Glucose and weight control in mice with a designed ghrelin O-acyltransferase inhibitor

Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Science (Impact Factor: 31.48). 12/2010; 330(6011):1689-92. DOI: 10.1126/science.1196154
Source: PubMed

ABSTRACT Ghrelin is a gastric peptide hormone that stimulates weight gain in vertebrates. The biological activities of ghrelin require octanoylation of the peptide on Ser(3), an unusual posttranslational modification that is catalyzed by the enzyme ghrelin O-acyltransferase (GOAT). Here, we describe the design, synthesis, and characterization of GO-CoA-Tat, a peptide-based bisubstrate analog that antagonizes GOAT. GO-CoA-Tat potently inhibits GOAT in vitro, in cultured cells, and in mice. Intraperitoneal administration of GO-CoA-Tat improves glucose tolerance and reduces weight gain in wild-type mice but not in ghrelin-deficient mice, supporting the concept that its beneficial metabolic effects are due specifically to GOAT inhibition. In addition to serving as a research tool for mapping ghrelin actions, GO-CoA-Tat may help pave the way for clinical targeting of GOAT in metabolic diseases.

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Available from: Henriette Kirchner, Jul 28, 2015
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    • ". ghrelin o-acyltransferase (goAt): GOAT has been regarded as an orphan member of a family of membrane-bound Oacyltransferase enzymes (MBOATs) and is the only known enzyme that has a capacity to acetylate ghrelin. This membrane-bound enzyme can transfer octanoate to serine-3 of ghrelin from octanoyl CoA [35] [36] "
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    ABSTRACT: Abstract Background: Ghrelin is a type of growth hormone (GH) secretagogue that stimulates the release of growth hormone (GH). It is a first hormone linking gastrointestinal-pituitary axis. Objective: This review highlights the interaction of ghrelin with GHRH and somatostatin to regulate the secretion of GH and intends to explore the possible physiological role of the ghrelin-pituitary-GH axis linkage system. Observation: Ghrelin is highly conserved among species and is classified into octanoylated (C8:0), decanoylated (C10:0), decenoylated (C10:1) and nonacylated,ghrelin. Acylated ghrelin is the major active form of human ghrelin. The primary production site of ghrelin is the stomach, and it interacts with stomach ghrelin as well as hypothalamic GHRH and somatostatin in the regulation of pituitary GH secretion. Ghrelin stimulate GH release through the GHS receptor to increase intracellular Ca2+ ([Ca2+] levels via IP3 signal transduction pathway. Ghrelin is a specific endogenous ligand for the GHS receptor and provides a definitive proof of the occurance of a GHS–GHS receptor signalling system in the regulation of GH secretion. Conclusion: Studies suggests that ghrelin is a powerful pharmacological agent that exerts a potent, time-dependent stimulation of pulsatile secretion of GH. Keywords : Ghrelin, Growth Hormone, Ghrelin-Pituitary-Gh Axis Linkage System
    Journal of Clinical and Diagnostic Research 08/2014; 8(8):MC13-MC-17. DOI:10.7860/JCDR/2014/9863.4767 · 0.23 Impact Factor
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    • "). Therefore, due to this crucial role of AG in the regulation of pancreas and insulin physiology, it has been suggested that GHSR blockers and/or GOAT inhibitors might be used as putative antidiabetic drugs in the future (Gualillo et al. 2008, Barnett et al. 2010). "
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    ABSTRACT: Ghrelin is a 28-aa acylated hormone, highly expressed in the stomach, which binds to its cognate receptor (GHSR-1a) to regulate a plethora of relevant biological processes, including food intake, energy balance, hormonal secretions, learning, inflammation, etc. However, ghrelin is, in fact, the most notorious component of a complex, intricate regulatory system comprising a growing number of alternative peptides (i.e. obestatin, unacylated ghrelin, In1-ghrelin, etc.), known (GHSRs) and, necessarily unknown receptors, as well as modifying enzymes (i.e. ghrelin-O-acyl-transferase or GOAT), which interact among them as well as with other regulatory systems in order to tightly modulate key (patho)-physiological processes. This multiplicity of functions and versatility of the ghrelin system sprouts from a dual, genetic and functional, complexity. Importantly, a growing body of evidence suggests that dysregulation in some of the components of the ghrelin system can lead to or influence the development and/or progression of highly concerning pathologies such as endocrine-related tumors, inflammatory/cardiovascular diseases, and neurodegeneration, wherein these altered components could be used as diagnostic, prognostic or therapeutic targets. In this context, the aim of the present review is to integrate and comprehensively analyze the multiple components and functions of the ghrelin system described to date in order to define and understand its biological and (patho)-physiological significance.
    Journal of Endocrinology 11/2013; DOI:10.1530/JOE-13-0391 · 3.59 Impact Factor
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    • "To our knowledge, this is the first demonstration that GOAT blockade inhibits food intake and moreover food deprivation-induced increases in food hoarding and foraging in any species. Although we cannot completely rule out off-target effects of GO-CoA-Tat in contributing to changes in food intake, the inhibitor showed no obvious toxicity in mice after 30 d treatment (Barnett et al., 2010). As noted above, these effects of GO-CoA-Tat only were seen in the 10REV foraging group, a restriction that is not unique to this study. "
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    ABSTRACT: Ghrelin is an orexigenic hormone produced by the stomach in direct proportion to the time since the last meal and has therefore been called a 'hunger signal'. The octanoylation of ghrelin is critical for its orexigenic functions and is dependent upon ghrelin O-acyltransferase (GOAT) catalyzation. The GOAT inhibitor, GO-CoA-Tat, decreases the circulating concentrations of octanoylated ghrelin and attenuates weight gain on a high fat diet in mice. Unlike rats and mice, Siberian hamsters and humans do not increase food intake after food deprivation, but increase food hoarding after food deprivation. In Siberian hamsters, exogenous ghrelin increases ingestive behaviors similarly to 48-56h food deprivation. Therefore, we tested the necessity of increased ghrelin in food-deprived Siberian hamsters to stimulate ingestive behaviors. To do so we used our simulated natural housing system that allows hamsters to forage for and hoard food. Animals were given an injection of GO-CoA-Tat (i.p., 11μmol/kg) every 6h because that is the duration of its effective inhibition of octanoylated ghrelin concentrations during a 48h food deprivation. We found that GO-CoA-Tat attenuated food foraging (0-1h), food intake (0-1 and 2-4h), and food hoarding (0-1h and 2 and 3 d) post-refeeding compared with saline treated animals. This suggests that increased octanoylated ghrelin concentrations play a role in the food deprivation-induced increases in ingestive behavior. Therefore, ghrelin is a critical aspect of the multi-faceted mechanisms that stimulate ingestive behaviors, and might be a critical point for a successful clinical intervention scheme in humans.
    Hormones and Behavior 02/2013; 63(4). DOI:10.1016/j.yhbeh.2013.02.001 · 4.51 Impact Factor
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