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.

mRNA 稳定性和降解的控制对于适当的基因表达至关重要，其失调会导致各种疾病，包括癌症、神经退行性疾病、糖尿病和肥胖症。5'-3' 外切核糖核酸酶 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Xrn 1 空小鼠是胚胎致死的。Xrn1-cKO 小鼠表现出具有瘦素抵抗、高血糖、食欲亢进和能量消耗减少的肥胖。肥胖是由中枢神经系统和外周组织之间的通讯失调引起的。此外，在Xrn1 -cKO 小鼠的下丘脑中，编码调节食欲和能量消耗的蛋白质的 mRNA 的表达失调。因此，我们认为下丘脑中的 XRN1 功能对于维持代谢稳态至关重要。