Oxidised metabolites of the omega-6 fatty acid linoleic acid activate dFOXO

So Yeon Kwon, Karen Massey, Mark A Watson, Tayab Hussain, Giacomo Volpe, Christopher D Buckley, Anna Nicolaou, Paul Badenhorst

Research output: Contribution to journalArticlepeer-review


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.
Original languageEnglish
Pages (from-to)e201900356
JournalLife Science Alliance
Issue number2
Early online date28 Jan 2020
Publication statusPublished - 1 Feb 2020


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