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

Abstract

Unpaired ligands are secreted signals that act via a GP130-like receptor, domeless, to activate JAK/STAT signalling 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 signalling as a metabolic regulator in healthy adult Drosophila muscle. Adult muscles show basal JAK-STAT signalling activity in the absence of any immune challenge. Plasmatocytes (Drosophila macrophages) are an important source 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 that must be received in muscle to control AKT activity and metabolic homeostasis.

The Role of Muscle in Insect Energy Homeostasis

“…This dynamic is mediated through increased p-AKT levels and thereby increased insulin signaling. In addition to decreasing TAGs, loss of JAK/Stat and the consequent increased insulin signaling leads to TAG presence in the muscle and decreased total glucose and glycogen levels in the organism, likely resulting from an increased metabolic rate (Kierdorf et al, 2020). This result is similar to what was seen with loss of FoxO, a negative regulator of insulin signaling, which also results in ectopic lipid accumulation in muscle (Zhao and Karpac, 2017).…”

“…While loss of Wg signaling or Pvf1 in muscle increases TAG levels, loss of cytokine activated Janus Kinase/signal transducer and activator of transcription (JAK/Stat) signaling in muscle decreases TAGs (Kierdorf et al, 2020; Figure 2). This dynamic is mediated through increased p-AKT levels and thereby increased insulin signaling.…”

“…JAK/Stat ligands Upd1, 2, 3 are supplied by plasmocytes and activate JAK/Stat signaling in muscle. Suppression of JAK/Stat signaling in adult muscle results in increased insulin signaling in muscle, which shortens life span and decreases climbing ability (Kierdorf et al, 2020). This may simply be a difference between larvae and adults, however, it may also suggest that both low and high levels of JAK/Stat signaling in the muscle can result in increased insulin signaling.…”

Polarization of Macrophages in Insects: Opening Gates for Immuno-Metabolic Research

“…However, the direct link between plasmatocyte aerobic glycolysis and Upd3 production has not been satisfactorily studied to date. A systemic effect of Upd3 may be attributed to the activation of a JAK-STAT cascade, which often leads to an alleviation of the insulin signaling pathway in target tissues ( Yang et al, 2015 ; Kierdorf et al, 2020 ; Shin et al, 2020 ).…”

“…Also, the effects of Upd3 on muscle metabolism have been investigated. Plasmatocyte-derived Upd3 has been shown to limit remote lipid accumulation in muscles to maintain lipid homeostasis in the tissue via alleviation of insulin signaling in these cells through activation of the JAK-STAT singling pathway, which is documented by decreased pAKT occurrence ( Kierdorf et al, 2020 ). We suggest that such a mechanism may also be involved in the regulation of muscle lipid uptake upon infection, during which Upd3 expression in plasmatocytes is markedly elevated ( Péan et al, 2017 ).…”