Ade2 Functions in the Drosophila Fat Body To Promote Sleep

Abstract

Metabolic state is a potent modulator of sleep and circadian behavior, and animals acutely modulate their sleep in accordance with internal energy stores and food availability. Across phyla, hormones secreted from adipose tissue act in the brain to control neural physiology and behavior to modulate sleep and metabolic state. Growing evidence suggests the fat body is a critical regulator of complex behaviors, but little is known about the genes that function within the fat body to regulate sleep. To identify molecular factors functioning in non-neuronal tissues to regulate sleep, we performed an RNAi screen selectively knocking down genes in the fat body. We found that knockdown of Phosphoribosylformylglycinamidine synthase/Pfas (Ade2), a highly conserved gene involved the biosynthesis of purines, sleep regulation and energy stores. Flies heterozygous for multiple Ade2 mutations are also short sleepers and this effect is partially rescued by restoring Ade2 to the Drosophila fat body. Targeted knockdown of Ade2 in the fat body does not alter arousal threshold or the homeostatic response to sleep deprivation, suggesting a specific role in modulating baseline sleep duration. Together, these findings suggest Ade2 functions within the fat body to promote both sleep and energy storage, providing a functional link between these processes.

A salt-induced kinase (SIK) is required for the metabolic regulation of sleep

“…Central nervous system neurons control sleep in a top-down fashion [85, 86], but bottom-up metabolic signals from glia [17, 24, 87, 88], muscle cells [32, 88-90] and adipocytes [91, 92] affect activity of sleep regulating neurons. While several gene products have been reported to regulate both metabolism and sleep [4, 9, 21-23, 25, 26, 32, 41, 89, 90, 93, 94], the mechanism of the metabolic regulation of sleep has heretofore remained opaque.…”

AMPK signaling linked to the schizophrenia-associated 1q21.1 deletion is required for neuronal and sleep maintenance

“…Recent studies suggest that overall metabolic state, in particular when regulated within the fat body (the adipose and liver tissue of Drosophila ), may be an important regulator of complex behaviors such as sleep, reflecting the need to modulate these behaviors according to internal energy stores and availability of nutrients [34]. Ubiquitous AMPK down-regulation has previously been shown to increase overall dietary intake, yet flies with reduced AMPK activity have reduced nutrient stores and display starvation-like lipid accumulation in the fat body which suggests that they are in a persistent state of starvation [17].…”

Dietary fatty acids promote sleep through a taste‐independent mechanism

“…Given that sleep regulation by dietary fatty acids is independent of their role in taste regulation, it is possible that sleep regulation by dietary fatty acids occurs centrally. Multiple populations of central brain neurons that sense nutrient levels or modulate feeding behavior have been identified as essential for integrating sleep and activity with nutritional status . For example, the peptidergic Leucokinin ‐expressing neurons increase activity during starvation conditions, and when silenced, fail to suppress sleep .…”

“…Multiple populations of central brain neurons that sense nutrient levels or modulate feeding behavior have been identified as essential for integrating sleep and activity with nutritional status . For example, the peptidergic Leucokinin ‐expressing neurons increase activity during starvation conditions, and when silenced, fail to suppress sleep . Further, overexpression of short neuropeptide F ( sNPF )‐expressing neurons suppress sleep and promote food consumption, whereas activation of sNPF in small ventrolateral clock neurons promotes sleep .…”