RT Journal Article SR Electronic T1 Oxidised metabolites of the omega-6 fatty acid linoleic acid activate dFOXO JF Life Science Alliance JO Life Sci. Alliance FD Life Science Alliance LLC SP e201900356 DO 10.26508/lsa.201900356 VO 3 IS 2 A1 So Yeon Kwon A1 Karen Massey A1 Mark A Watson A1 Tayab Hussain A1 Giacomo Volpe A1 Christopher D Buckley A1 Anna Nicolaou A1 Paul Badenhorst YR 2020 UL https://www.life-science-alliance.org/content/3/2/e201900356.abstract AB 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.