Ghrelin Receptor Agonist Rescues Excess Neonatal Mortality in a Prader-Willi Syndrome Mouse Model
Ghrelin Receptor Agonist Rescues Excess Neonatal Mortality in a Prader-Willi Syndrome Mouse Model
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DOI：
10.1210/en.2018-00801
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发表时间：
2018-12-01
期刊：
影响因子：
4.8
通讯作者：
Zigman, Jeffrey M.
中科院分区：
文献类型：
--
作者：
Rodriguez, Juan A.;Bruggeman, Emily C.;Zigman, Jeffrey M.
在目前的研究中，我们试图确定胃饥饿素系统在普拉德-威利综合征（PWS）中的意义。PWS的特征是新生儿肌张力减退和喂养困难，以及儿童期开始较晚的暴食和肥胖。其他特征包括低GH、新生儿低血糖、性腺功能减退和加速死亡。尽管PWS中的暴食症和肥胖症已归因于促食欲激素生长素释放肽水平升高，但这种联系从未被牢固确立，也没有在PWS背景下研究生长素释放肽对增加GH分泌、血糖和存活的潜在保护作用。在目前的研究中，我们表明，将Snord 116 del小鼠模型PWS置于生长激素释放肽缺乏或生长激素释放肽受体[GH促分泌素受体（GHSR）]缺乏的背景下，不会影响其特征性体重减轻，血浆IGF-1降低，性成熟延迟或断奶前死亡率增加。然而，在ghrelin缺乏的背景下，雄性Snord 116 del幼仔的血糖进一步降低，在GHSR缺乏的背景下，雄性Snord 116 del幼仔的体重增加百分比和脂肪量百分比进一步降低。令人惊讶的是，每天给予Snord 116 del新生儿2周的GHSR激动剂HM 01显著改善了存活率，导致几乎完全挽救了由于父系Snord 116基因丢失而导致的过度死亡率。这些数据支持进一步探索GHSR激动剂给药在限制PWS死亡率方面的治疗潜力，特别是在以茁壮成长失败为特征的时期。
In the current study, we sought to determine the significance of the ghrelin system in Prader-Willi Syndrome (PWS). PWS is characterized by hypotonia and difficulty feeding in neonates and hyperphagia and obesity beginning later in childhood. Other features include low GH, neonatal hypoglycemia, hypogonadism, and accelerated mortality. Although the hyperphagia and obesity in PWS have been attributed to elevated levels of the orexigenic hormone ghrelin, this link has never been firmly established, nor have ghrelin's potentially protective actions to increase GH secretion, blood glucose, and survival been investigated in a PWS context. In the current study, we show that placing Snord116del mice modeling PWS on ghrelin-deficient or ghrelin receptor [GH secretagogue receptor (GHSR)]-deficient backgrounds does not impact their characteristically reduced body weight, lower plasma IGF-1, delayed sexual maturation, or increased mortality in the period prior to weaning. However, blood glucose was further reduced in male Snord116del pups on a ghrelindeficient background, and percentage body weight gain and percentage fat mass were further reduced in male Snord116del pups on a GHSR-deficient background. Strikingly, 2 weeks of daily administration of the GHSR agonist HM01 to Snord116del neonates markedly improved survival, resulting in a nearly complete rescue of the excess mortality owing to loss of the paternal Snord116 gene. These data support further exploration of the therapeutic potential of GHSR agonist administration in limiting PWS mortality, especially during the period characterized by failure to thrive.