Institute of Cancer and Genomic Sciences, University of Birmingham, Edgbaston, UK.
Bradford School of Pharmacy, University of Bradford, Bradford, UK.
Life Sci Alliance. 2020 Jan 28;3(2). doi: 10.26508/lsa.201900356. Print 2020 Feb.
Obesity-induced inflammation, or meta-inflammation, plays key roles in metabolic syndrome and is a significant risk factor in diabetes and cardiovascular disease. To investigate causal links between obesity, meta-inflammation, and insulin signaling we established a model to determine how elevated dietary fat and changes in the levels and balance of saturated fatty acids (SFAs) and polyunsaturated fatty acids (PUFAs) influence inflammation. We observe negligible effect of saturated fatty acid on inflammation but marked enhancement or suppression by omega-6 and omega-3 PUFAs, respectively. Using combined lipidomic and genetic analysis, we show omega-6 PUFA enhances meta-inflammation by producing linoleic acid-derived lipid mediator 9-hydroxy-octadecadienoic acid (9-HODE). Transcriptome analysis reveals 9-HODE functions by regulating FOXO family transcription factors. We show 9-HODE activates JNK, triggering FOXO nuclear localisation and chromatin binding. FOXO TFs are important transducers of the insulin signaling pathway that are normally down-regulated by insulin. By activating FOXO, 9-HODE could antagonise insulin signaling providing a molecular conduit linking changes in dietary fatty acid balance, meta-inflammation, and insulin resistance.
肥胖引起的炎症，或代谢炎症，在代谢综合征中起着关键作用，是糖尿病和心血管疾病的重要危险因素。为了研究肥胖、代谢炎症和胰岛素信号之间的因果关系，我们建立了一个模型来确定升高的饮食脂肪以及饱和脂肪酸（SFAs）和多不饱和脂肪酸（PUFAs）水平和平衡的变化如何影响炎症。我们观察到饱和脂肪酸对炎症几乎没有影响，但ω-6 和 ω-3 PUFAs 分别有明显的增强或抑制作用。通过联合脂质组学和遗传分析，我们表明 ω-6 PUFA 通过产生来源于亚油酸的脂质介质 9-羟基-十八碳二烯酸（9-HODE）来增强代谢炎症。转录组分析表明 9-HODE 通过调节 FOXO 家族转录因子来发挥作用。我们表明 9-HODE 激活 JNK，引发 FOXO 的核定位和染色质结合。FOXO TFs 是胰岛素信号通路的重要转导因子，通常被胰岛素下调。通过激活 FOXO，9-HODE 可以拮抗胰岛素信号，为饮食中脂肪酸平衡、代谢炎症和胰岛素抵抗的变化提供分子连接。
