates food intake and digestive functions. Ghrelin circulates as acylated and desacylated forms and recently the acylating enzyme, Ghrelin-O-Acyltransferase (GOAT) and the de-acylating enzyme, thioesterase 1/lysophospholipase 1 have been identified adding new layers of complexity to the regulation of Ghrelin. Stress is known to alter gastrointestinal motility and food intake and was recently shown to modify circulating Ghrelin and GOAT levels with differential responses related to the type of stressors including a reduction induced by physical stressors (abdominal surgery and immunological/endotoxin injection, exercise) and elevation by metabolic (cold exposure, acute fasting and caloric restriction) and psychological stressors. However, the pathways underlying the alterations of Ghrelin under these various stress conditions are still largely to be defined and may relate to stress-associated autonomic changes. There is evidence that alterations of circulating Ghrelin may contribute to the neuroendocrine and behavioral responses along with sustaining the energetic requirement needed upon repeated exposure to stressors. A better understanding of these mechanisms will allow targeting components of Ghrelin signaling that may improve food intake and gastric motility alterations induced by stress.
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Abdominal surgery inhibits circulating acyl Ghrelin and Ghrelin-O-Acyltransferase levels in rats: role of the somatostatin receptor subtype 2.
American journal of physiology. Gastrointestinal and liver physiology, 2011Co-Authors: Andreas Stengel, Miriam Goebel-stengel, Nils Lambrecht, Lixin Wang, Almaas Shaikh, Jean Rivier, Yvette TachéAbstract:Clinical studies are evaluating the efficacy of synthetic Ghrelin agonists in postoperative ileus management. However, the control of Ghrelin secretion under conditions of postoperative gastric ile...
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Lipopolysaccharide differentially decreases plasma acyl and desacyl Ghrelin levels in rats: potential role of the circulating Ghrelin-acylating enzyme GOAT.
Peptides, 2010Co-Authors: Andreas Stengel, Lixin Wang, Miriam Goebel, Yvette Taché, Joseph R. Reeve, Nils LambrechtAbstract:Abstract Bacterial lipopolysaccharide (LPS) in rodents is an established model for studying innate immune responses to gram-negative bacteria and mimicking symptoms of infections including reduced food intake associated with decreased circulating total Ghrelin levels. The Ghrelin-acylating enzyme, Ghrelin- O -acyltransferase (GOAT) involved in the formation of acyl Ghrelin (AG) was recently identified. We investigated changes in circulating AG, desacyl Ghrelin (DG) and GOAT induced by intraperitoneal LPS (100 μg/kg) and associated changes in food intake. Plasma AG and total Ghrelin were assessed by radioimmunoassay, GOAT protein by Western blot and mRNA by RT-qPCR. DG was derived from total minus AG. Plasma AG and DG were decreased at 2, 5 and 7 h ( p p p p
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Differential distribution of Ghrelin-O-Acyltransferase (GOAT) immunoreactive cells in the mouse and rat gastric oxyntic mucosa.
Biochemical and biophysical research communications, 2010Co-Authors: Andreas Stengel, Lixin Wang, Miriam Goebel, Yvette Taché, George Sachs, Nils LambrechtAbstract:Abstract The enzyme that acylates Ghrelin was recently identified in mice as the fourth member of the membrane-bound O-Acyltransferases superfamily (MBOAT4) and named Ghrelin-O-Acyltransferase (GOAT). Only one report showed GOAT mRNA expression in Ghrelin-expressing cells of the mouse stomach. We investigated the distribution of GOAT protein in peripheral tissues and co-expression with endocrine markers in the gastric mucosa using a custom-made anti-GOAT antibody. Tissues were collected from male Sprague–Dawley rats and C57BL/6 mice. Western blot revealed two immunoreactive bands in rat and mouse gastric corpus mucosal proteins, a 50 kDa band corresponding to the GOAT protein and a 100 kDa band likely corresponding to a dimer. Western blot also detected GOAT in the plasma and levels were strongly increased after 24-h fasting in mice and slightly in rats. GOAT-immunoreactive cells were located in the gastric corpus mucosa and the anterior pituitary gland, whereas other peripheral tissues of rats and mice examined were negative. In mice, GOAT-immunoreactive cells were mainly distributed throughout the middle portion of the oxyntic glands, whereas in rats they were localized mainly in the lower portion of the glands. Double labeling showed that 95 ± 1% of GOAT-immunoreactive cells in mice co-labeled with Ghrelin, whereas in rats only 56 ± 4% of GOAT-positive cells showed co-expression of Ghrelin. The remainder of the GOAT-immunopositive cells in rats co-expressed histidine decarboxylase (44 ± 3%). No co-localization was observed with somatostatin in rats or mice. These data suggest species differences between rats and mice in gastric GOAT expression perhaps resulting in a different role of the MBOAT4 enzyme in the rat stomach. Detection of GOAT in the plasma raises the possibility that Ghrelin octanoylation may occur in the circulation and the fasting-induced increase in GOAT may contribute to the increase of acylated Ghrelin after fasting.