Antisense oligonucleotide treatment produces a type I interferon response that protects against diet-induced obesity
Antisense oligonucleotide treatment produces a type I interferon response that protects against diet-induced obesity
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DOI：
10.1016/j.molmet.2020.01.010
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发表时间：
2020-04-01
影响因子：
8.1
通讯作者：
Tall, Alan R.
中科院分区：
文献类型：
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作者：
McCabe, Kristin M.;Hsieh, Joanne;Tall, Alan R.
目的：在小鼠模型中，TTC 39 B（T39）缺陷降低肝脏脂肪生成基因表达，并防止饮食诱导的脂肪性肝炎。在评估靶向T39的反义寡核苷酸（ASO）的治疗潜力时，我们发现了意想不到的体重减轻表型。本研究的目的是确定饮食诱导的obesity.Methods的阻力的机制：为了评估治疗潜力，我们使用反义寡核苷酸（阿索）敲低T39在西方或高脂肪，高胆固醇，高蔗糖饮食喂养的Ldlr（-/-）或野生型mice.Results的表达：T39阿索治疗导致肝脏脂肪生成基因的表达下降，降低肝脏甘油三酯。出乎意料的是，T39阿索治疗防止了饮食诱导的肥胖。用两种不同的ASO观察到体重增加减少，其降低脂肪组织巨噬细胞（ATM）中的T39 mRNA，但用肝靶向GalNac-ASO则没有。用T39阿索处理的小鼠显示出增加的性腺白色脂肪组织（gWAT）的布朗宁和增加的脂解的证据。然而，当用T39阿索治疗时，T39敲除小鼠显示出类似的体重减轻反应，表明脱靶效应。gWAT的RNA-seq分析显示I型干扰素（IFN）应答基因的广泛增加，并且IFN受体的敲除消除了由T39阿索诱导的体重减轻表型。一些人的T39 ASOs和ASOs与不同的修饰靶向低密度脂蛋白受体也诱导了I型IFN反应在THP 1 macrophages.Conclusion：我们的数据表明，肝外靶向T39 ASOs在ATM产生脱靶1型IFN反应，导致激活脂解，布朗宁的WAT，和体重减轻。虽然我们的研究结果表明，ASO可能比以前认为的更常见地诱导脱靶1型IFN应答，但它们也表明，在ATM中选择性地治疗性诱导1型IFN可能代表治疗肥胖的新方法。(C)2020年，任作家。由爱思唯尔有限公司出版。
Objective: In mouse models, deficiency of TTC39B (T39) decreases hepatic lipogenic gene expression and protects against diet-induced steatohepatitis. While assessing the therapeutic potential of antisense oligonucleotides (ASOs) targeting T39, we discovered an unexpected weight loss phenotype. The objective of this study was to determine the mechanism of the resistance to diet-induced obesity.Methods: To assess therapeutic potential, we used antisense oligonucleotides (ASO) to knock down T39 expression in a Western or high-fat, high-cholesterol, high-sucrose-diet-fed Ldlr(-/-) or wild-type mice.Results: T39 ASO treatment led to decreased hepatic lipogenic gene expression and decreased hepatic triglycerides. Unexpectedly, T39 ASO treatment protected against diet-induced obesity. The reduced weight gain was seen with two different ASOs that decreased T39 mRNA in adipose tissue macrophages (ATMs), but not with a liver-targeted GalNac-ASO. Mice treated with the T39 ASO displayed increased browning of gonadal white adipose tissue (gWAT) and evidence of increased lipolysis. However, T39 knockout mice displayed a similar weight loss response when treated with T39 ASO, indicating an off-target effect. RNA-seq analysis of gWAT showed a widespread increase in type I interferon (IFN)-responsive genes, and knockout of the IFN receptor abolished the weight loss phenotype induced by the T39 ASO. Some human T39 ASOs and ASOs with different modifications targeting LDLR also induced a type I IFN response in THP1 macrophages.Conclusion: Our data suggest that extrahepatic targeting of T39 by ASOs in ATMs produced an off-target type 1 IFN response, leading to activation of lipolysis, browning of WAT, and weight loss. While our findings suggest that ASOs may induce off-target type 1 IFN response more commonly than previously thought, they also suggest that therapeutic induction of type 1 IFN selectively in ATMs could potentially represent a novel approach to the treatment of obesity. (C) 2020 The Authors. Published by Elsevier GmbH.