Abstract
Dysregulation of sleep and metabolism has enormous health consequences. Sleep loss is linked to increased appetite and insulin insensitivity, and epidemiological studies link chronic sleep deprivation to obesity-related disorders including type II diabetes and cardiovascular disease. Interactions between sleep and metabolism involve the integration of signaling from brain regions regulating sleep, feeding, and metabolic function. Investigating the relationship between these processes provides a model to address more general questions of how the brain prioritizes homeostatically regulated behaviors. The availability of powerful genetic tools in the fruit fly, Drosophila melanogaster, allows for precise manipulation of neural function in freely behaving animals. There is a strong conservation of genes and neural circuit principles regulating sleep and metabolic function, and genetic screens in fruit flies have been effective in identifying novel regulators of these processes. Here, we review recent findings in the fruit fly that further our understanding of how the brain modulates sleep in accordance with metabolic state.
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References
Agosto J, Choi JC, Parisky KM, et al. (2009) NIH Public Access. 11:354–359. doi:10.1038/nn2046.Modulation
Ahima RS, Lazar MA (2008) Adipokines and the peripheral and neural control of energy balance. Mol Endocrinol 22:1023–1031. doi:10.1210/me.2007-0529
Akalal D-BG, Yu D, Davis RL (2011) The long-term memory trace formed in the Drosophila α/β mushroom body neurons is abolished in long-term memory mutants. J Neurosci 31:5643–5647. doi:10.1523/JNEUROSCI.3190-10.2011
Atkinson W, Shorrocks B (1977) Breeding site specificity in the domestic species of Drosophila. Oecologia 29:223–232. doi:10.1007/BF00345697
Barf RP, Desprez T, Meerlo P, Scheurink AJW (2012) Increased food intake and changes in metabolic hormones in response to chronic sleep restriction alternated with short periods of sleep allowance. Am J Physiol Regul Integr Comp Physiol 302:R112–R117. doi:10.1152/ajpregu.00326.2011
Bharucha KN, Tarr P, Zipursky SL (2008) A glucagon-like endocrine pathway in Drosophila modulates both lipid and carbohydrate homeostasis. J Exp Biol 211:3103–3110. doi:10.1242/jeb.016451
Britton JS, Edgar BA (1998) Environmental control of the cell cycle in Drosophila: nutrition activates mitotic and endoreplicative cells by distinct mechanisms. Development 125:2149–2158
Britton JS, Lockwood WK, Li L et al (2002) Drosophila’s insulin/PI3-kinase pathway coordinates cellular metabolism with nutritional conditions. Dev Cell 2:239–249
Brogiolo W, Stocker H, Ikeya T et al (2001) An evolutionarily conserved function of the Drosophila insulin receptor and insulin-like peptides in growth control. Curr Biol 11:213–221
Broughton SJ, Piper MDW, Ikeya T et al (2005) Longer lifespan, altered metabolism, and stress resistance in Drosophila from ablation of cells making insulin-like ligands. Proc Natl Acad Sci USA 102:3105–3110. doi:10.1073/pnas.0405775102
Broughton SJ, Slack C, Alic N et al (2010) DILP-producing median neurosecretory cells in the Drosophila brain mediate the response of lifespan to nutrition. Aging Cell 9:336–346. doi:10.1111/j.1474-9726.2010.00558.x
Burke CJ, Huetteroth W, Owald D et al (2012) Layered reward signalling through octopamine and dopamine in Drosophila. Nature 492:433–437. doi:10.1038/nature11614
Burt J, Dube L, Thibault L, Gruber R (2014) Sleep and eating in childhood: a potential behavioral mechanism underlying the relationship between poor sleep and obesity. Sleep Med 15:71–75. doi:10.1016/j.sleep.2013.07.015
Busch S, Selcho M, Ito K, Tanimoto H (2009) A map of octopaminergic neurons in the Drosophila brain. J Comp Neurol 513:643–667. doi:10.1002/cne.21966
Canavoso LE, Jouni ZE, Karnas KJ et al (2001) Fat metabolism in insects. Annu Rev Nutr 21:23–46. doi:10.1146/annurev.nutr.21.1.23
Carhan A, Tang K, Shirras CA et al (2011) Loss of Angiotensin-converting enzyme-related (ACER) peptidase disrupts night-time sleep in adult Drosophila melanogaster. J Exp Biol 214:680–686. doi:10.1242/jeb.049353
Catterson JH, Knowles-Barley S, James K et al (2010) Dietary modulation of Drosophila sleep-wake behaviour. PLoS ONE 5:e12062. doi:10.1371/journal.pone.0012062
Cavanaugh DJ, Geratowski JD, Wooltorton JRA et al (2014) Identification of a circadian output circuit for rest:activity rhythms in Drosophila. Cell 157:689–701. doi:10.1016/j.cell.2014.02.024
Chapman T, Partridge L (1996) Female fitness in Drosophila melanogaster: an interaction between the effect of nutrition and of encounter rate with males. Proc Biol Sci 263:755–759. doi:10.1098/rspb.1996.0113
Chaput J-P, Després J-P, Bouchard C, Tremblay A (2007) Association of sleep duration with type 2 diabetes and impaired glucose tolerance. Diabetologia 50:2298–2304. doi:10.1007/s00125-007-0786-x
Claridge-Chang A, Roorda RD, Vrontou E et al (2009) Writing memories with light-addressable reinforcement circuitry. Cell 139:405–415. doi:10.1016/j.cell.2009.08.034
Crocker A, Sehgal A (2008) Octopamine regulates sleep in drosophila through protein kinase A-dependent mechanisms. J Neurosci 28:9377–9385. doi:10.1523/JNEUROSCI.3072-08a.2008
Crocker A, Shahidullah M, Levitan IB, Sehgal A (2010) Identification of a neural circuit that underlies the effects of octopamine on sleep:wake behavior. Neuron 65:670–681. doi:10.1016/j.neuron.2010.01.032
Dahanukar A, Lei Y-T, Kwon JY, Carlson JR (2007) Two Gr genes underlie sugar reception in Drosophila. Neuron 56:503–516. doi:10.1016/j.neuron.2007.10.024
Danguir J, Nicolaidis S (1979) Dependence of sleep on nutrients’ availability. Physiol Behav 22:735–740
Davis RL (2011) Traces of Drosophila memory. Neuron 70:8–19. doi:10.1016/j.neuron.2011.03.012
DiAngelo JR, Birnbaum MJ (2009) Regulation of fat cell mass by insulin in Drosophila melanogaster. Mol Cell Biol 29:6341–6352. doi:10.1128/MCB.00675-09
Donelson NC, Donelson N, Kim EZ et al (2012) High-resolution positional tracking for long-term analysis of Drosophila sleep and locomotion using the “tracker” program. PLoS ONE 7:e37250. doi:10.1371/journal.pone.0037250
Donlea JM, Thimgan MS, Suzuki Y et al (2011) Inducing sleep by remote control facilitates memory consolidation in Drosophila. Science 332:1571–1576. doi:10.1126/science.1202249
Donlea J, Leahy A, Thimgan MS et al (2012) Foraging alters resilience/vulnerability to sleep disruption and starvation in Drosophila. Proc Natl Acad Sci USA 109:2613–2618. doi:10.1073/pnas.1112623109
Donlea JM, Pimentel D, Miesenböck G (2014) Neuronal machinery of sleep homeostasis in Drosophila. Neuron 81:860–872. doi:10.1016/j.neuron.2013.12.013
Dus M, Min S, Keene AC, et al. (2011) Taste-independent detection of the caloric content of sugar in Drosophila. 2–7. doi: 10.1073/pnas.1017096108/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1017096108
Edgar BA (2006) How flies get their size: genetics meets physiology. Nat Rev Genet 7:907–916. doi:10.1038/nrg1989
Erion R, DiAngelo JR, Crocker A, Sehgal A (2012) Interaction between sleep and metabolism in Drosophila with altered octopamine signaling. J Biol Chem 287:32406–32414. doi:10.1074/jbc.M112.360875
Fernandez R, Tabarini D, Azpiazu N et al (1995) The Drosophila insulin receptor homolog: a gene essential for embryonic development encodes two receptor isoforms with different signaling potential. EMBO J 14:3373–3384
Foltenyi K, Greenspan RJ, Newport JW (2007) Activation of EGFR and ERK by rhomboid signaling regulates the consolidation and maintenance of sleep in Drosophila. Nat Neurosci 10:1160–1167. doi:10.1038/nn1957
Froy O, Miskin R (2010) Effect of feeding regimens on circadian rhythms: implications for aging and longevity. Aging (Albany NY) 2:7–27
Gilestro GF (2012) Video tracking and analysis of sleep in Drosophila melanogaster. Nat Protoc 7:995–1007. doi:10.1038/nprot.2012.041
Good TP, Tatar M (2001) Age-specific mortality and reproduction respond to adult dietary restriction in Drosophila melanogaster. J Insect Physiol 47:1467–1473
Grandison RC, Piper MDW, Partridge L (2009) Amino-acid imbalance explains extension of lifespan by dietary restriction in Drosophila. Nature 462:1061–1064. doi:10.1038/nature08619
Green CB, Takahashi JS, Bass J (2008) The meter of metabolism. Cell 134:728–742. doi:10.1016/j.cell.2008.08.022
Griffith LC (2013) Neuromodulatory control of sleep in Drosophila melanogaster: integration of competing and complementary behaviors. Curr Opin Neurobiol 23:819–823. doi:10.1016/j.conb.2013.05.003
Grönke S, Mildner A, Fellert S et al (2005) Brummer lipase is an evolutionary conserved fat storage regulator in Drosophila. Cell Metab 1:323–330. doi:10.1016/j.cmet.2005.04.003
Heisenberg M (2003) Mushroom body memoir: from maps to models. Nat Rev Neurosci 4:266–275. doi:10.1038/nrn1074
Hendricks JC, Finn SM, Panckeri KA et al (2000) Rest in Drosophila is a sleep-like state. Neuron 25:129–138
Hendricks JC, Kirk D, Panckeri K et al (2003) Modafinil maintains waking in the fruit fly drosophila melanogaster. Sleep 26:139–146
Horne J (2009) REM sleep, energy balance and “optimal foraging”. Neurosci Biobehav Rev 33:466–474. doi:10.1016/j.neubiorev.2008.12.002
Ikeya T, Galic M, Belawat P et al (2002) Nutrient-dependent expression of insulin-like peptides from neuroendocrine cells in the CNS contributes to growth regulation in Drosophila. Curr Biol 12:1293–1300
Inutsuka A, Yamanaka A (2013) The physiological role of orexin/hypocretin neurons in the regulation of sleep/wakefulness and neuroendocrine functions. Front Endocrinol (Lausanne) 4:18. doi:10.3389/fendo.2013.00018
Isabel G, Martin J-R, Chidami S et al (2005) AKH-producing neuroendocrine cell ablation decreases trehalose and induces behavioral changes in Drosophila. Am J Physiol Regul Integr Comp Physiol 288:R531–R538. doi:10.1152/ajpregu.00158.2004
Joiner WJ, Crocker A, White BH, Sehgal A (2006) Sleep in Drosophila is regulated by adult mushroom bodies. Nature 441:757–760. doi:10.1038/nature04811
Kaneko M, Hall JC (2000) Neuroanatomy of cells expressing clock genes in Drosophila: transgenic manipulation of the period and timeless genes to mark the perikarya of circadian pacemaker neurons and their projections. J Comp Neurol 422(1):66–94
Kayser MS, Yue Z, Sehgal A (2014) A critical period of sleep for development of courtship circuitry and behavior in Drosophila. Science 344:269–274. doi:10.1126/science.1250553
Keene AC, Stratmann M, Keller A et al (2004) Diverse odor-conditioned memories require uniquely timed dorsal paired medial neuron output. Neuron 44:521–533. doi:10.1016/j.neuron.2004.10.006
Keene AC, Duboué ER, McDonald DM et al (2010) Clock and cycle limit starvation-induced sleep loss in Drosophila. Curr Biol 20:1209–1215. doi:10.1016/j.cub.2010.05.029
Kim SK, Rulifson EJ (2004) Conserved mechanisms of glucose sensing and regulation by Drosophila corpora cardiaca cells. 431:316–320. doi:10.1038/nature02913.1
Knutson KL, Van Cauter E (2008) Associations between sleep loss and increased risk of obesity and diabetes. Ann NY Acad Sci 1129:287–304. doi:10.1196/annals.1417.033
Laposky AD, Shelton J, Bass J et al (2006) Altered sleep regulation in leptin-deficient mice. Am J Physiol Regul Integr Comp Physiol 290:R894–R903. doi:10.1152/ajpregu.00304.2005
Laposky AD, Bass J, Kohsaka A, Turek FW (2008) Sleep and circadian rhythms: key components in the regulation of energy metabolism. FEBS Lett 582:142–151. doi:10.1016/j.febslet.2007.06.079
Lazareva Aa, Roman G, Mattox W et al (2007) A role for the adult fat body in Drosophila male courtship behavior. PLoS Genet 3:e16. doi:10.1371/journal.pgen.0030016
Lebestky T, Chang J-SC, Dankert H et al (2009) Two different forms of arousal in Drosophila are oppositely regulated by the dopamine D1 receptor ortholog DopR via distinct neural circuits. Neuron 64:522–536. doi:10.1016/j.neuron.2009.09.031
Lee W-C, Micchelli CA (2013) Development and characterization of a chemically defined food for Drosophila. PLoS ONE 8:e67308. doi:10.1371/journal.pone.0067308
Lee G, Park JH (2004) Hemolymph sugar homeostasis and starvation-induced hyperactivity affected by genetic manipulations of the adipokinetic hormone-encoding gene in Drosophila melanogaster. Genetics 167:311–323
Linford NJ, Chan TP, Pletcher SD (2012) Re-patterning sleep architecture in Drosophila through gustatory perception and nutritional quality. PLoS Genet 8:e1002668. doi:10.1371/journal.pgen.1002668
Liu G, Seiler H, Wen A et al (2006) Distinct memory traces for two visual features in the Drosophila brain. Nature 439:551–556. doi:10.1038/nature04381
Liu W, Guo F, Lu B, Guo A (2008) Amnesiac regulates sleep onset and maintenance in Drosophila melanogaster. Biochem Biophys Res Commun 372:798–803. doi:10.1016/j.bbrc.2008.05.119
Liu Q, Liu S, Kodama L et al (2012) Two dopaminergic neurons signal to the dorsal fan-shaped body to promote wakefulness in Drosophila. Curr Biol 22:2114–2123. doi:10.1016/j.cub.2012.09.008
Mair W, Piper MDW, Partridge L (2005) Calories do not explain extension of life span by dietary restriction in Drosophila. PLoS Biol 3:e223. doi:10.1371/journal.pbio.0030223
Mattaliano MD, Montana ES, Parisky KM et al (2007) The Drosophila ARC homolog regulates behavioral responses to starvation. Mol Cell Neurosci 36:211–221. doi:10.1016/j.mcn.2007.06.008
McDonald DM, Keene AC (2010) The sleep-feeding conflict: understanding behavioral integration through genetic analysis in Drosophila. Aging (Albany NY) 2:519–522
Metaxakis A, Tain LS, Grönke S et al (2014) Lowered insulin signalling ameliorates age-related sleep fragmentation in Drosophila. PLoS Biol 12:e1001824. doi:10.1371/journal.pbio.1001824
Morton GJ, Schwartz MW (2011) Leptin and the central nervous system control of glucose metabolism. Physiol Rev 91:389–411. doi:10.1152/physrev.00007.2010
Nitz DA, van Swinderen B, Tononi G, Greenspan RJ (2002) Electrophysiological correlates of rest and activity in Drosophila melanogaster. Curr Biol 12:1934–1940
Okamoto N, Yamanaka N, Yagi Y et al (2009) A fat body-derived IGF-like peptide regulates postfeeding growth in Drosophila. Dev Cell 17:885–891. doi:10.1016/j.devcel.2009.10.008
Osborne KA, Robichon A, Burgess E, Butland S, Shaw RA, Coulthard A, Pereira HS, Greenspan RJ, Sokolowski MB (1997) Natural behavior polymorphism due to a cGMP-dependent protein kinase of Drosophila. Science 277:834–836
Parisky KM, Agosto J, Pulver SR et al (2008) PDF cells are a GABA-responsive wake-promoting component of the Drosophila sleep circuit. Neuron 60:672–682. doi:10.1016/j.neuron.2008.10.042
Park D, Veenstra Ja, Park JH, Taghert PH (2008) Mapping peptidergic cells in Drosophila: where DIMM fits in. PLoS ONE 3:e1896. doi:10.1371/journal.pone.0001896
Pfeiffenberger C, Lear BC, Keegan KP, Allada R (2010) Locomotor activity level monitoring using the Drosophila Activity Monitoring (DAM) System. Cold Spring Harb Protoc:pdb.prot5518
Piper MDW, Blanc E, Leitão-Gonçalves R et al (2014) A holidic medium for Drosophila melanogaster. Nat Methods 11:100–105. doi:10.1038/nmeth.2731
Pitman JL, McGill JJ, Keegan KP, Allada R (2006) A dynamic role for the mushroom bodies in promoting sleep in Drosophila. Nature 441:753–756. doi:10.1038/nature04739
Poeck B, Triphan T, Neuser K, Strauss R (2008) Locomotor control by the central complex in Drosophila—an analysis of the tay bridge mutant. Dev Neurobiol 68:1046–1058. doi:10.1002/dneu.20643
Rajan A, Perrimon N (2012) Drosophila cytokine unpaired 2 regulates physiological homeostasis by remotely controlling insulin secretion. Cell 151:123–137. doi:10.1016/j.cell.2012.08.019
Renn SC, Park JH, Rosbash M et al (1999) A pdf neuropeptide gene mutation and ablation of PDF neurons each cause severe abnormalities of behavioral circadian rhythms in Drosophila. Cell 99:791–802. doi:10.1016/S0092-8674(00)81676-1
Root CM, Masuyama K, Green DS et al (2008) A presynaptic gain control mechanism fine-tunes olfactory behavior. Neuron 59:311–321. doi:10.1016/j.neuron.2008.07.003
Rulifson EJ, Kim SK, Nusse R (2002) Ablation of insulin-producing neurons in flies: growth and diabetic phenotypes. Science 296:1118–1120. doi:10.1126/science.1070058
Saltiel AR, Kahn CR (2001) Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414:799–806. doi:10.1038/414799a
Sassu ED, McDermott JE, Keys BJ et al (2012) Mio/dChREBP coordinately increases fat mass by regulating lipid synthesis and feeding behavior in Drosophila. Biochem Biophys Res Commun 426:43–48. doi:10.1016/j.bbrc.2012.08.028
Seelig JD, Jayaraman V (2013) Feature detection and orientation tuning in the Drosophila central complex. Nature 503:262–266. doi:10.1038/nature12601
Sehgal A, Mignot E (2011) Genetics of sleep and sleep disorders. Cell 146:194–207. doi:10.1016/j.cell.2011.07.004
Seugnet L, Suzuki Y, Donlea JM et al (2011) Sleep deprivation during early-adult development results in long-lasting learning deficits in adult Drosophila. Sleep 34:137–146
Shaw PJ, Cirelli C, Greenspan RJ, Tononi G (2000) Correlates of sleep and waking in Drosophila melanogaster. Science 287:1834–1837
Sinakevitch I, Strausfeld NJ (2006) Comparison of octopamine-like immunoreactivity in the brains of the fruit fly and blow fly. J Comp Neurol 494:460–475. doi:10.1002/cne.20799
Skorupa Da, Dervisefendic A, Zwiener J, Pletcher SD (2008) Dietary composition specifies consumption, obesity, and lifespan in Drosophila melanogaster. Aging Cell 7:478–490. doi:10.1111/j.1474-9726.2008.00400.x
Taheri S, Lin L, Austin D et al (2004) Short sleep duration is associated with reduced leptin, elevated ghrelin, and increased body mass index. PLoS Med 1:e62. doi:10.1371/journal.pmed.0010062
Tanaka NK, Tanimoto H, Ito K (2008) Neuronal assemblies of the Drosophila mushroom body. J Comp Neurol 508:711–755. doi:10.1002/cne.21692
Thimgan MS, Suzuki Y, Seugnet L et al (2010) The perilipin homologue, lipid storage droplet 2, regulates sleep homeostasis and prevents learning impairments following sleep loss. PLoS Biol. doi:10.1371/journal.pbio.1000466
Ueno T, Tomita J, Tanimoto H et al (2012) Identification of a dopamine pathway that regulates sleep and arousal in Drosophila. Nat Neurosci 15:1516–1523. doi:10.1038/nn.3238
Unger RH, Cherrington AD (2012) Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover. J Clin Invest 122:4–12. doi:10.1172/JCI60016
Van Alphen B, Yap MHW, Kirszenblat L et al (2013) A dynamic deep sleep stage in Drosophila. J Neurosci 33:6917–6927. doi:10.1523/JNEUROSCI.0061-13.2013
Van der Horst DJ (2003) Insect adipokinetic hormones: release and integration of flight energy metabolism. Comp Biochem Physiol B Biochem Mol Biol 136:217–226
Winther AME, Acebes A, Ferrús A (2006) Tachykinin-related peptides modulate odor perception and locomotor activity in Drosophila. Mol Cell Neurosci 31:399–406. doi:10.1016/j.mcn.2005.10.010
Wu Q, Zhao Z, Shen P (2005) Regulation of aversion to noxious food by Drosophila neuropeptide Y- and insulin-like systems. Nat Neurosci 8:1350–1355. doi:10.1038/nn1540
Wu MN, Ho K, Crocker A et al (2009) The effects of caffeine on sleep in Drosophila require PKA activity, but not the adenosine receptor. J Neurosci 29:11029–11037. doi:10.1523/JNEUROSCI.1653-09.2009
Xu K, Zheng X, Sehgal A (2008) Regulation of feeding and metabolism by neuronal and peripheral clocks in Drosophila. Cell Metab 8:289–300. doi:10.1016/j.cmet.2008.09.006
Xu K, DiAngelo JR, Hughes ME et al (2011) The circadian clock interacts with metabolic physiology to influence reproductive fitness. Cell Metab 13:639–654. doi:10.1016/j.cmet.2011.05.001
Yu D, Keene AC, Srivatsan A et al (2005) Drosophila DPM neurons form a delayed and branch-specific memory trace after olfactory classical conditioning. Cell 123:945–957. doi:10.1016/j.cell.2005.09.037
Zheng X, Yang Z, Yue Z et al (2007) FOXO and insulin signaling regulate sensitivity of the circadian clock to oxidative stress. Proc Natl Acad Sci USA 104:15899–15904. doi:10.1073/pnas.0701599104
Zimmerman JE, Raizen DM, Maycock MH et al (2008) A video method to study Drosophila sleep. Sleep 31:1587–1598
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Yurgel, M.E., Masek, P., DiAngelo, J. et al. Genetic dissection of sleep–metabolism interactions in the fruit fly. J Comp Physiol A 201, 869–877 (2015). https://doi.org/10.1007/s00359-014-0936-9
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DOI: https://doi.org/10.1007/s00359-014-0936-9