The gene Ade2 links metabolism and sleep in the fat bodies of Drosophila.
All animals need to eat and sleep. In fact, these critical behaviors are intertwined: animals adjust their sleep needs based on food availability and energy storage. In a Featured article in G3, Yurgel et al. delved into the molecular mechanisms that connect sleep and metabolism in the fruit fly.
A growing body of evidence suggests that the fat body, an adipose-like organ in Drosophila responsible for fat storage and detoxification, regulates complex behaviors—but little is known about its relationship to sleep. Somewhat analogous to the mammalian liver, the fat body secretes hormones that influence fly behaviors, much the same way that human organs like the pancreas and stomach secrete hormones that trigger hunger or satiation, which in turn drive you to eat—or not.
Because sleep and metabolism are so interconnected, the authors hypothesized that genes in the fat body that are associated with hunger might also play a role in regulating sleep. Using RNAi, they knocked down the expression of 113 genes previously reported to be upregulated in the fly fat body under conditions of starvation. They then measured how long these flies slept compared to controls.
The screen showed that decreasing fat body expression of Ade2, a highly conserved purine biosynthesis gene, caused flies to sleep, on average, 200 minutes less than controls—a reduction of ~20%. Since homozygous mutations in Ade2 are lethal, the authors confirmed that flies with heterozygous mutations also sleep less than wild-type, phenocopying the knockdown results.
Expressing additional Ade2 in the fat bodies of mutant flies partially rescued the short sleep phenotype; however, overexpression of Ade2 in wild-type fly fat bodies had no effect on sleep. This suggests that Ade2 is needed for normal sleep, but additional Ade2 isn’t enough to increase that normal sleep duration.
Other behaviors, including walking activity and arousal threshold, are connected to sleep behaviors in the fly. Ade2-deficient flies showed no change in arousal threshold, but some mutants trended toward increased walking activity. The authors interpret this increased walking activity as similar to the hyperactivity observed in starving flies.
Analysis of energy stores revealed decreased levels of triglycerides and free glucose but normal levels of glycogen—consistent with a starvation state. Energy stores that mirror starvation are consistent with the hyperactivity observed in the walking activity assays, since that behavior is also seen in starving flies. These data led the authors to propose that Ade2 is required for normal storage of triglycerides and free glucose and that its loss puts the fly into a starvation-like state, which in turn promotes sleep.
Typically, genetic studies of behavior have focused on the nervous system, but this study highlights the importance of also considering non-neuronal factors like fat tissue, which may be significant pieces of the puzzle.
Ade2 Functions in the Drosophila Fat Body To Promote Sleep
Maria E. Yurgel, Kreesha D. Shah, Elizabeth B. Brown, Carter Burns, Ryan A. Bennick, Justin R. DiAngelo, Alex C. Keene
G3: Genes, Genomes, Genetics
November 2018 8: 3385-3395; https://doi.org/10.1534/g3.118.200554