Sleep-Dependent Modulation of Metabolic Rate in Drosophila

Stahl, Bethany A.; Slocumb, Melissa E.; Chaitin, Hersh; DiAngelo, Justin R.; Keene, Alex C.

doi:10.1093/sleep/zsx084

Cited by 70 publications

(103 citation statements)

References 67 publications

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“…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.…”

Section: Discussionmentioning

confidence: 99%

“…Sleep is associated with reduced neural energetic demands across phylogeny [10-12]; for example, slow wave sleep in mammals is associated with reduced nervous system energetic demands [13-15], and the reduction in neural activity in a sleeping C. elegans is likely similarly associated with reduced energy demands [11]. Despite this apparent reduced energy demand in neurons, overall metabolic rates during sleep in mammals [15, 16] and Drosophila [17] are only modestly reduced, suggesting that during sleep energetic stores are allocated to other metabolic functions [18], such as the synthesis of proteins [19] and other macromolecules [20]. Importantly, while there are genes reported to function both in metabolic regulation and in sleep [21-26], mechanisms by which these gene products couple the two processes at the level of the whole organism remain unclear.…”

Section: Introductionmentioning

confidence: 99%

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

Grubbs

Lopes

Linden

et al. 2019

Preprint

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ABSTRACTMany lines of evidence point to links between sleep regulation and energy homeostasis, but mechanisms underlying these connections are unknown. During C. elegans sleep, energetic stores are allocated to non-neural tasks with a resultant drop in the overall fat stores and energy charge. Mutants lacking KIN-29, the C. elegans homolog of a mammalian Salt-Inducible Kinase (SIK) that signals sleep pressure, have low ATP levels despite high fat stores, indicating a defective response to cellular energy deficits. Liberating energy stores corrects adiposity and sleep defects of kin-29 mutants. kin-29 sleep and energy homeostasis roles map to a small number of sensory neurons that act upstream of fat regulation as well as of central sleep-controlling neurons, suggesting hierarchical somatic/neural interactions regulating sleep and energy homeostasis. Genetic interaction between kin-29 and the histone deacetylase hda-4 coupled with subcellular localization studies indicate that KIN-29 acts in the nucleus to regulate sleep. We propose that KIN-29/SIK acts in nuclei of sensory neuroendocrine cells to transduce low cellular energy charge into the mobilization of energy stores, which in turn promotes sleep.HighlightsSleep is associated with fat mobilization and low ATP levelsMetabolic regulation of sleep requires the salt-induced kinase (SIK) homolog KIN-29KIN-29 acts in sensory neurons upstream of sleep-promoting neuronsNuclear localization of KIN-29 is required for the metabolic regulation of sleepA type 2 histone deacetylase acts down stream of KIN-29 in the regulation of sleep.Liberation of energy from fat-storage cells promotes sleep.Beta-oxidation promotes sleep.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Grubbs

Lopes

Linden

et al. 2019

Preprint

View full text Add to dashboard Cite

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“…Metabolic rate was measured using the Sleep and Activity Metabolic Monitor (SAMM) system at 367 25 ºC through indirect calorimetry using a stop-flow, push-through respirometry system (Sable 368 Systems International). Metabolic rate in group-housed adult flies was measured as previously 369 described (Stahl et al, 2018;Stahl et al, 2017). Briefly, the experimental system assessed 370 baseline CO2 levels from an empty chamber to measure CO2 production and O2 consumption 371 from 25 male adult flies.…”

Section: Indirect Calorimetry 366mentioning

confidence: 99%

“…132133To gain further insight into the mechanistic underpinnings of the metabolic phenotype, we 134 turned to stop-flow respirometry, quantifying O2 consumed and CO2 produced with stop-flow 135 respirometry (Fig. 3A)(Stahl et al, 2017). Mutant Nf1 P1 adult flies exhibited increased O2 136…”

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confidence: 99%

Neurofibromin regulates metabolic rate via neuronal mechanisms in Drosophila

Botero

Stahl

Grenci

et al. 2019

Preprint

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1Neurofibromatosis type 1 (NF1) is a genetic disorder predisposing patients to a range of 2 features, the most characteristic of which include areas of abnormal skin pigmentation and 3 benign tumors associated with peripheral nerves, termed neurofibromas. Less common, but 4 more serious symptoms also include malignant peripheral nerve sheath tumors, other 5 malignancies, and learning disabilities. The NF1 gene encodes neurofibromin, a large protein 6 that functions as a negative regulator of Ras signaling and mediates pleiotropic cellular and 7 organismal function. Recent evidence suggests NF1 may regulate metabolism, though the 8 mechanisms are unknown. Here we show that the Drosophila ortholog of NF1, dNf1 regulates 9 metabolic homeostasis in fruit flies by functioning within a discrete brain circuit. Loss of dNf1 10 increases metabolic rate and feeding, enhances starvation susceptibility, and decreases lipid 11 stores while increasing lipid turnover rate. The increase in metabolic rate is independent of 12 locomotor activity (grooming), and maps to a subset of neurons in the ventral nervous system. 13The feeding and metabolic rate effects are due to loss of dNf1 in the same set of neurons, 14suggesting that increased feeding may be a compensatory effect driven by the increase in 15 metabolic rate and lipid turnover. Finally, we show that the Ras GAP-related domain of 16 neurofibromin is required for normal metabolism, demonstrating that Ras signaling downstream 17 of dNf1 mediates the metabolic effects. These data demonstrate that dNf1 regulates metabolic 18 rate via neuronal mechanisms, suggest that cellular and systemic metabolic alterations may 19 represent a pathophysiological mechanism in NF1, and provide a platform for investigating the 20 cellular role of neurofibromin in metabolic homeostasis. 21

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“…A. Stahl, Slocumb, Chaitin, DiAngelo, & Keene, 2017). In addition, genetic analyses suggest the molecular and neural circuit principles regulating sleep, as well as the functional effects of sleep loss, are highly conserved between flies and mammals (Donlea, 2017; Sehgal & Mignot, 2011).…”

Section: Introductionmentioning

confidence: 94%

Dietary fatty acids promote sleep through a taste-independent mechanism

Pamboro

Brown

Keene³

2019

Preprint

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300 words 16 Introduction: 559 words Abstract 19Consumption of foods that are high in fat contributes to obesity and metabolism-related 20 disorders that are increasing in prevalence and present an enormous health burden throughout 21 the world. Dietary lipids are comprised of triglycerides and fatty acids, and the highly palatable 22 taste of dietary fatty acids promotes food consumption, activates reward centers in mammals, 23 and underlies hedonic feeding. Despite a central role of dietary fats in the regulation of food 24 intake and the etiology of metabolic diseases, little is known about how fat consumption 25 regulates sleep. The fruit fly, Drosophila melanogaster, provides a powerful model system for 26 the study of sleep and metabolic traits, and flies potently regulate sleep in accordance with food 27 availability. To investigate the effects of dietary fats on sleep regulation, we have supplemented 28 fatty acids into the diet of Drosophila and measured their effects on sleep and activity. We found 29 that feeding flies a diet of hexanoic acid, a medium-chain fatty acid that is a by-product of yeast 30 fermentation, promotes sleep by increasing the number of sleep episodes. This increase in 31 sleep is dose-dependent and independent of the light-dark cues. Diets consisting of other fatty 32acids, including medium-and long-chain fatty acids, also increase sleep, suggesting many fatty 33 acid types promote sleep. To assess whether dietary fatty acids regulate sleep through the taste 34 system, we assessed sleep in flies with a mutation in the hexanoic acid receptor Ionotropic 35 receptor 56d, which is required for fatty acid taste perception. We found that these flies also 36 increase their sleep when fed a hexanoic acid diet, suggesting the sleep promoting effect of 37 hexanoic acid is not dependent on sensory perception. Overall, these results define a role for 38 fatty acids in sleep regulation, providing a foundation to investigate the molecular and neural 39 basis for fatty acid-dependent modulation of sleep duration. 40 41

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Sleep-Dependent Modulation of Metabolic Rate in Drosophila

Abstract: Therefore, this system provides the unique ability to simultaneously measure sleep and oxidative metabolism, providing novel insight into the physiological changes associated with sleep and wakefulness in the fruit fly.

Cited by 70 publications

References 67 publications

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

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

Neurofibromin regulates metabolic rate via neuronal mechanisms in Drosophila

Dietary fatty acids promote sleep through a taste-independent mechanism

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