Novel GOAT inhibitor, LP479, reduces body weight & consumption of high fat diet in C57BL/6J male mice

Z.R. Patterson, M.K. Wellman, A.B. Abizaid

Location: Halls B-H
Presentation Time: Wednesday, Nov 13, 2013, 11:00 AM – 12:00 PM
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Ghrelin is a 28 amino acid hormonal peptide that is intimately related to the regulation of food intake and body weight. Ghrelin is secreted by specialized cells in the gastric oxyntic mucosa lining the stomach and serves a wide range of physiological roles, primarily the promotion of food intake and adiposity. Once secreted, ghrelin seeks to bind to the growth hormone secretagogue receptor-1a (GHSR-1a), the only known receptor for ghrelin. The ability of ghrelin to bind to GHSR-1a, and thus carry out its biological activity, is dependent on a post translation modification of the mature ghrelin protein, wherein an n-octanoic acid is added to the third serine residue on the ghrelin molecule. Modification with an n-octanoyl group induces a conformational change that renders the ghrelin molecule biologically active. The enzyme responsible for the acylation of ghrelin is called ghrelin-O-acyl-transferase (GOAT), a member of the membrane bound-O-acyl-transferase (MBOAT) family. To date, GOAT is the only known enzyme capable of acylating ghrelin and it is therefore thought to be involved in all processes related to ghrelin. Once activated, ghrelin promotes food intake and body weight through interactions with GHSR-1a, primarily in the hypothalamus. Over the past decade, ghrelin has been linked extensively to the development of obesity, Type II diabetes and metabolic syndrome, which has lead to an eruption of research examining the role of ghrelin in these processes. Interruption of ghrelin signaling, via genetic manipulations or pharmacological interventions, has been shown to reduce some of the consequences associated with obesity and metabolic syndrome. Here we present a novel peptide, LP479, capable of inhibiting GOAT and therefore subsequent ghrelin acylation. To this end, we show that IP administration of LP479 was sufficient to reduce circulating plasma acylated ghrelin levels, body mass and total adipose tissue mass in male C57BL6J mice, relative to vehicle-injected controls. Interestingly, LP479 caused a significant increase in regular chow intake while blunting the consumption of a high fat diet in a dose-dependent fashion, suggesting it may shift dietary preference away from energy dense foods. Furthermore, LP479 administration reduced overall caloric intake in a dose dependent fashion following an overnight fast, relative to vehicle injected controls. LP479 injections did not elicit any changes in anxiety or depressive-like behaviors, as measured by social interaction and open field test. Here we propose a novel compound to be further investigated for the potential treatment of metabolic disorders associated with body weight gain and adiposity.