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Title: Abnormal response to the anorexic effect of GHS-R inhibitors and exenatide in male Snord116 deletion mouse model for Prader-Willi Syndrome

Author
item LIN, DAHE - Xiamen University
item QI, WANG - Xiamen University
item RAN, RUICHUAN - Xiamen University
item KAI, LIU - Xiamen University
item WANG, YAO - Xiamen University
item WANG, JUANJUAN - Xiamen University
item LIU, YAZHEN - Xiamen University
item CHEN, RUICHUAN - Xiamen University
item SUN, YUXIANG - Children'S Nutrition Research Center (CNRC)
item LIU, RUNZHONG - Xiamen University
item DING, FENG - Xiamen University

Submitted to: Endocrinology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/9/2014
Publication Date: 7/1/2014
Citation: Lin, D., Qi, W., Ran, R., Kai, L., Wang, Y., Wang, J., Liu, Y., Chen, R., Sun, Y., Liu, R., Ding, F. 2014. Abnormal response to the anorexic effect of GHS-R inhibitors and exenatide in male Snord116 deletion mouse model for Prader-Willi Syndrome. Endocrinology. 155(7):2355-2362.

Interpretive Summary: Prader-Willi Syndrome (PWS) is a disease characterized by persistent hunger and a huge appetite. A gene called Snord116 is linked to PWS. We have observed that a mouse model without the Snord116 gene showed a 14% higher food intake, and this increase is more pronounced after fasting. Gut hormone ghrelin, an appetite stimulant, is thought to have a role in PWS. We tested 3 substances which block ghrelin signaling, and all of them failed to alter overall food intake of either Snord116 deleted mice or normal mice. Exenatide is a synthetic compound, which activates gut peptide (GLP-1). Interestingly, we found that exenatide effectively inhibits food intake of the mice. This study suggests that while blocking ghrelin signaling is not likely to be beneficial for PWS, exenatide represents a very promising therapeutic option for treating PWS.

Technical Abstract: Prader-Willi syndrome (PWS) is a genetic disease characterized by persistent hunger and hyperphagia. The lack of the Snord116 small nucleolar RNA cluster has been identified as the major contributor to PWS symptoms. The Snord116 deletion (Snord116del) mouse model manifested a subset of PWS symptoms including hyperphagia and hyperghrelinemia. In this study, male Snord116del mice were characterized and tested for their acute and chronic responses to anorexic substances related to the ghrelin pathway. In comparison with their wild-type littermates, the food intake rate of Snord116del mice was 14% higher when fed ad libitum, and 32% to 49% higher within 12 hours after fasting. Fasted Snord116del mice were less sensitive to the acute anorexic effect of competitive antagonist [d-Lys(3)]-GHRP6, YIL-781, and reverse agonist [d-Arg(1),d-Phe(5),d-Trp(7,9),Leu(11)]-substance P (SPA) of ghrelin receptor GHS-R. All 3 GHS-R inhibitors failed to inhibit chronic food intake of either Snord116del or wild-type mice due to rapid adaptation. Although fasted Snord116del mice had normal sensitivity to the acute anorexic effect of glucagon-like peptide 1 receptor agonist exenatide, those fed ad libitum required a higher dose and more frequent delivery to achieve ~15% suppression of long-term food intake in comparison with wild-type mice. Ghrelin, however, is unlikely to be essential for the anorexic effect of exenatide in fed mice, as shown by the fact 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 anorexic effect in PWS individuals.