title: Macrophage-derived upd3 cytokine causes impaired glucose homeostasis and reduced lifespan in Drosophila fed a lipid-rich diet.
abstract: Long-term consumption of fatty foods is associated with obesity, macrophage activation and inflammation, metabolic imbalance, and a reduced lifespan. We took advantage of Drosophila genetics to investigate the role of macrophages and the pathway(s) that govern their response to dietary stress. Flies fed a lipid-rich diet presented with increased fat storage, systemic activation of JAK-STAT signaling, reduced insulin sensitivity, hyperglycemia, and a shorter lifespan. Drosophila macrophages produced the JAK-STAT-activating cytokine upd3, in a scavenger-receptor (crq) and JNK-dependent manner. Genetic depletion of macrophages or macrophage-specific silencing of upd3 decreased JAK-STAT activation and rescued insulin sensitivity and the lifespan of Drosophila, but did not decrease fat storage. NF-κB signaling made no contribution to the phenotype observed. These results identify an evolutionarily conserved "scavenger receptor-JNK-type 1 cytokine" cassette in macrophages, which controls glucose metabolism and reduces lifespan in Drosophila maintained on a lipid-rich diet via activation of the JAK-STAT pathway.
authors.forename: Katie J
authors.initials: KJ
authors.lastname: Woodcock
authors.forename: Katrin
authors.initials: K
authors.lastname: Kierdorf
authors.forename: Clara A
authors.initials: CA
authors.lastname: Pouchelon
authors.forename: Valérie
authors.initials: V
authors.lastname: Vivancos
authors.forename: Marc S
authors.initials: MS
authors.lastname: Dionne
authors.forename: Frédéric
authors.initials: F
authors.lastname: Geissmann
mesh_terms: D019588:Aging, Premature / Q000209:etiology / Q000235:genetics / Q000276:immunology*; D000818:Animals; D002478:Cells, Cultured; D059305:Diet, High-Fat / Q000009:adverse effects; D004330:Drosophila / Q000235:genetics / Q000276:immunology*; D029721:Drosophila Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007249:Inflammation; D007333:Insulin Resistance / Q000235:genetics; D053612:Janus Kinases / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008262:Macrophage Activation / Q000235:genetics; D008264:Macrophages / Q000502:physiology*; D009765:Obesity / Q000209:etiology / Q000517:prevention & control*; D034741:RNA, Small Interfering / Q000235:genetics; D051116:Receptors, Scavenger / Q000378:metabolism; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D029721:Drosophila Proteins; D034741:RNA, Small Interfering; D051116:Receptors, Scavenger; D050791:STAT Transcription Factors; C558732:Upd3 protein, Drosophila; D053612:Janus Kinases; D048670:MAP Kinase Kinase 4