A Transcriptomic Signature of the Hypothalamic Response to Fasting and BDNF Deficiency in Prader-Willi Syndrome.
A Transcriptomic Signature of the Hypothalamic Response to Fasting and BDNF Deficiency in Prader-Willi Syndrome.
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DOI：
10.1016/j.celrep.2018.03.018
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发表时间：
2018-03-27
期刊：
影响因子：
8.8
通讯作者：
Farooqi IS
中科院分区：
文献类型：
--
作者：
Bochukova EG;Lawler K;Croizier S;Keogh JM;Patel N;Strohbehn G;Lo KK;Humphrey J;Hokken-Koelega A;Damen L;Donze S;Bouret SG;Plagnol V;Farooqi IS
对肥胖原因有分子定义的人的脑组织进行转录分析，可能会突出疾病机制和治疗目标。我们对Prader-Willi综合征(PWS)患者的下丘脑进行了RNA测序，PWS是一种以严重吞噬功能亢进为特征的遗传性肥胖综合征。我们发现，上调的基因与小鼠AgRP神经元发出饥饿信号的转录组重叠，而下调的基因与摄食激活的POMC神经元的表达谱重叠。下调的基因主要在神经细胞中表达，参与神经发生、神经递质释放和突触可塑性，而上调的主要是小胶质细胞的基因参与炎症反应。这种转录特征可能是通过减少脑源性神经营养因子的表达来调节的。此外，我们暗示选择性剪接的中断是PWS神经元功能障碍的潜在分子机制。对人类下丘脑的转录分析可能确定与能量平衡有关的神经机制，以及潜在的减肥治疗目标。人类PWS下丘脑和小鼠AgRP神经元表达基因重叠，下调的基因参与神经元发育，SNORD116缺失减少神经发育和细胞存活，选择性剪接受到干扰，在PWS中Prader-Willi综合征(PWS)是一种遗传性肥胖综合征。Bochukova等人。报告了PWS患者下丘脑中支持神经退行性变和神经炎症的基因表达变化，这些基因是参与这种疾病的关键过程。
Transcriptional analysis of brain tissue from people with molecularly defined causes of obesity may highlight disease mechanisms and therapeutic targets. We performed RNA sequencing of hypothalamus from individuals with Prader-Willi syndrome (PWS), a genetic obesity syndrome characterized by severe hyperphagia. We found that upregulated genes overlap with the transcriptome of mouse Agrp neurons that signal hunger, while downregulated genes overlap with the expression profile of Pomc neurons activated by feeding. Downregulated genes are expressed mainly in neuronal cells and contribute to neurogenesis, neurotransmitter release, and synaptic plasticity, while upregulated, predominantly microglial genes are involved in inflammatory responses. This transcriptional signature may be mediated by reduced brain-derived neurotrophic factor expression. Additionally, we implicate disruption of alternative splicing as a potential molecular mechanism underlying neuronal dysfunction in PWS. Transcriptomic analysis of the human hypothalamus may identify neural mechanisms involved in energy homeostasis and potential therapeutic targets for weight loss. Overlap between genes expressed in human PWS hypothalamus and mouse Agrp neurons Downregulated genes are involved in neuronal development SNORD116 deletion reduces neural development and survival in cells Alternative splicing is disturbed in PWS Prader-Willi syndrome (PWS) is a genetic obesity syndrome. Bochukova et al. report gene expression changes in the hypothalamus of people with PWS that support neurodegeneration and neuroinflammation as key processes involved in this condition.
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