Abnormal Response to the Anorexic Effect of GHS-R Inhibitors and Exenatide in Male Snord116 Deletion Mouse Model for Prader-Willi Syndrome
Abnormal Response to the Anorexic Effect of GHS-R Inhibitors and Exenatide in Male Snord116 Deletion Mouse Model for Prader-Willi Syndrome
复制标题
在患有 Prader-Willi 综合征的雄性 Snord116 缺失小鼠模型中，GHS-R 抑制剂和艾塞那肽的厌食作用出现异常反应。
DOI：
10.1210/en.2013-2083
复制
发表时间：
2014-07-01
期刊：
影响因子：
4.8
通讯作者：
Ding, Feng
中科院分区：
文献类型：
--
作者：
Lin, Dahe;Wang, Qi;Ding, Feng
Prader-Willi综合征（PWS）是一种以持续饥饿和暴食为特征的遗传性疾病。Snord 116小核仁RNA簇的缺乏已被确定为PWS症状的主要贡献者。Snord 116缺失（Snord 116 del）小鼠模型表现出PWS症状的子集，包括摄食过多和高生长激素血症。在这项研究中，雄性Snord 116 del小鼠的特点和测试其急性和慢性反应相关的生长激素释放肽途径的代谢产物。与野生型同窝小鼠相比，Snord 116 del小鼠的摄食率在自由进食时高出14%，在禁食后12小时内高出32%至49%。禁食Snord 116 del小鼠对GHS-R的竞争性拮抗剂[d-Lys（3）]-GHRP 6，YIL-781和反向激动剂[d-Arg（1），d-Phe（5），d-Trp（7，9），Leu（11）]-P物质（SPA）的急性兴奋作用不敏感。由于快速适应，所有3种GHS-R抑制剂均未能抑制Snord 116 del或野生型小鼠的慢性食物摄入。尽管禁食的Snord 116 del小鼠对胰高血糖素样肽1受体激动剂依塞那肽的急性毒性作用具有正常的敏感性，但与野生型小鼠相比，那些自由进食的小鼠需要更高的剂量和更频繁的给药，以实现15%的长期食物摄入抑制。然而，胃饥饿素不太可能是艾塞那肽在喂食小鼠中的促生长作用所必需的，如艾塞那肽不降低喂食小鼠中的胃饥饿素水平并且随意喂食胃饥饿素（-/-）小鼠的食物摄入可被艾塞那肽抑制的事实所示。总之，本研究表明GHS-R可能不是有效的治疗靶点，相反，艾塞那肽可能对PWS个体产生厌食作用。
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.