Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY, 10032, USA.
Naomi Berrie Diabetes Center, Department of Medicine, Columbia University, New York, NY, 10032, USA.
Mol Metab. 2020 Apr;34:146-156. doi: 10.1016/j.molmet.2020.01.010. Epub 2020 Jan 30.
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.
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.
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.
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.
在小鼠模型中，TTC39B（T39）的缺乏会降低肝脂肪生成基因的表达，并防止饮食引起的肝炎。在评估针对 T39 的反义寡核苷酸（ASO）的治疗潜力时，我们发现了一种意外的体重减轻表型。本研究的目的是确定对饮食诱导肥胖的抵抗力的机制。
为了评估治疗潜力，我们使用反义寡核苷酸（ASO）敲低 Western 或高脂肪、高胆固醇、高蔗糖饮食喂养的 Ldlr 或野生型小鼠中的 T39 表达。
T39 ASO 处理导致肝脂肪生成基因表达降低和肝甘油三酯降低。出乎意料的是，T39 ASO 处理可防止饮食引起的肥胖。两种不同的 ASO 可降低脂肪组织巨噬细胞（ATMs）中的 T39 mRNA，从而导致体重减轻，但肝靶向 GalNac-ASO 则不能。用 T39 ASO 处理的小鼠表现出性腺白色脂肪组织（gWAT）的褐色增加和脂解增加的证据。然而，当用 T39 ASO 处理时，T39 敲除小鼠显示出相似的体重减轻反应，表明存在脱靶效应。gWAT 的 RNA-seq 分析显示 I 型干扰素（IFN）反应基因的广泛增加，并且 IFN 受体的敲除消除了 T39 ASO 诱导的体重减轻表型。一些人 T39 ASO 和靶向 LDLR 的不同修饰的 ASO 也在 THP1 巨噬细胞中诱导 I 型 IFN 反应。
我们的数据表明，ASO 在 ATMs 中对 T39 的肝外靶向产生了脱靶的 I 型 IFN 反应，导致脂解、WAT 褐色化和体重减轻。虽然我们的发现表明 ASO 可能比以前认为的更常见地诱导脱靶 I 型 IFN 反应，但它们也表明在 ATMs 中选择性诱导 I 型 IFN 治疗可能代表肥胖治疗的一种新方法。
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