Protectin DX ameliorates palmitate- or high-fat diet-induced insulin resistance and inflammation through an AMPK-PPARα-dependent pathway in mice.
Protectin DX ameliorates palmitate- or high-fat diet-induced insulin resistance and inflammation through an AMPK-PPARα-dependent pathway in mice.
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DOI：
10.1038/s41598-017-01603-9
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发表时间：
2017-05-03
影响因子：
4.6
通讯作者：
Jeong JH
中科院分区：
文献类型：
--
作者：
Jung TW;Kim HC;Abd El-Aty AM;Jeong JH
Protectin DX（PDX）是二十二碳六烯酸的双脂氧合酶衍生物，据报道可减轻炎症和胰岛素抵抗。本研究通过腺苷酸活化蛋白激酶（AMPK）和过氧化物酶体增殖物激活受体α（PPARα）探讨PDX对高血压诱导的胰岛素抵抗和炎症的影响。PDX减弱了棕榈酸酯处理的分化C2 C12细胞和HFD喂养小鼠比目鱼肌骨骼肌中胰岛素受体底物1/Akt介导的胰岛素信号传导的损伤。此外，PDX治疗显著改善了HFD诱导的体重增加，并改善了小鼠的葡萄糖耐量。在体外和体内模型中，PDX均显著减弱核因子kB核转位、抑制性kBα磷酸化和促炎细胞因子的表达。PDX处理显著增加C2 C12细胞和小鼠骨骼肌中AMPK磷酸化和PPARα表达。AMPK和PPARα特异性siRNA显著消除了PDX对棕榈酸诱导的胰岛素抵抗和炎症的抑制作用。此外，PDX显着刺激脂肪酸氧化相关基因的表达。AMPK和PPARα siRNA可显著抑制PDX的上述作用。总之，我们的研究结果表明，PDX改善胰岛素抵抗和炎症，并通过AMPK和PPARα介导的途径刺激骨骼肌中的脂肪酸氧化。
Protectin DX (PDX), a double lipoxygenase derivative of docosahexaenoic acid, has been reported to attenuate inflammation and insulin resistance. In the current study, we explored the effects of PDX on hyperlipidemia-induced insulin resistance and inflammation through AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor α (PPARα). PDX attenuated the impairment of insulin receptor substrate 1/Akt–mediated insulin signaling in palmitate-treated differentiated C2C12 cells and soleus skeletal muscle of HFD-fed mice. Furthermore, PDX treatment significantly ameliorated HFD-induced weight gain and improved glucose tolerance in mice. Nuclear factor kB nuclear translocation, inhibitory kBα phosphorylation, and expression of proinflammatory cytokines were markedly attenuated by PDX in both in vitro and in vivo models. PDX treatment markedly augmented AMPK phosphorylation and PPARα expression in C2C12 cells and in skeletal muscle of mice. AMPK- and PPARα-specific siRNAs significantly abrogated the suppressive effects of PDX on palmitate-induced insulin resistance and inflammation. Furthermore, PDX markedly stimulated the expression of genes related to fatty acid oxidation. These effects of PDX were significantly suppressed by AMPK and PPARα siRNAs. In conclusion, our results demonstrate that PDX ameliorates insulin resistance and inflammation and stimulates fatty acid oxidation through AMPK- and PPARα-mediated pathways in skeletal muscle.