肥胖是世界范围内的主要公共卫生问题,会导致脂肪组织出现炎症和胰岛素抵抗。我们研究了从马齿苋中分离的 ( E )-5-hydroxy-7-methoxy-3-(2'-hydroxybenzyl)-4-chromanone (HM-chromanone) 的能力减弱与肿瘤坏死因子 (TNF)-α 介导的炎症和 3T3-L1 脂肪细胞中的胰岛素抵抗相关的炎性细胞因子和信号通路的激活。TNF-α 触发炎性细胞因子的释放和丝裂原活化蛋白激酶和核因子 (NF)-κB 信号通路的激活。在这项研究中,HM-色原酮抑制炎症细胞因子和趋化因子 [TNF-α、白细胞介素 (IL)-6、IL-1β 和单核细胞趋化蛋白 1] 的产生,这些因子与炎症和胰岛素抵抗有关。此外,TNF-α 处理增加了 c-Jun-NH2 末端激酶 (JNK) 磷酸化,而 HM-色满酮以剂量依赖性方式显着降低了 JNK 磷酸化。TNF-α 治疗增加了抑制剂 kappa B (IκB) 激酶 (IKK)、IκBα、和 NF-κBp65 与对照相比。然而,HM-色原酮显着阻断了 IKK、IκBα 和 NF-κBp65 的活化。与对照组相比,用 TNF-α 刺激脂肪细胞后,磷酸化胰岛素受体底物 (pIRS)-1 丝氨酸 307 水平升高,而 pIRS-1 酪氨酸 612 水平降低。在用 HM-色原酮处理后,IRS-1 的丝氨酸 307 磷酸化被抑制,IRS-1 的酪氨酸 612 磷酸化增加。因此,HM-色原酮通过调节 JNK 活化和 NF-κB 通路改善 TNF-α 介导的炎症和胰岛素抵抗,从而减少炎性细胞因子分泌并抑制胰岛素信号通路中 IRS-1 的丝氨酸磷酸化。这些结果表明 HM-色满酮具有改善脂肪细胞炎症状况和胰岛素抵抗的潜力。
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HM-chromanone attenuates TNF-α-mediated inflammation and insulin resistance by controlling JNK activation and NF-κB pathway in 3T3-L1 adipocytes
Obesity is a major public health problem worldwide and causes inflammation and insulin resistance in adipose tissue. We investigated the ability of (E)-5-hydroxy-7-methoxy-3-(2′-hydroxybenzyl)-4-chromanone (HM-chromanone) isolated from Portulaca oleracea to attenuate the activation of inflammatory cytokines and signaling pathways associated with tumor necrosis factor (TNF)-α-mediated inflammation and insulin resistance in 3T3-L1 adipocytes. TNF-α triggers the release of inflammatory cytokines and activation of the mitogen-activated protein kinase and nuclear factor (NF)-κB signaling pathways. In this study, HM-chromanone inhibited the production of inflammatory cytokines and chemokines [TNF-α, interleukin (IL)-6, IL-1β, and monocyte chemoattractant protein 1] involved in inflammation and insulin resistance. Furthermore, TNF-α treatment increased c-Jun-NH2 terminal kinase (JNK) phosphorylation, whereas HM-chromanone significantly decreased JNK phosphorylation in a dose-dependent manner. TNF-α treatment increased the activation of inhibitor kappa B (IκB) kinase (IKK), IκBα, and NF-κBp65 compared with that of the control. However, HM-chromanone significantly blocked IKK, IκBα, and NF-κBp65 activation. Upon adipocyte stimulation with TNF-α, phosphorylated insulin receptor substrate (pIRS)-1 serine 307 levels increased and pIRS-1 tyrosine 612 levels decreased compared with those of the control. Upon treatment with HM-chromanone, serine 307 phosphorylation of IRS-1 was inhibited and tyrosine 612 phosphorylation of IRS-1 was increased. Thus, HM-chromanone improved TNF-α-mediated inflammation and insulin resistance by regulating JNK activation and the NF-κB pathway, thereby reducing inflammatory cytokine secretion and inhibiting serine phosphorylation of IRS-1 in the insulin signaling pathway. These results suggest the potential of HM-chromanone to improve inflammatory conditions and insulin resistance in adipocytes.