Drosophila Neuronal Glucose 6 Phosphatase is a Modulator of Neuropeptide Release that Regulates Muscle Glycogen Stores via FMRFamide Signaling

SUMMARY Neuropeptides (NPs) and their cognate receptors are critical effectors of diverse physiological processes and behaviors. We recently reported of a non-canonical function of the Drosophila Glucose-6-Phosphatase ( G6P ) gene in a subset of neurosecretory cells in the CNS that governs systemic glucose homeostasis in food deprived flies. Here, we show that G6P expressing neurons define 6 groups of neuropeptide secreting cells, 4 in the brain and 2 in the thoracic ganglion. Using the glucose homeostasis phenotype as a screening tool, we find that neurons located in the thoracic ganglion expressing FMRFamide neuropeptides ( FMRFa G6P neurons) are necessary and sufficient to maintain systemic glucose homeostasis in starved flies. We further show that G6P is essential in FMRFa G6P neurons for attaining a prominent Golgi apparatus and secreting neuropeptides efficiently. Finally, we establish that G6P 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 G6P 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 neuropeptides and enhancing signaling to respective target tissues expressing cognate receptors. SIGNIFICANCE STATEMENT Glucose-6-phosphtase (G6P) is a critical enzyme in sugar synthesis and catalyzes the final step in glucose production. In Drosophila - and insects in general - where trehalose is the circulating sugar and Trehalose phosphate synthase, and not G6P, is used for sugar production, G6P has adopted a novel and unique role in peptidergic neurons in the CNS. Interestingly, flies lacking G6P show diminished Neuropeptide secretions and have a smaller Golgi apparatus in peptidergic neurons. It is hypothesized that the role of G6P is to counteract glycolysis, thereby creating a cellular environment that is more amenable to efficient neuropeptide secretion.