Cerebral Metabolic Changes During Sleep

Current Neurology and Neuroscience Reports

Volumn 18, Issue 9, 2018, Pages

  Aalling, Nadia Nielsen ^a   Nedergaard, Maiken ^a,b   DiNuzzo, Mauro ^a  

^a UNIVERSITY OF COPENHAGEN   (Denmark)

^b UNIVERSITY OF ROCHESTER SCHOOL OF MEDICINE AND DENTISTRY   (United States)

Author keywords

Brain energy metabolism; Fatty acid oxidation; Sleep wake cycle

Indexed keywords

4 AMINOBUTYRIC ACID RECEPTOR; CARBOHYDRATE; FATTY ACID; FATTY ACID TRANSPORTER; GLUCOSE; KETONE; LACTIC ACID; LONG CHAIN FATTY ACID; MESSENGER RNA; PHOSPHOLIPID;

ADULT; AEROBIC METABOLISM; AWARENESS; BRAIN FUNCTION; BRAIN METABOLISM; CELL MEMBRANE; DISEASE ASSOCIATION; ENERGY METABOLISM; ENERGY RESOURCE; FATTY ACID OXIDATION; GLUCOSE UTILIZATION; GLYCOLYSIS; HUMAN; LIPOGENESIS; METABOLIC DISORDER; METABOLITE; MOUSE; MYELINATION; NERVE CELL PLASTICITY; NONHUMAN; NONREM SLEEP; OLIGODENDROGLIA; PHAGOCYTOSIS; PREOPTIC NUCLEUS; PROTEIN BINDING; RAT; REM SLEEP; REVIEW; SLEEP; SLEEP WAKING CYCLE; WAKEFULNESS; ANIMAL; BRAIN; METABOLISM; NERVE CELL; PHYSIOLOGY; SLEEP STAGE;

ANIMALS; BRAIN; ENERGY METABOLISM; GLUCOSE; HUMANS; LACTIC ACID; NEURONS; SLEEP STAGES; WAKEFULNESS;

EID: 85050130811     PISSN: 15284042     EISSN: 15346293     Source Type: Journal    
DOI: 10.1007/s11910-018-0868-9     Document Type: Review

References (160)

1. Chatelle C, Laureys S, Schnakers C. Disorders of consciousness: what do we know? In: Dehaene S, Christen Y, editors. Characterizing consciousness: from cognition to the clinic? Berlin: Springer; 2011. p. 85–98
2. Bodart O, Gosseries O, Wannez S, Thibaut A, Annen J, Boly M, et al. Measures of metabolism and complexity in the brain of patients with disorders of consciousness. NeuroImage Clin. 2017;14:354–62. 10.1016/j.nicl.2017.02.002
3. Shulman RG, Hyder F, Rothman DL. Baseline brain energy supports the state of consciousness. Proc Natl Acad Sci U S A. 2009;106(27):11096–101. 10.1073/pnas.0903941106
4. Stender J, Mortensen KN, Thibaut A, Darkner S, Laureys S, Gjedde A, et al. The minimal energetic requirement of sustained awareness after brain injury. Curr Biol. 2016;26(11):1494–9. 10.1016/j.cub.2016.04.024
5. DiNuzzo M, Nedergaard M. Brain energetics during the sleep-wake cycle. Curr Opin Neurobiol. 2017;47:65–72. 10.1016/j.conb.2017.09.010
6. Shulman RG. A philosophical analysis of neuroenergetics. Front Neuroenerg. 2011;3:6. 10.3389/fnene.2011.00006
7. DiNuzzo M. Astrocyte-neuron interactions during learning may occur by lactate signaling rather than metabolism. Front Integr Neurosci. 2016;10:2. 10.3389/fnint.2016.00002
8. Burdakov D, Jensen LT, Alexopoulos H, Williams RH, Fearon IM, O'Kelly I, et al. Tandem-pore K+ channels mediate inhibition of orexin neurons by glucose. Neuron. 2006;50(5):711–22. 10.1016/j.neuron.2006.04.032
9. Varin C, Rancillac A, Geoffroy H, Arthaud S, Fort P, Gallopin T. Glucose induces slow-wave sleep by exciting the sleep-promoting neurons in the ventrolateral preoptic nucleus: a new link between sleep and metabolism. J Neurosci. 2015;35(27):9900–11. 10.1523/jneurosci.0609-15.2015
10. Tang F, Lane S, Korsak A, Paton JF, Gourine AV, Kasparov S, et al. Lactate-mediated glia-neuronal signalling in the mammalian brain. Nat Commun. 2014;5:3284. 10.1038/ncomms4284
11. Khan MZ, He L. The role of polyunsaturated fatty acids and GPR40 receptor in brain. Neuropharmacology. 2017;113(Pt B):639–51. 10.1016/j.neuropharm.2015.05.013
12. Offermanns S, Schwaninger M. Nutritional or pharmacological activation of HCA(2) ameliorates neuroinflammation. Trends Mol Med. 2015;21(4):245–55. 10.1016/j.molmed.2015.02.002
13. Morland C, Lauritzen KH, Puchades M, Holm-Hansen S, Andersson K, Gjedde A, et al. The lactate receptor, G-protein-coupled receptor 81/hydroxycarboxylic acid receptor 1: expression and action in brain. J Neurosci Res. 2015;93(7):1045–55. 10.1002/jnr.23593
14. Chang P, Augustin K, Boddum K, Williams S, Sun M, Terschak JA, et al. Seizure control by decanoic acid through direct AMPA receptor inhibition. Brain. 2016;139(2):431–43. 10.1093/brain/awv325
15. Yang J, Ruchti E, Petit JM, Jourdain P, Grenningloh G, Allaman I, et al. Lactate promotes plasticity gene expression by potentiating NMDA signaling in neurons. Proc Natl Acad Sci U S A. 2014;111(33):12228–33. 10.1073/pnas.1322912111
16. Simeone TA, Simeone KA, Rho JM. Ketone bodies as anti-seizure agents. Neurochem Res. 2017;42(7):2011–8. 10.1007/s11064-017-2253-5
17. Bourassa MW, Alim I, Bultman SJ, Ratan RR. Butyrate, neuroepigenetics and the gut microbiome: can a high fiber diet improve brain health? Neurosci Lett. 2016;625:56–63. 10.1016/j.neulet.2016.02.009
18. Kayaba M, Park I, Iwayama K, Seya Y, Ogata H, Yajima K, et al. Energy metabolism differs between sleep stages and begins to increase prior to awakening. Metabolism. 2017;69:14–23. 10.1016/j.metabol.2016.12.016
19. Hibi M, Kubota C, Mizuno T, Aritake S, Mitsui Y, Katashima M, et al. Effect of shortened sleep on energy expenditure, core body temperature, and appetite: a human randomised crossover trial. Sci Rep. 2017;7:39640. 10.1038/srep39640
20. Shechter A, Rising R, Albu JB, St-Onge MP. Experimental sleep curtailment causes wake-dependent increases in 24-h energy expenditure as measured by whole-room indirect calorimetry. Am J Clin Nutr. 2013;98(6):1433–9. 10.3945/ajcn.113.069427
21. Klingenberg L, Chaput JP, Holmback U, Jennum P, Astrup A, Sjodin A. Sleep restriction is not associated with a positive energy balance in adolescent boys. Am J Clin Nutr. 2012;96(2):240–8. 10.3945/ajcn.112.038638
22. Wildenhoff KE, Johansen JP, Karstoft H, Yde H, Sorensen NS. Diurnal variations in the concentrations of blood acetoacetate and 3-hydroxybutyrate. The ketone body peak around midnight and its relationship to free fatty acids, glycerol, insulin, growth hormone and glucose in serum and plasma. Acta Med Scand. 1974;195:25–8
23. Schlierf G, Dorow E. Diurnal patterns of triglycerides, free fatty acids, blood sugar, and insulin during carbohydrate-induction in man and their modification by nocturnal suppression of lipolysis. J Clin Invest. 1973;52:732–40. 10.1172/JCI107235
24. Iwata S, Ozawa K, Shimahara Y, Mori K, Kobayashi N, Kumada K, et al. Diurnal fluctuations of arterial ketone body ratio in normal subjects and patients with liver dysfunction. Gastroenterology. 1991;100:1371–8
25. De Gasquet P, Griglio S, Pequignot-Planche E, Malewiak MI. Diurnal changes in plasma and liver lipids and lipoprotein lipase activity in heart and adipose tissue in rats fed a high and low fat diet. J Nutr. 1977;107:199–212
26. Chavan R, Feillet C, Costa SSF, Delorme JE, Okabe T, Ripperger JA, et al. Liver-derived ketone bodies are necessary for food anticipation. Nat Commun. 2016;7:1–10. 10.1038/ncomms10580
27. Ang JE, Revell V, Mann A, Mantele S, Otway DT, Johnston JD, et al. Identification of human plasma metabolites exhibiting time-of-day variation using an untargeted liquid chromatography-mass spectrometry metabolomic approach. Chronobiol Int. 2012;29(7):868–81. 10.3109/07420528.2012.699122
28. Dallmann R, Viola AU, Tarokh L, Cajochen C, Brown SA. The human circadian metabolome. Proc Natl Acad Sci. 2012;109:2625–9. 10.1073/pnas.1114410109
29. Van Den Berg R, Mook-Kanamori DO, Donga E, Van Dijk M, Van Dijk JG, Lammers GJ, et al. A single night of sleep curtailment increases plasma acylcarnitines: novel insights in the relationship between sleep and insulin resistance. Arch Biochem Biophys. 2016;589:145–51. 10.1016/j.abb.2015.09.017
30. • Bellesi M, Pfister-Genskow M, Maret S, Keles S, Tononi G, Cirelli C. Effects of sleep and wake on oligodendrocytes and their precursors. J Neurosci. 2013;33(36):14288–300. 10.1523/JNEUROSCI.5102-12.2013. Using translating ribosome affinity purification (TRAP) technology combined with microarray analysis, this study generated cell-type specific transcriptomic profiles of oligodendrocytes after longer periods of sleep, wake, or acute sleep deprivation. They show that genes involved in phospholipid synthesis and myelination or promoting OPC proliferation are transcribed preferentially during sleep, and experimentally validate some of their findings
31. Poduslo SE, Miller K. Ketone bodies as precursors for lipid synthesis in neurons, astrocytes, and oligodendroglia (myelin) in hyperthyroidism, hyperketonemia and hypoketonemia. Neurochem Int. 1991;18(1):85–8
32. Feneberg R, Sparber M, Veldhuis JD, Mehls O, Ritz E, Schaefer F. Synchronous fluctuations of blood insulin and lactate concentrations in humans. J Clin Endocrinol Metab. 1999;84(1):220–7. 10.1210/jcem.84.1.5377
33. Netchiporouk L, Shram N, Salvert D, Cespuglio R. Brain extracellular glucose assessed by voltammetry throughout the rat sleep-wake cycle. Eur J Neurosci. 2001;13(7):1429–34
34. Van den Noort S, Brine K. Effect of sleep on brain labile phosphates and metabolic rate. Am J Phys. 1970;218(5):1434–9
35. Dash MB, Bellesi M, Tononi G, Cirelli C. Sleep/wake dependent changes in cortical glucose concentrations. J Neurochem. 2013;124(1):79–89. 10.1111/jnc.12063
36. Cespuglio R, Netchiporouk L, Glucose SN. Lactate monitoring across the rat sleep–wake cycle. In: Marinesco S, Dale N, editors. Microelectrode Biosensors. Totowa, NJ: Humana Press; 2013. p. 241–56
37. Naylor E, Aillon DV, Barrett BS, Wilson GS, Johnson DA, Johnson DA, et al. Lactate as a biomarker for sleep. Sleep. 2012;35(9):1209–22. 10.5665/sleep.2072
38. McNay EC, Fries TM, Gold PE. Decreases in rat extracellular hippocampal glucose concentration associated with cognitive demand during a spatial task. Proc Natl Acad Sci U S A. 2000;97(6):2881–5
39. Mangia S, Tkac I, Gruetter R, Van de Moortele PF, Maraviglia B, Ugurbil K. Sustained neuronal activation raises oxidative metabolism to a new steady-state level: evidence from 1H NMR spectroscopy in the human visual cortex. J Cereb Blood Flow Metab. 2007;27(5):1055–63. 10.1038/sj.jcbfm.9600401
40. Merboldt KD, Bruhn H, Hanicke W, Michaelis T, Frahm J. Decrease of glucose in the human visual cortex during photic stimulation. Magn Reson Med. 1992;25(1):187–94
41. Clegern WC, Moore ME, Schmidt MA, Wisor J. Simultaneous electroencephalography, real-time measurement of lactate concentration and optogenetic manipulation of neuronal activity in the rodent cerebral cortex. J Vis Exp. 2012;70:e4328. 10.3791/4328
42. Shram N, Netchiporouk L, Cespuglio R. Lactate in the brain of the freely moving rat: voltammetric monitoring of the changes related to the sleep-wake states. Eur J Neurosci. 2002;16(3):461–6
43. Rempe MJ, Wisor JP. Cerebral lactate dynamics across sleep/wake cycles. Front Comput Neurosci. 2014;8:174. 10.3389/fncom.2014.00174
44. Dash MB, Tononi G, Cirelli C. Extracellular levels of lactate, but not oxygen, reflect sleep homeostasis in the rat cerebral cortex. Sleep. 2012;35(7):909–19. 10.5665/sleep.1950
45. Richter D, Dawson RM. Brain metabolism in emotional excitement and in sleep. Am J Phys. 1948;154(1):73–9
46. Lin Y, Stephenson MC, Xin L, Napolitano A, Morris PG. Investigating the metabolic changes due to visual stimulation using functional proton magnetic resonance spectroscopy at 7 T. J Cereb Blood Flow Metab. 2012;32(8):1484–95. 10.1038/jcbfm.2012.33
47. Urrila AS, Hakkarainen A, Heikkinen S, Vuori K, Stenberg D, Hakkinen AM, et al. Metabolic imaging of human cognition: an fMRI/1H-MRS study of brain lactate response to silent word generation. J Cereb Blood Flow Metab. 2003;23(8):942–8. 10.1097/01.WCB.0000080652.64357.1D
48. Frahm J, Kruger G, Merboldt KD, Kleinschmidt A. Dynamic uncoupling and recoupling of perfusion and oxidative metabolism during focal brain activation in man. Magn Reson Med. 1996;35(2):143–8
49. Frahm J, Krueger G, Merboldt KD, Kleinschmidt A. Dynamic NMR studies of perfusion and oxidative metabolism during focal brain activation. Advances in Experimental Medicine and Biology. 1997;413:195–203
50. Prichard J, Rothman D, Novotny E, Petroff O, Kuwabara T, Avison M, et al. Lactate rise detected by 1H NMR in human visual cortex during physiologic stimulation. Proc Natl Acad Sci U S A. 1991;88(13):5829–31
51. Sappey-Marinier D, Calabrese G, Fein G, Hugg JW, Biggins C, Weiner MW. Effect of photic stimulation on human visual cortex lactate and phosphates using 1H and 31P magnetic resonance spectroscopy. J Cereb Blood Flow Metab. 1992;12(4):584–92
52. •• Hinard V, Mikhail C, Pradervand S, Curie T, Houtkooper RH, Auwerx J, et al. Key electrophysiological, molecular, and metabolic signatures of sleep and wakefulness revealed in primary cortical cultures. J Neurosci. 2012;32(36):12506–17. https://doi.org/10.1523/JNEUROSCI.2306-12.2012. This is the only study that have investigated how sleep deprivation affects the mouse cortex metabolome. Based on results of this study and from stimulation of neuronal cell cultures, the authors suggest that sleep might play a major role in reestablishing the neuronal membrane homeostasis
53. Dworak M, McCarley RW, Kim T, Kalinchuk AV, Basheer R. Sleep and brain energy levels: ATP changes during sleep. J Neurosci. 2010;30(26):9007–16. 10.1523/jneurosci.1423-10.2010
54. Maquet P, Dive D, Salmon E, Sadzot B, Franco G, Poirrier R, et al. Cerebral glucose utilization during stage 2 sleep in man. Brain Res. 1992;571(1):149–53
55. Buchsbaum MS, Gillin JC, Wu J, Hazlett E, Sicotte N, Dupont RM, et al. Regional cerebral glucose metabolic rate in human sleep assessed by positron emission tomography. Life Sci. 1989;45(15):1349–56
56. Franck G, Salmon E, Poirrier R, Sadzot B, Franco G. Study of regional cerebral glucose metabolism, in man, while awake or asleep, by positron emission tomography. Rev Electroencephalogr Neurophysiol Clin. 1987;17(1):71–7
57. Maquet P, Dive D, Salmon E, Sadzot B, Franco G, Poirrier R, et al. Cerebral glucose utilization during sleep-wake cycle in man determined by positron emission tomography and [18F]2-fluoro-2-deoxy-D-glucose method. Brain Res. 1990;513(1):136–43
58. Kennedy C, Gillin JC, Mendelson W, Suda S, Miyaoka M, Ito M, et al. Local cerebral glucose utilization in non-rapid eye movement sleep. Nature. 1982;297(5864):325–7
59. Ramm P, Frost BJ. Cerebral and local cerebral metabolism in the cat during slow wave and REM sleep. Brain Res. 1986;365(1):112–24
60. Heiss WD, Pawlik G, Herholz K, Wagner R, Wienhard K. Regional cerebral glucose metabolism in man during wakefulness, sleep, and dreaming. Brain Res. 1985;327(1–2):362–6
61. Fox PT, Raichle ME, Mintun MA, Dence C. Nonoxidative glucose consumption during focal physiologic neural activity. Science. 1988;241(4864):462–4
62. Madsen PL, Schmidt JF, Wildschiodtz G, Friberg L, Holm S, Vorstrup S, et al. Cerebral O2 metabolism and cerebral blood flow in humans during deep and rapid-eye-movement sleep. J Appl Physiol (Bethesda, Md: 1985). 1991;70(6):2597–601
63. Madsen PL, Schmidt JF, Holm S, Vorstrup S, Lassen NA, Wildschiodtz G. Cerebral oxygen metabolism and cerebral blood flow in man during light sleep (stage 2). Brain Res. 1991;557(1–2):217–20
64. Mangold R, Sokoloff L, Conner E, Kleinerman J, Therman PO, Kety SS. The effects of sleep and lack of sleep on the cerebral circulation and metabolism of normal young men. J Clin Invest. 1955;34(7, Part 1):1092–100. 10.1172/jci103158
65. Fox PT, Raichle ME. Focal physiological uncoupling of cerebral blood flow and oxidative metabolism during somatosensory stimulation in human subjects. Proc Natl Acad Sci U S A. 1986;83(4):1140–4
66. Roland PE, Eriksson L, Stone-Elander S, Widen L. Does mental activity change the oxidative metabolism of the brain? J Neurosci. 1987;7(8):2373–89
67. •• Cirelli C, Gutierrez CM, Tononi G. Extensive and divergent effects of sleep and wakefulness on brain gene expression. Neuron. 2004;41(1):35–43. Using microarray technology, a neat experimental design and clever contextual integration, this study shows that ~10% of transcripts in the rat cerebral cortex are differentially expressed between day and night and that half of these are modulated by sleep and wakefulness independent of circadian rythms
68. Bellesi M, de Vivo L, Tononi G, Cirelli C. Effects of sleep and wake on astrocytes: clues from molecular and ultrastructural studies. BMC Biol. 2015;13:66. 10.1186/s12915-015-0176-7
69. Andreone BJ, Chow BW, Tata A, Lacoste B, Ben-Zvi A, Bullock K, et al. Blood-brain barrier permeability is regulated by lipid transport-dependent suppression of Caveolae-mediated transcytosis. Neuron. 2017;94(3):581–94 e5. https://doi.org/10.1016/j.neuron.2017.03.043
70. Hatori M, Vollmers C, Zarrinpar A, DiTacchio L, Bushong EA, Gill S, et al. Time-restricted feeding without reducing caloric intake prevents metabolic diseases in mice fed a high-fat diet. Cell Metab. 2012;15(6):848–60. 10.1016/j.cmet.2012.04.019
71. Neufeld-Cohen A, Robles MS, Aviram R, Manella G, Adamovich Y, Ladeuix B, et al. Circadian control of oscillations in mitochondrial rate-limiting enzymes and nutrient utilization by PERIOD proteins. Proc Natl Acad Sci U S A. 2016;113(12):E1673–82. 10.1073/pnas.1519650113
72. Hertz L, Dienel GA. Energy metabolism in the brain. Int Rev Neurobiol. 2002;51:1–102
73. Boyle PJ, Scott JC, Krentz AJ, Nagy RJ, Comstock E, Hoffman C. Diminished brain glucose metabolism is a significant determinant for falling rates of systemic glucose utilization during sleep in normal humans. J Clin Investig. 1994;93:529–35. 10.1172/JCI117003
74. Bailey SM, Udoh US, Young ME. Circadian regulation of metabolism. J Endocrinol. 2014;222(2):R75–96. 10.1530/JOE-14-0200
75. Broussard JL, Chapotot F, Abraham V, Day A, Delebecque F, Whitmore HR, et al. Sleep restriction increases free fatty acids in healthy men. Diabetologia. 2015;58(4):791–8. 10.1007/s00125-015-3500-4
76. Clarke DD, Sokoloff L. Basic neurochemistry. In: Agranoff BW, Fisher RW, Uhler MD, editors. Siegel GJ. Philadelphia: Lippincott Williams & Wilkins; 1999
77. Courtice FC. The metabolism of the brain. J Neurol Psychiatry. 1940;3(4):306–10
78. Siesjo DP. Brain energy metabolism. New York: Wiley; 1978
79. Chute AL, Smyth DH. Metabolism of the isolated perfused cat’s brain. Quarterly Journal of Experimental Physiology and Cognate Medical Sciences. 1939;29(4):379–94. 10.1113/expphysiol.1939.sp000816
80. Himwich HE, Nahum LH. The respiratory quotient of the brain. American Journal of Physiology-Legacy Content. 1932;101(3):446–53. 10.1152/ajplegacy.1932.101.3.446
81. Kerpel-Fronius S. Discussion. In: Wolstenholme GEW, editor. Somatic stability in the newly born. London: J. & a. Churchill LTD; 1961. p. 73
82. Edmond J. Energy metabolism in developing brain cells. Can J Physiol Pharmacol. 1992;70(Suppl):S118–29
83. Dienel GA. Brain lactate metabolism: the discoveries and the controversies. J Cereb Blood Flow Metab. 2012;32(7):1107–38. 10.1038/jcbfm.2011.175
84. Dienel GA, Cruz NF. Aerobic glycolysis during brain activation: adrenergic regulation and influence of norepinephrine on astrocytic metabolism. J Neurochem. 2016;138(1):14–52. 10.1111/jnc.13630
85. DiNuzzo M, Giove F, Maraviglia B, Mangia S. Monoaminergic control of cellular glucose utilization by glycogenolysis in neocortex and hippocampus. Neurochem Res. 2015;40:2493–504. 10.1007/s11064-015-1656-4
86. Lundgaard I, Lu ML, Yang E, Peng W, Mestre H, Hitomi E, et al. Glymphatic clearance controls state-dependent changes in brain lactate concentration. J Cereb Blood Flow Metab. 2016;37:2112–24. 10.1177/0271678x16661202
87. Kong J, Shepel PN, Holden CP, Mackiewicz M, Pack AI, Geiger JD. Brain glycogen decreases with increased periods of wakefulness: implications for homeostatic drive to sleep. J Neurosci. 2002;22(13):5581–7. doi:20026500
88. DiNuzzo M, Giove F. Activity-dependent energy budget for neocortical signaling: effect of short-term synaptic plasticity on the energy expended by spiking and synaptic activity. J Neurosci Res. 2012;90(11):2094–102. 10.1002/jnr.23098
89. Rey G, Valekunja UK, Feeney KA, Wulund L, Milev NB, Stangherlin A, et al. The pentose phosphate pathway regulates the circadian clock. Cell Metab. 2016;24(3):462–73. 10.1016/j.cmet.2016.07.024
90. Ramm P, Smith CT. Rates of cerebral protein synthesis are linked to slow wave sleep in the rat. Physiol Behav. 1990;48(5):749–53. 10.1016/0031-9384(90)90220-X
91. Mackiewicz M, Shockley KR, Romer MA, Galante RJ, Zimmerman JE, Naidoo N, et al. Macromolecule biosynthesis: a key function of sleep. Physiol Genomics. 2007;31(3):441–57. 10.1152/physiolgenomics.00275.2006
92. Grønli J, Soulé J, Bramham CR. Sleep and protein synthesis-dependent synaptic plasticity: impacts of sleep loss and stress. Front Behav Neurosci. 2013;7:224. 10.3389/fnbeh.2013.00224
93. Seibt J, Dumoulin MC, Aton SJ, Coleman T, Watson A, Naidoo N, et al. Protein synthesis during sleep consolidates cortical plasticity in vivo. Curr Biol. 2012;22(8):676–82. 10.1016/j.cub.2012.02.016
94. Ebert D, Haller RG, Walton ME. Energy contribution of octanoate to intact rat brain metabolism measured by 13C nuclear magnetic resonance spectroscopy. J Neurosci. 2003;23:5928–35
95. •• Miller JC, Gnaedinger JM, Rapoport SI. Utilization of plasma fatty acid in rat brain: distribution of [14C]palmitate between oxidative and synthetic pathways. J Neurochem. 1987;49:1507–14. Building on knowlegde from prior in vitro studies, this study shows that intravenously injected [14C]palmitate into awake rats are taken up by the brain in vivo, about 50% undergo beta-oxidation and are temporally incoorporated into aqueous metabolite pools. The rest is incoorporated into stable lipid and protein compartments
96. Gnaedinger J, Miller J. Cerebral metabolism of plasma palmitate in awake, adult rat: subcellular localization. Neurochem Res. 1988;13:21–9
97. Freed LM, Wakabayashi S, Bell JM, Rapoport SI. Effect of inhibition of β-oxidation on incorporation of [U-14C]palmitate and [1-14C]arachidonate into brain lipids. Brain Res. 1994;645(1–2):41–8. 10.1016/0006-8993(94)91636-5
98. Arai T, Wakabayashi S-i, Channing MA, Dunn BB, Der MG, Bell JM, et al. Incorporation of [1-carbon-11]palmitate in monkey brain using PET. J Nucl Med. 1995;36:2261–7
99. 18 F]fluoro-6-thia-heptadecanoic acid are taken up by the human brain primarily in gray matter regions
100. Frohnert BI, Jacobs DR Jr, Steinberger J, Moran A, Steffen LM, Sinaiko AR. Relation between serum free fatty acids and adiposity, insulin resistance, and cardiovascular risk factors from adolescence to adulthood. Diabetes. 2013;62(9):3163–9. 10.2337/db12-1122
101. Salgin B, Ong KK, Thankamony A, Emmett P, Wareham NJ, Dunger DB. Higher fasting plasma free fatty acid levels are associated with lower insulin secretion in children and adults and a higher incidence of type 2 diabetes. J Clin Endocrinol Metab. 2012;97(9):3302–9. 10.1210/jc.2012-1428
102. Seelig A. The role of size and charge for blood-brain barrier permeation of drugs and fatty acids. J Mol Neurosci. 2007;33(1):32–41
103. Li W, Yang X, Zheng T, Xing S, Wu Y, Bian F, et al. TNF-alpha stimulates endothelial palmitic acid transcytosis and promotes insulin resistance. Sci Rep. 2017;7:44659. 10.1038/srep44659
104. Mitchell RW, Hatch GM. Fatty acid transport into the brain: of fatty acid fables and lipid tails. Prostaglandins Leukot Essent Fat Acids. 2011;85(5):293–302. 10.1016/j.plefa.2011.04.007
105. Gerstner JR, Bremer QZ, Vander Heyden WM, LaVaute TM, Yin JC, Landry CF. Brain fatty acid binding protein (Fabp7) is diurnally regulated in astrocytes and hippocampal granule cell precursors in adult rodent brain. PLoS One. 2008;3:e1631. 10.1371/journal.pone.0001631
106. • Vanlandewijck M, He L, Mae MA, Andrae J, Ando K, Del Gaudio F, et al. A molecular atlas of cell types and zonation in the brain vasculature. Nature. 2018;554(7693):475–80. 10.1038/nature25739. Using single-cell transcriptomics, the Betsholtz lab have created a user-friendy open-access transcriptome database of the mouse brain vasculature zonation: www.betsholtzlab.org/VascularSingleCells/database.html
107. Edmond J, Robbins RA, Bergstrom JD, Cole RA, de Vellis J. Capacity for substrate utilization in oxidative metabolism by neurons, astrocytes, and oligodendrocytes from developing brain in primary culture. J Neurosci Res. 1987;18(4):551–61. 10.1002/jnr.490180407
108. Auestad N, Korsak RA, Morrow JW, Edmond J. Fatty acid oxidation and ketogenesis by astrocytes in primary culture. J Neurochem. 1991;56(4):1376–86
109. Jernberg JN, Bowman CE, Wolfgang MJ, Scafidi S. Developmental regulation and localization of carnitine palmitoyltransferases (CPTs) in rat brain. J Neurochem. 2017;142(3):407–19. 10.1111/jnc.14072
110. Quehenberger O, Armando AM, Brown AH, Milne SB, Myers DS, Merrill AH, et al. Lipidomics reveals a remarkable diversity of lipids in human plasma. J Lipid Res. 2010;51(11):3299–305. 10.1194/jlr.M009449
111. Tognini P, Murakami M, Liu Y, Eckel-Mahan KL, Newman JC, Verdin E, et al. Distinct circadian signatures in liver and gut clocks revealed by ketogenic diet. Cell Metab. 2017;26(3):523–38 e5. https://doi.org/10.1016/j.cmet.2017.08.015
112. Vancura P, Wolloscheck T, Baba K, Tosini G, Iuvone PM, Spessert R. Circadian and dopaminergic regulation of fatty acid oxidation pathway genes in retina and photoreceptor cells. PLoS One. 2016;11(10):e0164665. 10.1371/journal.pone.0164665
113. Davies SK, Ang JE, Revell VL, Holmes B, Mann A, Robertson FP, et al. Effect of sleep deprivation on the human metabolome. Proc Natl Acad Sci U S A. 2014;111(29):10761–6. 10.1073/pnas.1402663111
114. Ishii-Iwamoto EL, Ferrarese MLL, Constantin J, Salgueiro-Pagadigorria C, Bracht A. Effects of norepinephrine on the metabolism of fatty acid with different chain lengths in the perfused rat liver. Mol Cell Biochem. 2000;205:13–23
115. Chang MC, Wakabayashi S, Bell JM. The effect of methyl palmoxirate on incorporation of [U-14C] palmitate into rat brain. Neurochem Res. 1994;19(9):1217–23
116. Sherpa AD, Xiao F, Joseph N, Aoki C, Hrabetova S. Activation of beta-adrenergic receptors in rat visual cortex expands astrocytic processes and reduces extracellular space volume. Synapse. 2016;70(8):307–16. 10.1002/syn.21908
117. Bellesi M, de Vivo L, Chini M, Gilli F, Tononi G, Cirelli C. Sleep loss promotes astrocytic phagocytosis and microglial activation in mouse cerebral cortex. J Neurosci. 2017;37(21):5263–73. 10.1523/jneurosci.3981-16.2017
118. Schonfeld P, Reiser G. Why does brain metabolism not favor burning of fatty acids to provide energy? Reflections on disadvantages of the use of free fatty acids as fuel for brain. J Cereb Blood Flow Metab. 2013;33(10):1493–9. 10.1038/jcbfm.2013.128
119. Laranjeira A, Schulz J, Dotti CG. Genes related to fatty acid beta-oxidation play a role in the functional decline of the Drosophila brain with age. PLoS One. 2016;11(8):e0161143. 10.1371/journal.pone.0161143
120. Wong-Riley M. What is the meaning of the ATP surge during sleep? Sleep. 2011;34(7):833–4. 10.5665/sleep.1102
121. Rabinovitch RC, Samborska B, Faubert B, Ma EH, Gravel SP, Andrzejewski S, et al. AMPK maintains cellular metabolic homeostasis through regulation of mitochondrial reactive oxygen species. Cell Rep. 2017;21(1):1–9. 10.1016/j.celrep.2017.09.026
122. Schönfeld P, Wojtczak L. Short- and medium-chain fatty acids in energy metabolism: the cellular perspective. J Lipid Res. 2016;57(6):943–54. 10.1194/jlr.R067629
123. Nomura T, Iguchi A, Sakamoto N, Harris RA. Effects of octanoate and acetate upon hepatic glycolysis and lipogenesis. Biochim Biophys Acta. 1983;754(3):315–20
124. Morand C, Besson C, Demigne C, Remesy C. Importance of the modulation of glycolysis in the control of lactate metabolism by fatty acids in isolated hepatocytes from fed rats. Arch Biochem Biophys. 1994;309(2):254–60. 10.1006/abbi.1994.1110
125. Herrero-Mendez A, Almeida A, Fernandez E, Maestre C, Moncada S, Bolanos JP. The bioenergetic and antioxidant status of neurons is controlled by continuous degradation of a key glycolytic enzyme by APC/C-Cdh1. Nat Cell Biol. 2009;11(6):747–52. 10.1038/ncb1881
126. Thevenet J, De Marchi U, Domingo JS, Christinat N, Bultot L, Lefebvre G, et al. Medium-chain fatty acids inhibit mitochondrial metabolism in astrocytes promoting astrocyte-neuron lactate and ketone body shuttle systems. FASEB J. 2016;30(5):1913–26. 10.1096/fj.201500182
127. Pierre K, Pellerin L. Monocarboxylate transporters in the central nervous system: distribution, regulation and function. J Neurochem. 2005;94(1):1–14. 10.1111/j.1471-4159.2005.03168.x
128. Chowdhury GMI, Jiang L, Rothman DL, Behar KL. The contribution of ketone bodies to basal and activity-dependent neuronal oxidation in vivo. J Cereb Blood Flow Metab. 2014;34(7):1233–42. 10.1038/jcbfm.2014.77
129. Le Foll C, Levin BE. Fatty acid-induced astrocyte ketone production and the control of food intake. Am J Physiol Regul Integr Comp Physiol. 2016;310(11):R1186–92. 10.1152/ajpregu.00113.2016
130. Guzman M, Blazquez C. Is there an astrocyte-neuron ketone body shuttle? Trends Endocrinol Metab. 2001;12(4):169–73
131. Ruderman NB, Ross PS, Berger M, Goodman MN. Regulation of glucose and ketone-body metabolism in brain of anaesthetized rats. Biochem J. 1974;138(1):1–10
132. Hasselbalch SG, Madsen PL, Hageman LP, Olsen KS, Justesen N, Holm S, et al. Changes in cerebral blood flow and carbohydrate metabolism during acute hyperketonemia. Am J Phys. 1996;270(5 Pt 1):E746–51. 10.1152/ajpendo.1996.270.5.E746
133. Rogawski MA, Loscher W, Rho JM. Mechanisms of action of antiseizure drugs and the ketogenic diet. Cold Spring Harb Perspect Med. 2016;6(5) 10.1101/cshperspect.a022780
134. • Chikahisa S, Shimizu N, Shiuchi T, Sei H. Ketone body metabolism and sleep homeostasis in mice. Neuropharmacology. 2014;79:399–404. 10.1016/j.neuropharm.2013.12.009. This work shows how ketone bodies injected in to the cerebral spinal fluid influence sleep/wake states
135. Juge N, Gray JA, Omote H, Miyaji T, Inoue T, Hara C, et al. Metabolic control of vesicular glutamate transport and release. Neuron. 2010;68(1):99–112. 10.1016/j.neuron.2010.09.002
136. • Dash MB, Douglas CL, Vyazovskiy VV, Cirelli C, Tononi G. Long-term homeostasis of extracellular glutamate in the rat cerebral cortex across sleep and waking states. J Neurosci. 2009;29(3):620–9. 10.1523/jneurosci.5486-08.2009. This study reports the glutamate concentration in two cortical areas of freely behaving rats, recorded with high temporal resolution simultaneously with local field potentials (LFPs) and electroencephalograms (EEGs) from the contralateral cortex. They show that the concentration of glutamate varies as a function of behavioral state
137. Zimmerman JE, Chan MT, Lenz OT, Keenan BT, Maislin G, Pack AI. Glutamate is a wake-active neurotransmitter in Drosophila melanogaster. Sleep. 2017;40(2). 10.1093/sleep/zsw046
138. Newman JC, Verdin E. Ketone bodies as signaling metabolites. Trends Endocrinol Metab. 2014;25(1):42–52. 10.1016/j.tem.2013.09.002
139. Fu SP, Wang JF, Xue WJ, Liu HM, Liu BR, Zeng YL, et al. Anti-inflammatory effects of BHBA in both in vivo and in vitro Parkinson's disease models are mediated by GPR109A-dependent mechanisms. J Neuroinflammation. 2015;12:9. 10.1186/s12974-014-0230-3
140. Nohr MK, Egerod KL, Christiansen SH, Gille A, Offermanns S, Schwartz TW, et al. Expression of the short chain fatty acid receptor GPR41/FFAR3 in autonomic and somatic sensory ganglia. Neuroscience. 2015;290:126–37. 10.1016/j.neuroscience.2015.01.040
141. Kimura I, Inoue D, Maeda T, Hara T, Ichimura A, Miyauchi S, et al. Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41). Proc Natl Acad Sci U S A. 2011;108(19):8030–5. 10.1073/pnas.1016088108
142. Trinder J, Kleiman J, Carrington M, Smith S, Breen S, Tan N, et al. Autonomic activity during human sleep as a function of time and sleep stage. J Sleep Res. 2001;10(4):253–64
143. Kessler G, Friedman J. Metabolism of fatty acids and glucose. Circulation. 1998;98(13):1350a-3. 10.1161/01.CIR.98.13.1350.a
144. Mellanby K. Metabolic water and desiccation. Nature. 1942;150:21. 10.1038/150021a0
145. Roomets E, Lundbom N, Pihko H, Heikkinen S, Tyni T. Lipids detected by brain MRS during coma caused by carnitine palmitoyltransferase 1 deficiency. Neurology. 2006;67(8):1516–7. 10.1212/01.wnl.0000240118.82937.ed
146. • Schulz JG, Laranjeira A, Van Huffel L, Gartner A, Vilain S, Bastianen J, et al. Glial beta-oxidation regulates Drosophila energy metabolism. Sci Rep. 2015;5:7805. https://doi.org/10.1038/srep07805. Using Drosophila as a model organism, this is the first study showing that glial fatty acid beta-oxidation is important for energy-homeostasis and prevention of triacylglycerol build-up
147. Bazinet RP, Laye S. Polyunsaturated fatty acids and their metabolites in brain function and disease. Nat Rev Neurosci. 2014;15(12):771–85. 10.1038/nrn3820
148. Watson BO, Levenstein D, Greene JP, Gelinas JN, Buzsaki G. Network homeostasis and state dynamics of neocortical sleep. Neuron. 2016;90(4):839–52. 10.1016/j.neuron.2016.03.036
149. Mak-McCully RA, Rolland M, Sargsyan A, Gonzalez C, Magnin M, Chauvel P, et al. Coordination of cortical and thalamic activity during non-REM sleep in humans. Nat Commun. 2017;8:15499. 10.1038/ncomms15499
150. Miyagawa T, Miyadera H, Tanaka S, Kawashima M, Shimada M, Honda Y, et al. Abnormally low serum acylcarnitine levels in narcolepsy patients. Sleep. 2011;34:349–53A
151. Miyagawa T, Kawamura H, Obuchi M, Ikesaki A, Ozaki A, Tokunaga K, et al. Effects of oral l-carnitine administration in narcolepsy patients: a randomized, double-blind, cross-over and placebo-controlled trial. PLoS One. 2013;8(1):e53707. 10.1371/journal.pone.0053707
152. Tafti M, Petit B, Chollet D, Neidhart E, de Bilbao F, Kiss JZ, et al. Deficiency in short-chain fatty acid beta-oxidation affects theta oscillations during sleep. Nat Genet. 2003;34:320–5. 10.1038/ng1174
153. Tononi G, Cirelli C. Sleep and the price of plasticity: from synaptic and cellular homeostasis to memory consolidation and integration. Neuron. 2014;81(1):12–34. 10.1016/j.neuron.2013.12.025
154. •• Knobloch M, Pilz GA, Ghesquiere B, Kovacs WJ, Wegleiter T, Moore DL, et al. A fatty acid oxidation-dependent metabolic shift regulates adult neural stem cell activity. Cell Rep. 2017;20(9):2144–55. 10.1016/j.celrep.2017.08.029. The first study to show how fatty acid oxidation capacity changes the state and function of cell types in the mouse brain. Inhibition of fatty acid oxidation by increased malonyl-CoA levels shifts quiescents neural stem cells to become proliferative
155. Lamers JM, Stinis HT, Montfoort A, Hulsmann WC. The effect of lipid intermediates on Ca2+ and Na+ permeability and (Na+ / K+)-ATPase of cardiac sarcolemma. A possible role in myocardial ischemia. Biochim Biophys Acta. 1984;774(1):127–37
156. Nałȩcz KA, Miecz D, Berezowski V, Cecchelli R. Carnitine: transport and physiological functions in the brain. Mol Asp Med. 2004;25:551–67. 10.1016/j.mam.2004.06.001
157. Schonfeld P, Wojtczak L. Fatty acids decrease mitochondrial generation of reactive oxygen species at the reverse electron transport but increase it at the forward transport. Biochim Biophys Acta. 2007;1767(8):1032–40. 10.1016/j.bbabio.2007.04.005
158. Mailloux RJ, McBride SL, Harper ME. Unearthing the secrets of mitochondrial ROS and glutathione in bioenergetics. Trends Biochem Sci. 2013;38(12):592–602. 10.1016/j.tibs.2013.09.001
159. •• Díaz-Muñoz M, Hernández-Muñoz R, Suárez J, de Sánchez VC. Day-night cycle of lipid peroxidation in rat cerebral cortex and their relationship to the gperoxide dismutase activity. Neuroscience. 1985;16:859–63. 10.1016/0306-4522(85)90100-9. This study measures the state of lipoperoxidation, glutathione cycle components and superoxide dismutase activity every four hour in the the cerebral cortex of the rat, and shows that these parameters exhibit day-night rhythms
160. Dringen R. Metabolism and functions of glutathione in brain. Prog Neurobiol. 2000;62(6):649–71