A Drosophila JAK-STAT Pathway Mediates Sleep-promoting Effects of Threonine

Abstract

Amino acids are newly emerging as sleep supplements yet their neural and molecular bases underlying sleep regulation still remain elusive. Here we demonstrate sleep-promoting effects of threonine in Drosophila genetic models. Feeding individual amino acids to wild-type flies differentially affected baseline sleep behaviors. Glycine, one of ligands for NMDA receptor, lengthened the average duration of sleep bouts and thus improved sleep quality consistent with its effects on human sleep. In contrast, threonine increased sleep quantity and shortened sleep latency in a dose-dependent manner. We reasoned threonine effects on sleep behaviors might involve metabolic pathways as previous studies have showed that threonine blocks the formation of fatty liver in mammals and that metabolic mutant flies display altered sleep homeostasis. Indeed, loss-of-function mutation in a Drosophila leptin-like cytokine unpaired 3 (upd3) gene desensitized sleep-promoting effects of threonine. Upd3 depletion in fat body, a Drosophila tissue analogous to mammalian adipose tissue and liver, was sufficient to phenocopy upd3 mutant flies. In addition, pan-neuronal depletion of a UPD3 receptor domeless (dome) caused resistance to threonine effects on baseline sleep. Given that DOME is an upstream activator of JAK-STAT signaling, our data suggest that a specific JAK-STAT pathway may physiologically link the metabolic organ to a sleep-relevant neural circuitry in brain to mediate threonine-dependent sleep effects.