Modulation of ghrelin O-acyltransferase by food deprivation and food restriction and central knock-down by vivo-morpholino

M. Wellman, A. Abizaid
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Ghrelin is a peptide hormone that is implicated in the regulation of feeding and energy balance. Secreted primarily by the stomach, ghrelin requires activation by the enzyme ghrelin O-acyltransferase (GOAT) in order for it to bind to its only known receptor, the growth hormone secretagogue receptor type 1a (GHSR1a). This activation involves the transfer of an acyl side chain from a fatty acid to the third amino acid residue of the ghrelin molecule, resulting in acylated ghrelin. While the main source of ghrelin appears to be the stomach, a number of reports have pointed to the possibility that ghrelin is also produced and released by a subset of hypothalamic neurons, and that these could regulate energy balance within the hypothalamus. Interestingly, the GOAT enzyme is produced in hypothalamic tissue supporting the notion of a central source of active ghrelin. Furthermore, while the role of peripheral GOAT has been examined by intraperitoneal injection of a GOAT inhibitor, the role of GOAT specifically in the brain has not been examined, and indeed in rats, to the best of our knowledge, central GOAT mRNA has never been measured. In this study, we first demonstrated, in rats, that the ghrelin system, in terms of GOAT, ghrelin, and GHSR1a mRNA, can be modulated by exposing animals to metabolic challenges involving either chronic three-week food restriction or acute two-day food deprivation. We then attempted to knock-down central GOAT using a vivo-morpholino anti-sense directed directly into the lateral ventricles of rats via subcutaneous osmotic mini-pumps attached to cannulae, providing continuous infusion of the drug. We observed that drug-treated animals, while eating comparable amounts of a high-fat diet, gained significantly less weight over a three-week period. Our results support the notion that GOAT, and ghrelin, are synthesized in the brain, and for the first time demonstrate the importance of central GOAT in terms of metabolism.