RESUMEN
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.
Asunto(s)
Proteínas de Drosophila/metabolismo , Drosophila/metabolismo , Proteína Forkhead Box O3/metabolismo , Factores de Transcripción Forkhead/metabolismo , Ácido Linoleico/metabolismo , Obesidad/metabolismo , Animales , Animales Modificados Genéticamente , Núcleo Celular/metabolismo , Cromatina/metabolismo , Grasas de la Dieta/efectos adversos , Modelos Animales de Enfermedad , Drosophila/genética , Proteínas de Drosophila/genética , Ácidos Grasos Omega-3/metabolismo , Ácidos Grasos Omega-3/farmacología , Proteína Forkhead Box O3/genética , Factores de Transcripción Forkhead/genética , Regulación de la Expresión Génica/efectos de los fármacos , Células HeLa , Humanos , Inflamación/inducido químicamente , Inflamación/metabolismo , Insulina/metabolismo , Ácido Linoleico/farmacología , Ácidos Linoleicos Conjugados/genética , Ácidos Linoleicos Conjugados/metabolismo , Ácidos Linoleicos Conjugados/farmacología , Obesidad/inducido químicamente , Unión Proteica , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Transcriptoma , TransfecciónRESUMEN
Selenium is implicated in many diseases, including cancer, but its function at the molecular level is poorly understood. BthD is one of three selenoproteins recently identified in Drosophila. To elucidate the function of BthD and the role of selenoproteins in cellular metabolism and health, we analyzed the developmental expression profile of this protein and used inducible RNA interference (RNAi) to ablate function. We find that BthD is dynamically expressed during Drosophila development. bthD mRNA and protein are abundant in the ovaries of female flies and are deposited into the developing oocyte. Maternally contributed protein and RNA persist during early embryonic development but decay by the onset of gastrulation. At later stages of embryogenesis, BthD is expressed highly in the developing salivary gland. We generated transgenic fly lines carrying an inducible gene-silencing construct, in which an inverted bthD genomic-cDNA hybrid is under the control of the Drosophila Gal4 upstream activation sequence system. Duplex RNAi induced from this construct targeted BthD mRNA for destruction and reduced BthD protein levels. We found that loss of BthD compromised salivary gland morphogenesis and reduced animal viability.