Adipocyte-derived microvesicles from obese mice induce M1 macrophage phenotype through secreted miR-155
Adipocyte-derived microvesicles from obese mice induce M1 macrophage phenotype through secreted miR-155
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肥胖小鼠脂肪细胞来源的微泡通过分泌 miR-155 诱导 M1 巨噬细胞表型
DOI：
10.1093/jmcb/mjw040
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发表时间：
2016
影响因子：
5.5
通讯作者：
Han Xiao
中科院分区：
文献类型：
--
作者：
Zhang Yaqin;Mei Hongliang;Chang Xiaoai;Chen Fang;Zhu Yunxia;Han Xiao
脂肪组织中M1巨噬细胞聚集的促炎状态是导致肥胖代谢并发症的中心事件。然而，在体重增加过程中，M1巨噬细胞在脂肪组织中浓缩的机制仍不完全清楚。在这里，我们研究了脂肪细胞来源的微囊泡(ADM)对小鼠巨噬细胞表型的调节作用，并探索了相关的分子信号通路。我们发现，与瘦小鼠来源的ADM(SD ADM)相比，肥胖小鼠的ADM(HFD ADM)显著增强M1标记物的表达。定量RT-PCR检测表明，在HFD ADM和HFD ADM处理的巨噬细胞中miR-155表达上调。通过抑制HFD ADM中miR-155的表达和上调SD ADM中miR-155的水平，我们进一步阐明了miR-155在ADM诱导的M1巨噬细胞极化中的作用。从功能上讲，与SD ADM相比，HFD ADM显著降低了已被证实的miR-155靶标MSOCS1的蛋白质水平，导致STAT1激活，并抑制STAT6信号转导；这些作用可通过沉默HFD ADM中的miR-155而逆转。此外，含有miR-155的ADM预先刺激骨髓来源的巨噬细胞的上清干扰了胰岛素信号和胰岛素诱导的脂肪细胞的葡萄糖摄取。总之，这些结果提供了第一个证据，表明M1巨噬细胞的极化可以由携带miR-155的ADM介导，它相互调节脂肪细胞中的胰岛素信号和葡萄糖摄取。我们的研究揭示了一种新的机制，肥胖通过诱导脂肪组织中M1/M2巨噬细胞比例的失衡，从而导致慢性炎症和局部胰岛素抵抗。
The pro-inflammatory profile of M1 macrophage accumulation in adipose tissue is a central event leading to the metabolic complications of obesity. However, the mechanisms by which M1 macrophages are enriched in adipose tissue during weight gain remain incompletely understood. Here, we investigated the effects of adipocyte-derived microvesicles (ADM) on modulating macrophage phenotype in mice and explored the involved molecular signalling pathways. We found that, compared with ADM from lean mice (SD ADM), ADM from obese mice (HFD ADM) significantly enhanced M1 marker expression. The quantitative RT-PCR assay demonstrated that miR-155 was upregulated in both HFD ADM and HFD ADM-treated macrophages. By depleting miR-155 expression in HFD ADM and increasing miR-155 level in SD ADM, we further illustrated that miR-155 in ADM-induced M1 macrophage polarization. Functionally, in contrast to SD ADM, HFD ADM significantly decreased the protein level of SOCS1, a proven miR-155 target, leading to activation of STAT1, and suppression of STAT6 signalling; these effects were reversed by silencing miR-155 in HFD ADM. Furthermore, the supernatant of bone marrow-derived macrophages pre-stimulated with miR-155-bearing ADM interfered with insulin signalling and insulin-induced glucose uptake in adipocytes. Collectively, these results provide the first evidence that M1 macrophage polarization can be mediated by miR-155-bearing ADM, which reciprocally regulates insulin signalling and glucose uptake in adipocytes. Our study reveals a novel mechanism through which obesity induces an imbalance in the M1-to-M2 macrophage ratio in adipose tissue, thus causing chronic inflammation and local insulin resistance.