Transgenic restoration of long-chain n-3 fatty acids in insulin target tissues improves resolution capacity and alleviates obesity-linked inflammation and insulin resistance in high-fat-fed mice.
Transgenic restoration of long-chain n-3 fatty acids in insulin target tissues improves resolution capacity and alleviates obesity-linked inflammation and insulin resistance in high-fat-fed mice.
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作者：
White PJ;Arita M;Taguchi R;Kang JX;Marette A
炎症的缓解是由n-3衍生的促消退脂质介质指导的主动过程。我们的目的是确定高脂饮食诱导的n-3缺乏是否会损害肥胖小鼠的分辨能力，从而导致肥胖相关的炎症和胰岛素抵抗。我们利用转基因表达的脂肪酸去饱和酶fat-1 n-3从C. elegans内源性恢复HF喂养的小鼠中的n-3脂肪酸。在HF或普通食物饮食8周后，对野生型和fat-1转基因小鼠进行胰岛素和葡萄糖耐量试验，并进行分辨率测定。然后收获代谢组织用于生化分析。我们报告说，n-3类二十二烷分辨率介质保护素D1是缺乏HF喂养的野生型小鼠的肌肉和脂肪组织。因此，HF-喂养的野生型小鼠具有受损的能力，以解决急性炎症反应，并显示脂肪巨噬细胞增加和趋化因子/细胞因子表达升高。这与胰岛素抵抗以及肌肉和肝脏中iNOS和JNK的较高活化有关。这些缺陷在HF喂养的fat-1小鼠中被逆转，其中这种重要的n-3二十二烷类化合物分解介质的生物合成得到改善。重要的是，n-3脂肪酸的转基因恢复在HF喂养的小鼠中预防了肥胖相关的炎症和胰岛素抵抗，而不改变食物摄入、体重增加或肥胖。我们的结论是，在肌肉和脂肪组织中的n-3分辨率介质的生物合成效率低下，有助于维持慢性炎症的肥胖，这些新的脂质提供了令人兴奋的潜力，用于治疗胰岛素抵抗和糖尿病。
The catabasis of inflammation is an active process directed by n-3 derived pro-resolving lipid mediators. We aimed to determine whether high-fat (HF) diet-induced n-3 deficiency compromises the resolution capacity of obese mice and thereby contributes to obesity-linked inflammation and insulin resistance. We used transgenic expression of the fat-1 n-3 fatty acid desaturase from C. elegans to endogenously restore n-3 fatty acids in HF-fed mice. After 8 weeks on HF or chow diets, wild-type and fat-1 transgenic mice were subjected to insulin and glucose tolerance tests and a resolution assay was performed. Metabolic tissues were then harvested for biochemical analyses. We report that the n-3 docosanoid resolution mediator protectin D1 is lacking in muscle and adipose tissue of HF-fed wild-type mice. Accordingly, HF-fed wild-type mice have an impaired capacity to resolve an acute inflammatory response and display elevated adipose macrophage accrual and chemokine/cytokine expression. This is associated with insulin resistance and higher activation of iNOS and JNK in muscle and liver. These defects are reversed in HF-fed fat-1 mice, in which the biosynthesis of this important n-3 docosanoid resolution mediator is improved. Importantly, transgenic restoration of n-3 fatty acids prevented obesity-linked inflammation and insulin resistance in HF-fed mice without altering food intake, weight gain, or adiposity. We conclude that inefficient biosynthesis of n-3 resolution mediators in muscle and adipose tissue contributes to the maintenance of chronic inflammation in obesity and that these novel lipids offer exciting potential for the treatment of insulin resistance and diabetes.