translin Is Required for Metabolic Regulation of Sleep

Abstract

Summary Dysregulation of sleep or feeding has enormous health consequences. In humans, acute sleep loss is associated with increased appetite and insulin insensitivity, while chronically sleep-deprived individuals are more likely to develop obesity, metabolic syndrome, type II diabetes, and cardiovascular disease. Conversely, metabolic state potently modulates sleep and circadian behavior; yet, the molecular basis for sleep-metabolism interactions remains poorly understood. Here, we describe the identification of translin (trsn), a highly conserved RNA/DNA binding protein, as essential for starvation-induced sleep suppression. Strikingly, trsn does not appear to regulate energy stores, free glucose levels, or feeding behavior suggesting the sleep phenotype of trsn mutant flies is not a consequence of general metabolic dysfunction or blunted response to starvation. While broadly expressed in all neurons, trsn is transcriptionally upregulated in the heads of flies in response to starvation. Spatially restricted rescue or targeted knockdown localizes trsn function to neurons that produce the tachykinin-family neuropeptide Leucokinin. Manipulation of neural activity in Leucokinin neurons revealed these neurons to be required for starvation-induced sleep suppression. Taken together, these findings establish trsn as an essential integrator of sleep and metabolic state, with implications for understanding the neural mechanism underlying sleep disruption in response to environmental perturbation.

Increased food intake after starvation enhances sleep in Drosophila melanogaster

“…Thus, we used the trsn mutants to further test whether the sleep increase after starvation might be due to sleep loss during starvation. In support of the study of Murakami et al (2016), we found that trsn mutants, unlike their wild-type controls, fail to decrease their sleep during starvation (Fig. 2B and C).…”

“…A recent study has shown that trsn fly mutants fail to show starvation-induced sleep suppression while preserving homeostatic feeding strategies, such as increased food intake, after starvation (Murakami et al, 2016). Thus, we used the trsn mutants to further test whether the sleep increase after starvation might be due to sleep loss during starvation.…”

“…1). Since sleep increase after starvation might be due to sleep loss during starvation, we tested trsn fly mutants, which do not show sleep suppression during starvation (Murakami et al, 2016; Fig. 2).…”

“…For example, during periods of starvation, flies increase their activity and decrease sleep amount (Lee and Park, 2004; Keene et al, 2010; Thimgan et al, 2010). Mutations in core circadian clock genes, clock and cycle , have been shown to amplify starvation-induced sleep suppression, while mutations in translin ( trsn ), an RNA-DNA binding protein, result in a loss of starvation-induced sleep suppression (Keene et al, 2010; Murakami et al, 2016). Mutations in adipokinetic hormone ( akh ), the insect analog of glucagon , have been shown to affect starvation-induced hyperactivity (Lee and Park, 2004).…”

Postprandial sleep mechanics in Drosophila

“…This suggests that ingested protein promotes both sleep and wakefulness, and that the wakefulness is normally counterbalanced by Lkr neuronal activity. While this study does not specifically identify the waking output for protein, it was previously shown that Translin acts through Lk-expressing cells to drive wakefulness in response to sucrose starvation (Murakami et al, 2016). While this does not explain rapid wake promotion in response to protein ingestion, it does demonstrate that Lk-expressing cells are capable of promoting wakefulness.…”