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    • Because sleep and metabolism are

    2022-06-23

    Because sleep and metabolism are intimately linked, the authors next move to study whether Eaat2 also controls metabolic rate. First, we must ask how sleep and metabolism are connected at a functional level. The SCH-900776 mg allocation hypothesis of sleep posits that organisms temporally partition specific biological functions to occur during sleep as a way to conserve (or even reduce) total energy expenditure [10]. For example, in mammals, thermoregulation and processes relevant for arousal are reduced during sleep, while evidence suggests that other processes (macromolecule synthesis and metabolite clearance) are increased during sleep [10]. Perhaps as a function of the changes in the metabolic processes occurring, or because of a reduction in energy expenditure, overall metabolic rate appears to decrease during sleep [10]. Given the few mechanistic insights into how sleep and metabolic rate are coordinated, the Keene Lab recently developed new approaches to monitor sleep and whole body metabolic rate simultaneously in fruit flies, based on single-fly respirometry (Sleep and Activity Metabolic Monitor, or SAMM) [11]. Drosophila, like mammals, were found to demonstrate reduced MR during sleep episodes. This system provided a leaping off point for exploring sleep and MR coupling in a tractable model system. To examine whether loss of Eaat2 affects MR in addition to sleep, Stahl and colleagues assayed Eaat2 mutants in the SAMM system. They observed reduced MR in mutants compared to controls during the day, coincident with increased sleep. Both phenotypes were rescued with re-expression of Eaat2 specifically in ensheathing glia, suggesting that effects of Eaat2 on sleep and MR arise from its function in the same cellular subtype. One might assume MR is lower simply because flies are sleeping more, but closer examination of the data indicate that loss of Eaat2 converts daytime sleep to be more like the deep sleep normally observed only during the night. In other words, reduced MR in Eaat2 mutants is not simply a function of increased total sleep duration, but reflects a change in the metabolic nature of sleep. Eaat2 might act as a molecular coupler of sleep–wake and MR; alternatively, loss of this gene might predominately impact sleep depth and, as a by-product, MR (or vice versa). Nonetheless, these findings raise the question of whether Eaat2 is unique in its dual role; previous work from the authors with the sleep mutant translin suggests this might be the case. Unlike wild-type flies, translin mutants do not suppress sleep during starvation [12], implicating this gene in a different feature of sleep and metabolic state integration. It would therefore not have been surprising if MR during sleep was altered in translin mutants; however, changes in MR with sleep were normal for translin flies in both fed and starved conditions [11], underscoring that Eaat2 might indeed be unique in its coordinated effect on both sleep and MR. This conclusion would be further supported by examining whether MR is altered in other previously characterized short- and long-sleeping Drosophila mutants. Moreover, future work will undoubtedly build on the results described here to study more precisely how Eaat2 might link sleep to changes in MR. Having established that Eaat2, an amino acid transporter, is important in ensheathing glia for both sleep and sleep-dependent changes in metabolic rate, an important question remains: what sleep-relevant substrates does Eaat2 transport? Although the authors are not able to definitively answer this question, their work provides some clues. Eaat2 is known to transport both aspartate and taurine 13, 14, although it is possible that Eaat2 has other substrates. Despite the fact that taurine is a common ingredient in energy drinks, there is actually no evidence that it promotes wake — in fact, taurine is a nervous system depressant, and in flies is a known sleep-promoting substance 15, 16. To see whether Eaat2 is required for the sleep-promoting effects of taurine, the authors assess sleep in Eaat2 mutant flies after taurine feeding. Unlike control flies, Eaat2 mutant flies do not further increase sleep upon taurine feeding, although because sleep is already increased with loss of Eaat2, this could reflect a ceiling effect. Still, these findings suggest taurine is a potential substrate for Eaat2 that may contribute to its sleep regulatory role.