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首页> 外文期刊>The journal of clinical investigation >Lipid-induced insulin resistance mediated by the proinflammatory receptor TLR4 requires saturated fatty acid–induced ceramide biosynthesis in mice
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Lipid-induced insulin resistance mediated by the proinflammatory receptor TLR4 requires saturated fatty acid–induced ceramide biosynthesis in mice

机译：促炎性受体TLR4介导的脂质诱导的胰岛素抵抗需要小鼠中饱和脂肪酸诱导的神经酰胺生物合成

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摘要

Obesity is associated with an enhanced inflammatory response that exacerbates insulin resistance and contributes to diabetes, atherosclerosis, and cardiovascular disease. One mechanism accounting for the increased inflammation associated with obesity is activation of the innate immune signaling pathway triggered by TLR4 recognition of saturated fatty acids, an event that is essential for lipid-induced insulin resistance. Using in vitro and in vivo systems to model lipid induction of TLR4-dependent inflammatory events in rodents, we show here that TLR4 is an upstream signaling component required for saturated fatty acid–induced ceramide biosynthesis. This increase in ceramide production was associated with the upregulation of genes driving ceramide biosynthesis, an event dependent of the activity of the proinflammatory kinase IKKβ. Importantly, increased ceramide production was not required for TLR4-dependent induction of inflammatory cytokines, but it was essential for TLR4-dependent insulin resistance. These findings suggest that sphingolipids such as ceramide might be key components of the signaling networks that link lipid-induced inflammatory pathways to the antagonism of insulin action that contributes to diabetes.
机译：肥胖与炎症反应增强有关，炎症反应加剧胰岛素抵抗并导致糖尿病，动脉粥样硬化和心血管疾病。解决肥胖症相关炎症增加的一种机制是激活TLR4识别饱和脂肪酸触发的先天性免疫信号通路，这是脂质诱导的胰岛素抵抗所必需的事件。使用体外和体内系统对啮齿类动物中TLR4依赖性炎症事件的脂质诱导进行建模，我们在这里显示TLR4是饱和脂肪酸诱导的神经酰胺生物合成所需的上游信号成分。神经酰胺产量的增加与驱动神经酰胺生物合成的基因上调相关，该事件取决于促炎激酶IKKβ的活性。重要的是，TLR4依赖性炎性细胞因子的诱导不需要增加神经酰胺的产生，但对于TLR4依赖性胰岛素抵抗而言，这是必不可少的。这些发现表明，鞘脂（如神经酰胺）可能是信号传导网络的关键组成部分，这些信号传导网络将脂质诱导的炎症途径与促成糖尿病的胰岛素作用的拮抗作用联系起来。

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