Cannabinoid Receptor 1 Blockade Attenuates Obesity and Adipose Tissue Type 1 Inflammation Through miR-30e-5p Regulation of Delta-Like-4 in Macrophages and Consequently Downregulation of Th1 Cells
Cannabinoid Receptor 1 Blockade Attenuates Obesity and Adipose Tissue Type 1 Inflammation Through miR-30e-5p Regulation of Delta-Like-4 in Macrophages and Consequently Downregulation of Th1 Cells
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DOI：
10.3389/fimmu.2019.01049
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发表时间：
2019-05-10
影响因子：
7.3
通讯作者：
Nagarkatti, Mitzi
中科院分区：
文献类型：
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作者：
Miranda, Kathryn;Mehrpouya-Bahrami, Pegah;Nagarkatti, Mitzi
肥胖的特征是慢性低度炎症，导致心脏代谢疾病的发生。大麻素受体1（CB 1）拮抗剂可减轻饮食诱导的肥胖（DIO）和相关炎症，尽管所涉及的确切抗炎机制尚未完全探索。在目前的研究中，我们使用DIO干预的小鼠模型来确定CB 1拮抗剂AM 251的microRNA（miRNA，miR）介导的抗肥胖和抗炎作用。喂食高脂肪饮食（HFD）12周的DIO小鼠用AM 251（10 mg/kg）处理另外4周。HFD + AM 251小鼠经历了快速和长期的体重减轻，并减少了炎性M1脂肪组织巨噬细胞（ATM）浸润。为了研究miRNA介导的ATM调节，对来自附睾脂肪的基质血管组分（SVF）的F4/80+细胞进行miR微阵列分析。在AM 251处理的小鼠中，几种miR的差异表达与卡路里限制无关。显著地，miR-30 e-5 p在来自HFD + AM 251小鼠的ATM中上调，而miR-30 e-5 p靶标DLL 4下调。与DLL 4-Notch信号传导的减少一致，AM 251处理后脂肪储存和促炎细胞因子/趋化因子表达减少。此外，我们发现AM 251处理的巨噬细胞可以抑制DLL 4介导的CD 4 + T细胞中的Th 1极化。总之，这些数据表明，阻断CB 1受体导致ATM中miR-30 e-5 p的上调和DLL 4的下调，这反过来又抑制DLL 4-Notch信号诱导的炎性Th 1细胞极化和脂肪细胞能量储存。ATM和T细胞的这种组合作用导致抗炎状态和DIO的衰减。这些数据支持miR-30在治疗心脏代谢疾病中的治疗潜力。
Obesity is characterized by chronic low-grade inflammation that contributes to development of cardiometabolic disorders. Cannabinoid receptor 1 (CB1) antagonists attenuate diet-induced obesity (DIO) and related inflammation, although the precise anti-inflammatory mechanisms involved have not been fully explored. In the current study we used a mouse model of DIO intervention to determine the microRNA (miRNA, miR)-mediated anti-obesity and anti-inflammatory effects of the CB1 antagonist, AM251. DIO mice that were fed high-fat diet (HFD) for 12 weeks were treated with AM251 (10 mg/kg) for an additional 4 weeks. HFD + AM251 mice experienced rapid and prolonged weight loss and reduced inflammatory M1 adipose tissue macrophage (ATM) infiltration. To investigate miRNA-mediated regulation of ATMs, F4/80+ cells from stromal vascular fractions (SVF) of epididymal fat were subjected to miR microarray analysis. Several miRs were differentially expressed in AM251-treated mice that were independent of calorie restriction. Prominently, miR-30e-5p was upregulated in ATMs from HFD + AM251 mice while the miR-30e-5p target, DLL4, was downregulated. Consistent with a decrease in DLL4-Notch signaling, fat storage and pro-inflammatory cytokine/chemokine expression was reduced following AM251 treatment. Furthermore, we found that AM251-treated macrophages can suppress DLL4-mediated Th1 polarization in CD4+ T cells. Together these data demonstrate that blocking CB1 receptors leads to upregulation of miR-30e-5p and down regulation of DLL4 in ATMs, which in turn suppress DLL4-Notch signaling-induced polarization of inflammatory Th1 cells and adipocyte energy storage. This combined effect of ATMs and T cells leads to an anti-inflammatory state and attenuation of DIO. These data support therapeutic potential of miR-30 in the treatment of cardiometabolic disorders.