title: Abnormal response to the anorexic effect of GHS-R inhibitors and exenatide in male Snord116 deletion mouse model for Prader-Willi syndrome.
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.
authors.affiliation: State Key Laboratory of Cellular Stress Biology (D.L., Q.W., H.R., K.L., Y.W., J.W., Y.L., R.C., R.L., F.D.), School of Life Sciences, Xiamen University, Xiamen 361101, Fujian, China; and Departments of Pediatrics and Molecular and Cellular Biology (Y.S.), Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Dahe
authors.initials: D
authors.lastname: Lin
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.forename: Haiying
authors.initials: H
authors.lastname: Ran
authors.forename: Kai
authors.initials: K
authors.lastname: Liu
authors.forename: Yao
authors.initials: Y
authors.lastname: Wang
authors.forename: Juanjuan
authors.initials: J
authors.lastname: Wang
authors.forename: Yazhen
authors.initials: Y
authors.lastname: Liu
authors.forename: Ruichuan
authors.initials: R
authors.lastname: Chen
authors.forename: Yuxiang
authors.initials: Y
authors.lastname: Sun
authors.forename: Runzhong
authors.initials: R
authors.lastname: Liu
authors.forename: Feng
authors.initials: F
authors.lastname: Ding
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000855:Anorexia / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D004435:Eating / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D000077270:Exenatide; D005215:Fasting / Q000097:blood; D054439:Ghrelin / Q000097:blood / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006963:Hyperphagia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009842:Oligopeptides / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D011218:Prader-Willi Syndrome / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D052999:Quinazolinones / Q000494:pharmacology; D020537:RNA, Small Nucleolar / Q000235:genetics* / Q000378:metabolism; D054440:Receptors, Ghrelin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013373:Substance P / Q000031:analogs & derivatives / Q000494:pharmacology; D014688:Venoms / Q000494:pharmacology*
chemical_list: C520836:GHRP-6, Lys(3)-; D054439:Ghrelin; D007004:Hypoglycemic Agents; D009842:Oligopeptides; D010455:Peptides; D010880:Piperidines; D052999:Quinazolinones; D020537:RNA, Small Nucleolar; D054440:Receptors, Ghrelin; D014688:Venoms; C524424:YIL 781; D013373:Substance P; C045800:substance P, Phe(5)-Trp(7,9)-Leu(11)-; D000077270:Exenatide