客观的
单酰基甘油酰基转移酶 (MGAT) 催化单酰基甘油合成二酰基甘油。以前的工作表明 MGAT 活性在肥胖相关的肝胰岛素抵抗发展中的重要性。实际上，反义寡核苷酸 (ASO) 介导的编码 MGAT1 的Mogat1 mRNA 敲低降低了肝脏 MGAT 活性并改善了高脂肪饮食 (HFD) 喂养小鼠的葡萄糖耐量和胰岛素抵抗。然而，最近的研究表明，一些 ASO 可能通过激活干扰素 α/β 受体 1 (IFNAR-1) 通路对体重和代谢参数产生脱靶效应。
方法
产生了具有全身Mogat1敲除或 Mogat1 的 floxed 等位基因以允许肝脏特异性Mogat1敲除（通过肝脏特异性转基因或腺相关病毒驱动的 Cre 重组酶）的小鼠。这些小鼠被置于 HFD 上，并在节食 16 周后评估葡萄糖代谢和胰岛素敏感性。在一些实验中，在存在或不存在 IFNAR-1 中和抗体的情况下，用对照 scramble 或Mogat1 ASO 处理小鼠。
结果
肝脏Mogat1的基因缺失，无论是急性还是慢性，都不会改善 HFD 喂养小鼠的肝脂肪变性、葡萄糖耐量或胰岛素敏感性。此外，所有组织中的组成型 Mogat1敲除实际上加剧了 HFD 引起的肥胖、胰岛素敏感性和 HFD 的葡萄糖不耐受。尽管Mogat1表达显着降低，但肝脏 MGAT 活性在所有基因敲除小鼠模型中均未受影响。Mogat1在肝细胞中的过表达增加了低脂喂养小鼠的肝脏 MGAT 活性和 TAG 含量，但不会引起胰岛素抵抗。多个Mogat1 ASO 序列改善了野生型和Mogat1的葡萄糖耐量null 小鼠，表明存在脱靶效应。肝脏 IFNAR-1 信号被多个Mogat1 ASO 激活，但它的阻断并没有阻止Mogat1 ASO 对葡萄糖稳态的影响。
结论
这些结果表明，Mogat1的遗传缺失不会影响肝脏 MGAT 活性或 HFD 的代谢稳态，并表明多个Mogat1 ASO 通过独立于靶向Mogat1或 IFNAR-1 信号传导激活的作用改善葡萄糖代谢。
"点击查看英文标题和摘要"
Multiple antisense oligonucleotides targeted against monoacylglycerol acyltransferase 1 (Mogat1) improve glucose metabolism independently of Mogat1
Objective
Monoacylglycerol acyltransferase (MGAT) enzymes catalyze the synthesis of diacylglycerol from monoacylglycerol. Previous work has suggested the importance of MGAT activity in the development of obesity-related hepatic insulin resistance. Indeed, antisense oligonucleotide (ASO)-mediated knockdown of Mogat1 mRNA, which encodes MGAT1, reduced hepatic MGAT activity and improved glucose tolerance and insulin resistance in high-fat diet (HFD)-fed mice. However, recent work has suggested that some ASOs may have off-target effects on body weight and metabolic parameters via activation of the interferon alpha/beta receptor 1 (IFNAR-1) pathway.
Methods
Mice with whole-body Mogat1 knockout or a floxed allele for Mogat1 to allow for liver-specific Mogat1-knockout (by either a liver-specific transgenic or adeno-associated virus-driven Cre recombinase) were generated. These mice were placed on an HFD, and glucose metabolism and insulin sensitivity were assessed after 16 weeks on diet. In some experiments, mice were treated with control scramble or Mogat1 ASOs in the presence or absence of IFNAR-1 neutralizing antibody.
Results
Genetic deletion of hepatic Mogat1, either acutely or chronically, did not improve hepatic steatosis, glucose tolerance, or insulin sensitivity in HFD-fed mice. Furthermore, constitutive Mogat1 knockout in all tissues actually exacerbated HFD-induced obesity, insulin sensitivity, and glucose intolerance on an HFD. Despite markedly reduced Mogat1 expression, liver MGAT activity was unaffected in all knockout mouse models. Mogat1 overexpression in hepatocytes increased liver MGAT activity and TAG content in low-fat-fed mice but did not cause insulin resistance. Multiple Mogat1 ASO sequences improved glucose tolerance in both wild-type and Mogat1 null mice, suggesting an off-target effect. Hepatic IFNAR-1 signaling was activated by multiple Mogat1 ASOs, but its blockade did not prevent the effects of either Mogat1 ASO on glucose homeostasis.
Conclusion
These results indicate that genetic loss of Mogat1 does not affect hepatic MGAT activity or metabolic homeostasis on HFD and show that multiple Mogat1 ASOs improve glucose metabolism through effects independent of targeting Mogat1 or activation of IFNAR-1 signaling.
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