Adipogenic miR-27a in adipose tissue upregulates macrophage activation via inhibiting PPARγ of insulin resistance induced by high-fat diet-associated obesity
Adipogenic miR-27a in adipose tissue upregulates macrophage activation via inhibiting PPARγ of insulin resistance induced by high-fat diet-associated obesity
复制标题
脂肪组织中的成脂 miR-27a 通过抑制高脂饮食相关肥胖引起的胰岛素抵抗的 PPAR γ 上调巨噬细胞活化
DOI：
10.1016/j.yexcr.2017.03.060
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发表时间：
2017-06-15
影响因子：
3.7
通讯作者：
Chen, Li
中科院分区：
文献类型：
--
作者：
Yao, Fan;Yu, Yang;Chen, Li
巨噬细胞活化引起的慢性低度炎症是肥胖引起胰岛素抵抗的关键因素。为了阐明脂肪组织中巨噬细胞活化的调节机制，我们评估了脂肪生成 miR-27a 通过阻断 PPAR γ 激活 M1 巨噬细胞极化的作用。建立肥胖小鼠模型和miR-27a过表达或敲低小鼠模型并检测相关生化指标。对Raw264.7和3T3-L1进行培养和共培养，以模拟局部炎症的微环境。观察到巨噬细胞浸润。测量血清和脂肪组织中的 MiR-27a 和细胞因子水平。观察巨噬细胞极化标志物和胰岛素或炎症信号通路中的蛋白质表达。在 4 周、8 周和 12 周的高脂肪饮食和 miR-27a 过表达小鼠中观察到葡萄糖耐量和胰岛素耐量受损。同时，血清中的 miR-27a 以时间依赖性方式增加，脂肪组织中的 M1 细胞因子和 M1 巨噬细胞明显增加。胰岛素信号通路被阻断，PPARγ被抑制。然而，NF-κ B 被激活。另一方面，miR-27a诱导的活化巨噬细胞和肥大脂肪细胞可以增加Raw264.7迁移的比例，包括改善细胞因子的产生，并显着阻断PPARγ表达。目前的研究旨在阐明肥胖中促炎细胞因子生成、巨噬细胞流入和 M1 巨噬细胞极化过程中 miR-27a 随上调而增加。这些表明 miR-27a 提供了干预肥胖炎症和胰岛素抵抗的新靶点。
Chronic low degree inflammation caused by macrophage activation is a crucial factor underlying insulin resistance induced by obesity. To illustrate the mechanism of regulating of macrophage activation in adipose tissue, the role of adipogenic miR-27a activating M1 macrophage polarization via blocking PPAR gamma was evaluated. Obese mice model and miR-27a overexpression or knockdown mice model were established and related biochemical index were examined. Raw264.7 and 3T3-L1 were cultured and co-cultured for mimicking the microenvironment of local inflammation. Macrophage infiltration was observed. MiR-27a and cytokines levels in serum and adipose tissue were measured. Macrophage polarization markers and protein expression in insulin or inflammatory signaling pathways were observed. Impaired glucose tolerance and insulin tolerance was observed in 4w, 8w and 12w of high fat diet and miR-27a overexpression mice. Concurrently, miR-27a was increased in serum in a time-dependent manner, along with M1 cytokines and M1 macrophages increasing in adipose tissue clearly. Insulin signaling pathway was blocked, and PPAR gamma was suppressed. However, NF-kappa B was activated. On the other hand, activated macrophages and hypertrophic adipocytes induced by miR-27a could increase the ratio of Raw264.7 migration, including improving cytokines generation, and blocking PPAR gamma expression markedly. The present studies are conducted to clarify that miR-27a has increased along with up regulation in the process of proinflammatory cytokines generation, macrophage influx and M1 macrophage polarization in obesity. These indicate that miR-27a gives the novel target of intervention for inflammation and insulin resistance in obesity.