OBJECTIVE Systemic low-grade inflammation associated with obesity and metabolic syndrome is a strong risk factor for the development of diabetes mellitus and associated cardiovascular complications. This inflammatory state is caused by release of proinflammatory cytokines by macrophages, especially in adipose tissue. Long noncoding RNAs regulate macrophage activation and inflammatory gene networks, but their role in macrophage dysfunction during diet-induced obesity has been largely unexplored. Approach and Results: We sequenced total RNA from peritoneal macrophages isolated from mice fed either high-fat diet or standard diet and performed de novo transcriptome assembly to identify novel differentially expressed mRNAs and long noncoding RNAs. A top candidate long noncoding RNA, macrophage inflammation-suppressing transcript (Mist), was downregulated in both peritoneal macrophages and adipose tissue macrophages from high-fat diet-fed mice. GapmeR-mediated Mist knockdown in vitro and in vivo upregulated expression of genes associated with immune response and inflammation and increased modified LDL (low-density lipoprotein) uptake in macrophages. Conversely, Mist overexpression decreased basal and LPS (lipopolysaccharide)-induced expression of inflammatory response genes and decreased modified LDL uptake. RNA-pull down coupled with mass spectrometry showed that Mist interacts with PARP1 (poly [ADP]-ribose polymerase-1). Disruption of this RNA-protein interaction increased PARP1 recruitment and chromatin PARylation at promoters of inflammatory genes, resulting in increased gene expression. Furthermore, human orthologous MIST was also downregulated by proinflammatory stimuli, and its expression in human adipose tissue macrophages inversely correlated with obesity and insulin resistance. CONCLUSIONS Mist is a novel protective long noncoding RNA, and its loss during obesity contributes to metabolic dysfunction and proinflammatory phenotype of macrophages via epigenetic mechanisms.

中文翻译：

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新型长链非编码 RNA，巨噬细胞炎症抑制转录本 (MIST)，在肥胖期间调节巨噬细胞活化。

目标与肥胖和代谢综合征相关的全身性低度炎症是发生糖尿病和相关心血管并发症的重要危险因素。这种炎症状态是由巨噬细胞释放促炎细胞因子引起的，尤其是在脂肪组织中。长链非编码 RNA 调节巨噬细胞激活和炎症基因网络，但它们在饮食诱导肥胖期间巨噬细胞功能障碍中的作用在很大程度上尚未得到探索。方法和结果：我们对从喂食高脂肪饮食或标准饮食的小鼠体内分离的腹膜巨噬细胞的总 RNA 进行了测序，并进行了从头转录组组装以鉴定新的差异表达 mRNA 和长链非编码 RNA。顶级候选长链非编码 RNA，巨噬细胞炎症抑制转录本 (Mist)，来自高脂肪饮食喂养的小鼠的腹膜巨噬细胞和脂肪组织巨噬细胞中的 。GapmeR 介导的体外和体内 Mist 敲低上调了与免疫反应和炎症相关的基因的表达，并增加了巨噬细胞中修饰的 LDL（低密度脂蛋白）摄取。相反，Mist 过表达降低了基础和 LPS（脂多糖）诱导的炎症反应基因的表达，并降低了修饰的 LDL 摄取。RNA 下拉与质谱联用表明 Mist 与 PARP1（聚 [ADP]-核糖聚合酶-1）相互作用。这种 RNA-蛋白质相互作用的破坏增加了炎症基因启动子处的 PARP1 募集和染色质 PARylation，导致基因表达增加。此外，人类直系同源 MIST 也被促炎刺激下调，及其在人脂肪组织巨噬细胞中的表达与肥胖和胰岛素抵抗呈负相关。结论 Mist 是一种新型的保护性长链非编码 RNA，它在肥胖期间的丢失通过表观遗传机制导致巨噬细胞的代谢功能障碍和促炎表型。