The Role of Ghrelin and Ghrelin O-Acyltransferase in Obesity: Targets for Treatment

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Wellman, Martin Koji




Ghrelin is the first identified circulating orexigenic hormone. Following translation of the mRNA to its initial prepropeptide, a variety of posttranslational modifications are performed that allow the peptide to bind to its only known receptor, the growth hormone secretagogue receptor type 1A (GHSR1a). The crucial step in this process is the attachment of an acyl sidechain to the serine-3 residue, which is accomplished through the activity of the enzyme ghrelin O-acyltransferase (GOAT), ultimately leading to the final product named acylated ghrelin. Acylated ghrelin has been shown to signal through various pathways that promote certain phenotypes associated with obesity, including insulin insensitivity, adiposity, and increased feeding. More recently, ghrelin peptides lacking the acyl sidechain have also been found to have influence in various pathways. Due to these effects, the ghrelin system has become a promising target in the goal of combating the current obesity epidemic. Since its discovery, however, ghrelin has been found to be involved in other pathways important for stress, anxiety, depression, and more, making side-effects associated with ghrelin-targeting pharmaceuticals likely. In order for the development of anti-obesity agents to be successful, a detailed knowledge of the ghrelin system and its interrelationships with others is important, not only to develop compounds to target ghrelin and its counterparts but also to help minimize and foresee complications as a result of side-effects. In the current thesis we examine the machinery of the ghrelin system and seek out to identify various ways that metabolic disorders can be approached pharmacologically. We identify two novel ways to inhibit the adipogenic effect of ghrelin using anti-sense strands targeting central GOAT and the development of our own drug, CF801, which reduces circulating acylated ghrelin levels when given peripherally. Both of these approaches contribute to a reduction in weight gain independent of food intake. By inhibiting the enzyme specifically in the brain, we also identify for the first time a role of central GOAT in promoting adiposity, an effect similar to what is found in the periphery.






Carleton University

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