Comparing Transgenic Production to Supplementation of ω-3 PUFA Reveals Distinct But Overlapping Mechanisms Underlying Protection Against Metabolic and Hepatic Disorders.

IF 5.1 Q2 CELL BIOLOGY
Noëmie Daniel, Mélanie Le Barz, Patricia L Mitchell, Thibault V Varin, Isabelle Bourdeau Julien, Dominique Farabos, Geneviève Pilon, Josée Gauthier, Carole Garofalo, Jing X Kang, Jocelyn Trottier, Olivier Barbier, Denis Roy, Benoit Chassaing, Emile Levy, Frédéric Raymond, Antonin Lamaziere, Nicolas Flamand, Cristoforo Silvestri, Christian Jobin, Vincenzo Di Marzo, André Marette
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引用次数: 3

Abstract

We compared endogenous ω-3 PUFA production to supplementation for improving obesity-related metabolic dysfunction. Fat-1 transgenic mice, who endogenously convert exogenous ω-6 to ω-3 PUFA, and wild-type littermates were fed a high-fat diet and a daily dose of either ω-3 or ω-6 PUFA-rich oil for 12 wk. The endogenous ω-3 PUFA production improved glucose intolerance and insulin resistance but not hepatic steatosis. Conversely, ω-3 PUFA supplementation fully prevented hepatic steatosis but failed to improve insulin resistance. Both models increased hepatic levels of ω-3 PUFA-containing 2-monoacylglycerol and N-acylethanolamine congeners, and reduced levels of ω-6 PUFA-derived endocannabinoids with ω-3 PUFA supplementation being more efficacious. Reduced hepatic lipid accumulation associated with the endocannabinoidome metabolites EPEA and DHEA, which was causally demonstrated by lower lipid accumulation in oleic acid-treated hepatic cells treated with these metabolites. While both models induced a significant fecal enrichment of the beneficial Allobaculum genus, mice supplemented with ω-3 PUFA displayed additional changes in the gut microbiota functions with a significant reduction of fecal levels of the proinflammatory molecules lipopolysaccharide and flagellin. Multiple-factor analysis identify that the metabolic improvements induced by ω-3 PUFAs were accompanied by a reduced production of the proinflammatory cytokine TNFα, and that ω-3 PUFA supplementation had a stronger effect on improving the hepatic fatty acid profile than endogenous ω-3 PUFA. While endogenous ω-3 PUFA production preferably improves glucose tolerance and insulin resistance, ω-3 PUFA intake appears to be required to elicit selective changes in hepatic endocannabinoidome signaling that are essential to alleviate high-fat diet-induced hepatic steatosis.

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比较转基因生产和补充ω-3 PUFA揭示了不同但重叠的机制,其对代谢和肝脏疾病的保护。
我们比较了内源性ω-3 PUFA的产生和补充对改善肥胖相关代谢功能障碍的作用。脂肪-1转基因小鼠(内源性将外源性ω-6多聚脂肪酸转化为ω-3多聚脂肪酸)和野生型幼崽喂食高脂肪饮食和每天服用富含ω-3或ω-6多聚脂肪酸的油,持续12周。内源性ω-3 PUFA的产生改善了葡萄糖耐受不良和胰岛素抵抗,但没有改善肝脂肪变性。相反,ω-3 PUFA补充完全预防肝脂肪变性,但不能改善胰岛素抵抗。两种模型均增加了肝脏中含有ω-3 PUFA的2-单酰基甘油和n -酰基乙醇胺同源物的水平,并降低了ω-6 PUFA衍生的内源性大麻素水平,其中ω-3 PUFA补充效果更好。减少肝脏脂质积累与内源性大麻素代谢产物EPEA和脱氢表雄酮有关,这是由油酸处理的肝细胞中脂质积累降低与这些代谢物处理的因果关系。虽然两种模型都诱导了粪便中有益的异杆菌属的显著富集,但补充ω-3 PUFA的小鼠肠道微生物群功能发生了额外的变化,粪便中促炎分子脂多糖和鞭毛蛋白的水平显著降低。多因素分析发现,ω-3 PUFA诱导的代谢改善伴随着促炎细胞因子TNFα的减少,ω-3 PUFA补充比内源性ω-3 PUFA对肝脏脂肪酸谱的改善作用更强。虽然内源性ω-3 PUFA的产生可以改善葡萄糖耐量和胰岛素抵抗,但ω-3 PUFA的摄入似乎需要引起肝内源性大麻素组信号的选择性改变,这对于减轻高脂肪饮食引起的肝脂肪变性至关重要。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
5.70
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