Macrophage-derived upd3 cytokine causes impaired glucose homeostasis and reduced lifespan in Drosophila fed a lipid-rich diet

Immunity. 2015 Jan 20;42(1):133-44. doi: 10.1016/j.immuni.2014.12.023.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging, Premature / etiology
  • Aging, Premature / genetics
  • Aging, Premature / immunology*
  • Animals
  • Cells, Cultured
  • Diet, High-Fat / adverse effects
  • Drosophila / genetics
  • Drosophila / immunology*
  • Drosophila Proteins / genetics
  • Drosophila Proteins / immunology
  • Drosophila Proteins / metabolism*
  • Humans
  • Inflammation
  • Insulin Resistance / genetics
  • Janus Kinases / metabolism
  • MAP Kinase Kinase 4 / metabolism
  • Macrophage Activation / genetics
  • Macrophages / physiology*
  • Obesity / etiology
  • Obesity / prevention & control*
  • RNA, Small Interfering / genetics
  • Receptors, Scavenger / metabolism
  • STAT Transcription Factors / metabolism
  • Signal Transduction


  • Drosophila Proteins
  • RNA, Small Interfering
  • Receptors, Scavenger
  • STAT Transcription Factors
  • Upd3 protein, Drosophila
  • Janus Kinases
  • MAP Kinase Kinase 4

Associated data

  • GEO/GSE63254