TY - JOUR T1 - Oxidised metabolites of the omega-6 fatty acid linoleic acid activate dFOXO JF - Life Science Alliance JO - Life Sci. Alliance DO - 10.26508/lsa.201900356 VL - 3 IS - 2 SP - e201900356 AU - So Yeon Kwon AU - Karen Massey AU - Mark A Watson AU - Tayab Hussain AU - Giacomo Volpe AU - Christopher D Buckley AU - Anna Nicolaou AU - Paul Badenhorst Y1 - 2020/02/01 UR - https://www.life-science-alliance.org/content/3/2/e201900356.abstract N2 - 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 Drosophila 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. ER -