Life Sciences ( IF 6.1 ) Pub Date : 2020-09-17 , DOI: 10.1016/j.lfs.2020.118424 Qiong Wu 1 , Yanan Ma 2 , Yang Liu 3 , Ningning Wang 4 , Xin Zhao 5 , Deliang Wen 3
Aims
Cannabinoid receptor 2 (CB2R) is an important regulator of immunoinflammatory responses. Interestingly, studies have demonstrated that CB2R was expressed in metabolically active tissue, so we speculated that CB2R might have a crucial impact on energy balance. We thus examined the anti-inflammatory activities of CB2R and a CB2R agonist, JWH-133, in diet-induced obese in mice as well as in cultured macrophages.
Materials and methods
We evaluated the in vivo effect of JWH-133 on diet-induced adipose tissue inflammation. We also assessed the in vitro effects of JWH-133 on lipopolysaccharide (LPS)-induced inflammation in RAW264.7 macrophages, with a focus on the nuclear factor E2-related factor 2/heme oxygenase 1 (Nrf2/HO-1) signaling pathway.
Key findings
We found that JWH-133 reduced body weight gain, relieved glucose tolerance, and enhanced insulin sensitivity in a mouse model. It also down-regulated the expression of M1 macrophage biomarkers (tumor necrosis factor-α, interleukin (IL)-6, inducible nitric oxide synthase (iNOS), IL-1β, CC motif chemokine ligand 2, and C-X-C motif chemokine 10) in vivo and in vitro, but up-regulated levels of M2 macrophage biomarkers (IL-10 and arginase-1) in both mice and cultured macrophages. Furthermore, the underlying mechanisms were studied in an LPS-treated RAW264.7 cell line. We found a role for JWH-133 in controlling M1 macrophage polarization by activating the Nrf2/HO-1 pathway, while the effect of JWH-133 was diminished by a HO-1 inhibitor, Sn(IV) protoporphyrin IX dichloride.
Significance
JWH-133 showed anti-obesity effects that ameliorated pro-inflammatory M1 macrophage polarization through the Nrf2/HO-1 pathway. Therefore, our results provide a new proof for the potential use of the CB2R agonist, JWH-133, in the treatment of obesity.
中文翻译:
CB2R 激动剂 JWH-133 通过在饮食诱导的肥胖小鼠中通过 Nrf2/HO-1 通路抑制 M1 巨噬细胞极化来减轻慢性炎症。
宗旨
大麻素受体 2 (CB2R) 是免疫炎症反应的重要调节剂。有趣的是,研究表明 CB2R 在代谢活跃的组织中表达,因此我们推测 CB2R 可能对能量平衡产生关键影响。因此,我们检查了 CB2R 和 CB2R 激动剂 JWH-133 在饮食诱导的肥胖小鼠以及培养的巨噬细胞中的抗炎活性。
材料和方法
我们评估了 JWH-133 对饮食诱导的脂肪组织炎症的体内影响。我们还评估了 JWH-133 对 RAW264.7 巨噬细胞中脂多糖 (LPS) 诱导的炎症的体外影响,重点是核因子 E2 相关因子 2/血红素加氧酶 1 (Nrf2/HO-1) 信号通路.
主要发现
我们发现 JWH-133 在小鼠模型中减少了体重增加、减轻了葡萄糖耐量并增强了胰岛素敏感性。它还下调 M1 巨噬细胞生物标志物(肿瘤坏死因子-α、白细胞介素 (IL)-6、诱导型一氧化氮合酶 (iNOS)、IL-1β、C C 基序趋化因子配体 2 和 CXC 基序趋化因子 10)的表达在体内和体外,但上调小鼠和培养巨噬细胞中 M2 巨噬细胞生物标志物(IL-10 和精氨酸酶-1)的水平。此外,在 LPS 处理的 RAW264.7 细胞系中研究了潜在机制。我们发现 JWH-133 通过激活 Nrf2/HO-1 通路在控制 M1 巨噬细胞极化中起作用,而 JWH-133 的作用被 HO-1 抑制剂 Sn(IV) 原卟啉 IX 二氯化物减弱。
意义
JWH-133 显示出抗肥胖作用,通过 Nrf2/HO-1 通路改善促炎 M1 巨噬细胞极化。因此,我们的结果为 CB2R 激动剂 JWH-133 在治疗肥胖症中的潜在用途提供了新的证据。