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

Research output: Contribution to journalArticle

Colleges, School and Institutes

Abstract

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 saturated (SFA) and polyunsaturated fatty acid (PUFA) balance influence inflammation.
We observe negligible effect of SFA 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 mediators 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.

Details

Original languageEnglish
Article numbere201900356
JournalLife Science Alliance
Volume3
Issue number2
Publication statusPublished - 28 Jan 2020