目的 探究转化生长因子-β激活激酶1（TAK1）抑制剂5Z-7-氧杂烯醇对肥胖大鼠p38丝裂原活化蛋白激酶（p38 MAPK）/核因子κB（NF-κB）通路及代谢紊乱的影响。方法 肥胖大鼠模型由高脂饲料喂养法构建，并随机分为模型组、5Z-7-氧杂烯醇（1、3 mg/kg）组及5Z-7-氧杂烯醇（3 mg/kg）＋p38 MAPK/NF-κB通路激活剂（Anisomycin 5 mg/kg）组，另设对照组，以普通饲料喂养，每组10只。检测大鼠体质量、体长、Lee’s指数、摄食量、空腹血糖（FBG）、血脂[总胆固醇（TC）、三酰甘油（TG）、低密度脂蛋白胆固醇（LDL-C）、高密度脂蛋白胆固醇（HDL-C）]、空腹胰岛素（FINS）、稳态模型胰岛素抵抗指数（HOMA-IR）及血清瘦素、脂联素、丙氨酸氨基转移酶（ALT）、天门冬氨酸氨基转移酶（AST）、肿瘤坏死因子-α（TNF-α）和白细胞介素-6（IL-6）水平；观察肝脏与附睾脂肪组织病理形态；测定肝脏组织TG、TC含量及TAK1/p38 MAPK/NF-κB通路蛋白磷酸化水平。结果 与模型组比较，5Z-7-氧杂烯醇各剂量组体质量、Lee’指数、FBG、TC、TG、LDL-C、FINS、HOMA-IR、瘦素、ALT、AST、TNF-α、IL-6、肝脏脂质含量、脂肪细胞平均面积及p-TAK1/TAK1、p-p38 MAPK/p38 MAPK、p-NF-κB/NF-κB蛋白表达均显著降低，HDL-C、脂联素水平显著升高（P＜0.05）。Anisomycin可显著逆转5Z-7-氧杂烯醇3 mg/kg组对多数代谢指标及p-p38 MAPK/p38 MAPK、p-NF-κB/NF-κB蛋白表达的影响（P＜0.05）。结论 5Z-7-氧杂烯醇可能通过抑制p38 MAPK/NF-κB通路改善肥胖大鼠代谢紊乱。

Objective To investigate the effect of TAK1 inhibitor 5Z-7-oxozeaenol on the p38 MAPK/NF-κB pathway and metabolic disorders in obese rats. Methods Obese rat model established using a high-fat diet were randomly assigned to the model group, 5Z-7-oxozeaenol (1, 3 mg/kg) groups, 5Z-7-oxozeaenol (3 mg/kg) + p38 MAPK/NF-κB pathway activator (Anisomycin 5 mg/kg) group. An additional control group was set up, which was fed with ordinary diet, with 10 rats in each group. Body weight, body length, Lee’s index, feed intake, and levels of FBG, blood lipids index (TC, TG, LDL-C, HDL-C), FINS, HOMA-IR, leptin, adiponectin, ALT, AST, TNF-α, and IL-6 of rats were measured. Histopathological morphology of liver and epididymal white adipose tissue was observed. Hepatic TG and TC contents were assessed, along with the phosphorylation levels of TAK1/p38 MAPK/NF-κB pathway proteins. Results Compared with the model group, body weight, Lee’s index, serum levels of FBG, TC, TG, LDL-C, FINS, HOMA-IR, leptin, ALT, AST, TNF-α, and IL-6, hepatic lipid content, average area of fat cells, and protein levels of p-TAK1/TAK1, p-p38 MAPK/p38 MAPK, and p-NF-κB/NF-κB were decreased, while HDL-C and adiponectin were increased in the 5Z-7-oxozeaenol groups (P < 0.05). Anisomycin markedly reversed the improvements induced by 5Z-7-oxozeaenol 3 mg/kg group on most metabolic parameters and protein levels of p-p38 MAPK/p38 MAPK and p-NF-κB/NF-κB (P < 0.05). Conclusion 5Z-7-oxozeaenol may ameliorate metabolic disorders in obese rats by suppressing the p38 MAPK/NF-κB signaling pathway.

R977

河南省医学科技攻关计划项目（LHGJ20240877）