Oxidised metabolites of the omega-6 fatty acid linoleic acid activate dFOXO.
So Yeon KwonKaren MasseyMark A WatsonTayab HussainGiacomo VolpeChristopher Dominic BuckleyAnna NicolaouPaul BadenhorstPublished in: Life science alliance (2020)
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.
Keyphrases
- fatty acid
- type diabetes
- signaling pathway
- oxidative stress
- insulin resistance
- metabolic syndrome
- transcription factor
- cardiovascular disease
- glycemic control
- pi k akt
- weight loss
- adipose tissue
- induced apoptosis
- risk factors
- diabetic rats
- weight gain
- high fat diet
- dna damage
- high fat diet induced
- single cell
- cardiovascular risk factors
- rna seq
- cell proliferation
- binding protein
- cardiovascular events
- drug induced