Neuronal XRN1 is required for maintenance of whole-body metabolic homeostasis.
Neuronal XRN1 is required for maintenance of whole-body metabolic homeostasis.
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DOI：
10.1016/j.isci.2021.103151
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发表时间：
2021-10-22
期刊：
影响因子：
5.8
通讯作者：
Yamamoto T
中科院分区：
文献类型：
--
作者：
Takaoka S;Yanagiya A;Mohamed HMA;Higa R;Abe T;Inoue KI;Takahashi A;Stoney P;Yamamoto T
控制mRNA的稳定性和降解对于基因的适当表达至关重要，其失调会导致各种疾病，包括癌症、神经退行性疾病、糖尿病和肥胖。5 ‘ -3 ’外核糖核酸酶XRN1执行RNA衰变的最后一步，但其生理影响尚不清楚。为了解决这个问题，产生了前脑特异性Xrn1条件敲除小鼠（Xrn1- cko），因为Xrn1缺失小鼠是胚胎致死的。Xrn1-cKO小鼠表现为肥胖、瘦素抵抗、高血糖、嗜食和能量消耗减少。肥胖是由中枢神经系统和外周组织之间的沟通失调引起的。此外，Xrn1-cKO小鼠下丘脑中编码调节食欲和能量消耗的蛋白质的mrna表达失调。因此，我们认为XRN1在下丘脑中的功能对于维持代谢稳态至关重要。前脑特异性Xrn1-cKO小鼠表现为肥胖并贪食Xrn1-cKO小鼠表现为瘦素抵抗、胰岛素抵抗和糖耐量受损Xrn1-cKO小鼠不能以脂肪为能量来源，主要以碳水化合物为能量来源，AgRP在Xrn1-cKO下丘脑生理中表达上调；分子生物学
Control of mRNA stability and degradation is essential for appropriate gene expression, and its dysregulation causes various disorders, including cancer, neurodegenerative diseases, diabetes, and obesity. The 5′–3′ exoribonuclease XRN1 executes the last step of RNA decay, but its physiological impact is not well understood. To address this, forebrain-specific Xrn1 conditional knockout mice (Xrn1-cKO) were generated, as Xrn1 null mice were embryonic lethal. Xrn1-cKO mice exhibited obesity with leptin resistance, hyperglycemia, hyperphagia, and decreased energy expenditure. Obesity resulted from dysregulated communication between the central nervous system and peripheral tissues. Moreover, expression of mRNAs encoding proteins that regulate appetite and energy expenditure was dysregulated in the hypothalamus of Xrn1-cKO mice. Therefore, we propose that XRN1 function in the hypothalamus is critical for maintenance of metabolic homeostasis. Forebrain specific Xrn1-cKO mice exhibit obesity with hyperphagia Xrn1-cKO mice exhibit leptin resistance, insulin resistance, and impaired glucose tolerance Xrn1-cKO mice cannot utilize fat as an energy source and mainly use carbohydrate AgRP expression is upregulated in the Xrn1-cKO hypothalamus Physiology; Molecular biology
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