Abnormal Response To The Anorexic Substances In Male Snord116Deletion Mouse Model For Prader-Willi Syndrome

Prader-Willi syndrome (PWS) is a genetic disease characterized by persistent hunger and hyperphagia. The lack of Snord116snoRNA cluster has been identified as the major contributor to PWS symptoms. Snord116deletion (Snordl16del) mouse model manifested a subset of PWS symptoms including hyperphagia and hyperghrelinemia. In this study, male Snord116del mice were characterized and tested for acute and chronic response to anorexic substances related to ghrelinpathway. In comparison to their wild-type littermates, food intake rate of Snord116del mice was14%higher when fed ad libitum, and32-49%higher within12hrs after fasting. Fasted Snord116del mice were less sensitive to the acute anorexic effect of competitive inhibitor [D-Lys3]-GHRP6, YIL-781,and reverse agonist [D-Arg1,D-Phe5,D-Trp7,9,Leu11]-substance P (SPA) of ghrelin receptor GHS-R. All three GHS-R inhibitors failed to inhibit chronic food intake of either Snord116del or wild-typemice due to rapid adaptation. Although fasted Snord116del mice had normal sensitivity to the acuteanorexic effect of GLP-1receptor agonist exenatide, those fed ad libitum required a higher dose andmore frequent delivery to achieve～15%suppression of long-term food intake in comparison to wildtype mice. Ghrelin, however, is unlikely to be essential for the anorexic effect of exenatide in fedmice, as shown by that exenatide did not reduce ghrelin levels in fed mice, and food intake of ghrelin-/-mice fed ad libitum could be suppressed by exenatide. In conclusion, this study suggests that GHS-R may not be an effective therapeutic target, and in contrast, exenatide may produce anorexiceffect in PWS individuals.