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Adam P Chambers,
Henriette Kirchner,
Hilary E Wilson-Perez, Jill A Willency,
John E Hale,
Bruce D Gaylinn,
Michael O Thorner,
Paul T Pfluger,
Jesus A Gutierrez,
Matthias H Tschöp,
Darleen A Sandoval,
Randy J Seeley
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Adam P Chambers,
Henriette Kirchner,
Hilary E Wilson-Perez, Jill A Willency,
John E Hale,
Bruce D Gaylinn,
Michael O Thorner,
Paul T Pfluger,
Jesus A Gutierrez,
Matthias H Tschöp,
Darleen A Sandoval,
Randy J Seeley
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ABSTRACT: Reductions in levels of the hunger-stimulating hormone ghrelin have been proposed to mediate part of the effects of vertical sleeve gastrectomy (VSG) and Roux-en-Y gastric bypass surgeries for obesity. We studied circulating levels of acyl and desacyl ghrelin in rats after these surgeries. We found that blood levels of ghrelin were reduced after VSG, but not after Roux-en-Y gastric bypass, based on enzyme-linked immunosorbent assay and mass-spectrometry analyses. We compared the effects of VSG in ghrelin-deficient mice and wild-type mice on food intake, body weight, dietary fat preference, and glucose tolerance. We found that VSG produced comparable outcomes in each strain. Reduced ghrelin signaling therefore does not appear to be required for these effects of VSG.
Gastroenterology 09/2012; · 11.68 Impact Factor
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ABSTRACT: The hormone ghrelin is a unique signaling peptide with powerful metabolic effects, mediated by its acylated forms. The acyl modification of ghrelin is unique in that it takes place via a susceptible ester linkage in the conserved serine-3 of ghrelin and is composed principally of octanoyl and, to lesser extent, decanoyl fatty acids. The nature of this ester linkage makes it susceptible to esterases, which convert it to its des-acyl forms, and, if not adequately inhibited, the conversion to des-acyl ghrelin, particularly post sample collection, can lead to artifactual and misleading results. Here, we describe sample processing and mass spectrometric methodologies for the accurate and simultaneous quantification of acylated and des-acylated forms of ghrelin. We exploited these methodologies (1) to characterize circulating and tissue-specific forms of acyl and des-acyl ghrelin, (2) to optimize a cell system for acyl ghrelin production and search for the enzyme responsible for ghrelin's acylation, and (3) to demonstrate that GOAT is ghrelin's O-acyl transferase.
Methods in enzymology 01/2012; 514:129-46. · 1.90 Impact Factor
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Henriette Kirchner,
Jesus A Gutierrez,
Patricia J Solenberg,
Paul T Pfluger,
Traci A Czyzyk, Jill A Willency,
Annette Schürmann,
Hans-Georg Joost,
Ronald J Jandacek,
John E Hale,
Mark L Heiman,
Matthias H Tschöp
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ABSTRACT: Central nervous system nutrient sensing and afferent endocrine signaling have been established as parallel systems communicating metabolic status and energy availability in vertebrates. The only afferent endocrine signal known to require modification with a fatty acid side chain is the orexigenic hormone ghrelin. We find that the ghrelin O-acyl transferase (GOAT), which is essential for ghrelin acylation, is regulated by nutrient availability, depends on specific dietary lipids as acylation substrates and links ingested lipids to energy expenditure and body fat mass. These data implicate the ghrelin-GOAT system as a signaling pathway that alerts the central nervous system to the presence of dietary calories, rather than to their absence as is commonly accepted.
Nature medicine 07/2009; 15(7):741-5. · 27.14 Impact Factor
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ABSTRACT: The peptide hormone ghrelin is the only known protein modified with an O-linked octanoyl side group, which occurs on its third serine residue. This modification is crucial for ghrelin's physiological effects including regulation of feeding, adiposity, and insulin secretion. Despite the crucial role for octanoylation in the physiology of ghrelin, the lipid transferase that mediates this novel modification has remained unknown. Here we report the identification and characterization of human GOAT, the ghrelin O-acyl transferase. GOAT is a conserved orphan membrane-bound O-acyl transferase (MBOAT) that specifically octanoylates serine-3 of the ghrelin peptide. Transcripts for both GOAT and ghrelin occur predominantly in stomach and pancreas. GOAT is conserved across vertebrates, and genetic disruption of the GOAT gene in mice leads to complete absence of acylated ghrelin in circulation. The occurrence of ghrelin and GOAT in stomach and pancreas tissues demonstrates the relevance of GOAT in the acylation of ghrelin and further implicates acylated ghrelin in pancreatic function.
Proceedings of the National Academy of Sciences 05/2008; 105(17):6320-5. · 9.68 Impact Factor
