Institute of Health Sciences, China Medical University, No.77 Puhe Road, Shenyang, Liaoning Province 110122, PR China; Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province 110004, PR China.
School of Public Health, China Medical University, Shenyang, Liaoning Province 110122, PR China.
Life Sci. 2020 Nov 1;260:118424. doi: 10.1016/j.lfs.2020.118424. Epub 2020 Sep 17.
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.
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.
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.
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.
大麻素受体 2 (CB2R) 是免疫炎症反应的重要调节因子。有趣的是，研究表明 CB2R 表达于代谢活跃的组织中，因此我们推测 CB2R 可能对能量平衡有至关重要的影响。我们因此在饮食诱导肥胖的小鼠以及培养的巨噬细胞中研究了 CB2R 和 CB2R 激动剂 JWH-133 的抗炎活性。
我们评估了 JWH-133 对饮食诱导的脂肪组织炎症的体内作用。我们还评估了 JWH-133 在 RAW264.7 巨噬细胞中对脂多糖 (LPS) 诱导的炎症的体外作用，重点关注核因子 E2 相关因子 2/血红素加氧酶 1 (Nrf2/HO-1) 信号通路。
我们发现 JWH-133 降低了小鼠模型中的体重增加，改善了葡萄糖耐量，并增强了胰岛素敏感性。它还在体内和体外下调了 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)、白细胞介素-1β、CC 基序趋化因子配体 2 和 C-X-C 基序趋化因子 10）的表达，但上调了 M2 巨噬细胞生物标志物（白细胞介素-10 和精氨酸酶-1）的表达。此外，在 LPS 处理的 RAW264.7 细胞系中研究了潜在的机制。我们发现 JWH-133 通过激活 Nrf2/HO-1 通路来控制 M1 巨噬细胞极化，而 HO-1 抑制剂 Sn(IV)原卟啉 IX 二氯化物则减弱了 JWH-133 的作用。
JWH-133 显示出抗肥胖作用，通过 Nrf2/HO-1 通路改善了促炎 M1 巨噬细胞极化。因此，我们的结果为 CB2R 激动剂 JWH-133 在肥胖治疗中的潜在用途提供了新的证据。
