<i>Drosophila</i> neuronal Glucose-6-Phosphatase is a modulator of neuropeptide release that regulates muscle glycogen stores via FMRFamide signaling.

Abstract

Neuropeptides (NPs) and their cognate receptors are critical effectors of diverse physiological processes and behaviors. We recently reported of a noncanonical function of the <i>Drosophila Glucose-6-Phosphatase</i> (<i>G6P</i>) gene in a subset of neurosecretory cells in the central nervous system that governs systemic glucose homeostasis in food-deprived flies. Here, we show that <i>G6P-</i>expressing neurons define six groups of NP-secreting cells, four in the brain and two in the thoracic ganglion. Using the glucose homeostasis phenotype as a screening tool, we find that neurons located in the thoracic ganglion expressing FMRFamide NPs (<i>FMRFa^G6P</i> neurons) are necessary and sufficient to maintain systemic glucose homeostasis in starved flies. We further show that <i>G6P</i> is essential in <i>FMRFa^G6P</i> neurons for attaining a prominent Golgi apparatus and secreting NPs efficiently. Finally, we establish that <i>G6P-</i>dependent FMRFa signaling is essential for the build-up of glycogen stores in the jump muscle which expresses the receptor for FMRFamides. We propose a general model in which the main role of <i>G6P</i> is to counteract glycolysis in peptidergic neurons for the purpose of optimizing the intracellular environment best suited for the expansion of the Golgi apparatus, boosting release of NPs and enhancing signaling to respective target tissues expressing cognate receptors.