Profound hyperphagia is a major disabling feature of Prader-Willi syndrome (PWS). Characterization of the mechanisms that underlie PWS-associated hyperphagia has been slowed by the paucity of animal models with increased food intake or obesity. Mice with a microdeletion encompassing the Snord116 cluster of noncoding RNAs encoded within the Prader-Willi minimal deletion critical region have previously been reported to show growth retardation and hyperphagia. Here, consistent with previous reports, we observed growth retardation in Snord116^+/–P mice with a congenital paternal Snord116 deletion. However, these mice neither displayed increased food intake nor had reduced hypothalamic expression of the proprotein convertase 1 gene PCSK1 or its upstream regulator NHLH2, which have recently been suggested to be key mediators of PWS pathogenesis. Specifically, we disrupted Snord116 expression in the mediobasal hypothalamus in Snord116^fl mice via bilateral stereotaxic injections of a Cre-expressing adeno-associated virus (AAV). While the Cre-injected mice had no change in measured energy expenditure, they became hyperphagic between 9 and 10 weeks after injection, with a subset of animals developing marked obesity. In conclusion, we show that selective disruption of Snord116 expression in the mediobasal hypothalamus models the hyperphagia of PWS.

中文翻译：

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下丘脑 Snord116 的缺失概括了 Prader-Willi 综合征的摄食过度

严重的摄食过多是 Prader-Willi 综合征 (PWS) 的主要致残特征。由于缺乏食物摄入量增加或肥胖的动物模型，导致 PWS 相关性摄食过多的机制的表征已经放缓。先前已报道具有包含在 Prader-Willi 最小缺失关键区域内编码的非编码 RNA的Snord116簇的微缺失的小鼠显示出生长迟缓和摄食过多。在这里，与之前的报道一致，我们观察到具有先天性父系Snord116缺失的Snord116 ^{+/-P小鼠的生长迟缓。}然而，这些小鼠既没有显示出食物摄入增加，也没有降低下丘脑前蛋白转化酶 1 基因PCSK1的表达。或其上游调节因子NHLH2，最近被认为是 PWS 发病机制的关键介质。具体来说，我们通过双侧立体定向注射表达 Cre 的腺相关病毒 (AAV)破坏了Snord116 ^fl小鼠中基底下丘脑中的Snord116表达。虽然注射了 Cre 的小鼠在测量的能量消耗方面没有变化，但它们在注射后 9 到 10 周之间变得过度进食，一部分动物出现明显的肥胖。总之，我们表明选择性破坏下丘脑中基底层中的Snord116表达模拟了 PWS 的摄食过多。