Increased alternate splicing of Htr2c in a mouse model for Prader-Willi syndrome leads disruption of 5HT(2C) receptor mediated appetite.
Increased alternate splicing of Htr2c in a mouse model for Prader-Willi syndrome leads disruption of 5HT(2C) receptor mediated appetite.
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DOI：
10.1186/s13041-016-0277-4
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发表时间：
2016-12-08
期刊：
影响因子：
3.6
通讯作者：
Isles AR
中科院分区：
文献类型：
--
作者：
Garfield AS;Davies JR;Burke LK;Furby HV;Wilkinson LS;Heisler LK;Isles AR
5-羟色胺（5-HT）2C受体（5-HT 2CR）前体RNA的选择性剪接受小核仁RNA Snord 115的负调控，在几乎所有患有Prader-Willi综合征（PWS）的个体中观察到Snord 115的丢失，PWS是一种以摄食过多和肥胖为特征的多基因疾病。鉴于5-HT 2CR在调节摄食行为中的作用，我们在基因型相关的PWS小鼠模型（PWS-IC）中研究了Snord 115缺乏对5-HT 2CR调节食欲的病理生理学影响。具体来说，我们证明Snord 115表达的损失与下丘脑截短的5-HT 2CR前mRNA水平的增加有关。5-HT 2CR通过参与中枢黑皮质素系统促进食欲抑制。在PWS-IC小鼠中，下丘脑弓状核（ARC）内的阿黑皮素原（Pomc）mRNA水平降低。然后，我们继续评估这些分子变化的功能后果，证明PWS-IC小鼠对厌食剂量的5-HT 2CR激动剂无反应，并且这与ARC内POMC神经元的减弱激活有关。这些数据提供了新的见解Htr 2c前mRNA加工的意义，食欲的生理调节和潜在的病理表现的食欲亢进PWS。此外，这些发现对于PWS患者具有转化相关性，这些患者可能会寻求用另一种5-HT 2CR激动剂，即新的肥胖治疗药物氯卡色林来控制食欲。本文的在线版本（doi：10.1186/s13041-016-0277-4）包含补充材料，可供授权用户使用。
Alternate splicing of serotonin (5-hydroxytryptamine; 5-HT) 2C receptor (5-HT2CR) pre-RNA is negatively regulated by the small nucleolar RNA, Snord115, loss of which is observed in nearly all individuals with Prader-Willi Syndrome (PWS), a multigenic disorder characterised by hyperphagia and obesity. Given the role of the 5-HT2CR in the regulation of ingestive behaviour we investigated the pathophysiological implications of Snord115 deficiency on 5-HT2CR regulated appetite in a genotypically relevant PWS mouse model (PWS-IC). Specifically, we demonstrate that loss of Snord115 expression is associated with increased levels of hypothalamic truncated 5-HT2CR pre-mRNA. The 5-HT2CR promotes appetite suppression via engagement of the central melanocortin system. Pro-opiomelancortin (Pomc) mRNA levels within the arcuate nucleus of the hypothalamus (ARC) were reduced in PWS-IC mice. We then went on to assess the functional consequences of these molecular changes, demonstrating that PWS-IC mice are unresponsive to an anorectic doses of a 5-HT2CR agonist and that this is associated with attenuated activation of POMC neurons within the ARC. These data provide new insight into the significance of Htr2c pre-mRNA processing to the physiological regulation of appetite and potentially the pathological manifestation of hyperphagia in PWS. Furthermore, these findings have translational relevance for individuals with PWS who may seek to control appetite with another 5-HT2CR agonist, the new obesity treatment lorcaserin. The online version of this article (doi:10.1186/s13041-016-0277-4) contains supplementary material, which is available to authorized users.
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影响因子：
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Garfield, Alastair S.;Heisler, Lora K.
通讯作者：
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