Muscle function and homeostasis require macrophage-derived cytokine inhibition of AKT activity in Drosophila

Unpaired ligands are secreted signals that act via a GP130-like receptor, domeless, to activate JAK-STAT signaling in Drosophila. Like many mammalian cytokines, unpaireds can be activated by infection and other stresses and can promote insulin resistance in target tissues. However, the importance of this effect in non-inflammatory physiology is unknown. Here, we identify a requirement for unpaired-JAK signaling as a metabolic regulator in healthy adult Drosophila muscle. Adult muscles show basal JAK-STAT signaling activity in the absence of any immune challenge. Macrophages are the source of much of this tonic signal. Loss of the dome receptor on adult muscles significantly reduces lifespan and causes local and systemic metabolic pathology. These pathologies result from hyperactivation of AKT and consequent deregulation of metabolism. Thus, we identify a cytokine signal from macrophages to muscle that controls AKT activity and metabolic homeostasis.