1932

Abstract

Various mechanisms in the mammalian body provide resilience against food deprivation and dietary stress. The ketone body β-hydroxybutyrate (BHB) is synthesized in the liver from fatty acids and represents an essential carrier of energy from the liver to peripheral tissues when the supply of glucose is too low for the body's energetic needs, such as during periods of prolonged exercise, starvation, or absence of dietary carbohydrates. In addition to its activity as an energetic metabolite, BHB is increasingly understood to have cellular signaling functions. These signaling functions of BHB broadly link the outside environment to epigenetic gene regulation and cellular function, and their actions may be relevant to a variety of human diseases as well as human aging.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-nutr-071816-064916
2017-08-21
2024-04-22
Loading full text...

Full text loading...

/deliver/fulltext/nutr/37/1/annurev-nutr-071816-064916.html?itemId=/content/journals/10.1146/annurev-nutr-071816-064916&mimeType=html&fmt=ahah

Literature Cited

  1. Anderson KA, Green MF, Huynh FK, Wagner GR, Hirschey MD. 1.  2014. SnapShot: mammalian sirtuins. Cell 159:4956–956.e1 [Google Scholar]
  2. Ang ZW, Er JZ, Tan NS, Lu JH, Liou YC. 2.  et al. 2016. Human and mouse monocytes display distinct signalling and cytokine profiles upon stimulation with FFAR2/FFAR3 short-chain fatty acid receptor agonists. Sci. Rep. 6:34145 [Google Scholar]
  3. Badman MK, Koester A, Flier JS, Kharitonenkov A, Maratos-Flier E. 3.  2009. Fibroblast growth factor 21-deficient mice demonstrate impaired adaptation to ketosis. Endocrinology 150:4931–40 [Google Scholar]
  4. Badman MK, Pissios P, Kennedy AR, Koukos G, Flier JS, Maratos-Flier E. 4.  2007. Hepatic fibroblast growth factor 21 is regulated by PPARα and is a key mediator of hepatic lipid metabolism in ketotic states. Cell Metab 5:426–37 [Google Scholar]
  5. Balietti M, Casoli T, Di Stefano G, Giorgetti B, Aicardi G, Fattoretti P. 5.  2010. Ketogenic diets: an historical antiepileptic therapy with promising potentialities for the aging brain. Ageing Res. Rev. 9:273–79 [Google Scholar]
  6. Barton KM, Palmer SE. 6.  2016. How to define the latent reservoir: tools of the trade. Curr. HIV/AIDS Rep. 13:77–84 [Google Scholar]
  7. Berg JM, Tymoczko JL, Stryer L. 7.  2012. Biochemistry New York: Freeman
  8. Bhaskara S, Knutson SK, Jiang G, Chandrasekharan MB, Wilson AJ. 8.  et al. 2010. Hdac3 is essential for the maintenance of chromatin structure and genome stability. Cancer Cell 18:436–47 [Google Scholar]
  9. Blad CC, Tang C, Offermanns S. 9.  2012. G protein-coupled receptors for energy metabolites as new therapeutic targets. Nat. Rev. Drug Discov. 11:603–19 [Google Scholar]
  10. Boden G. 10.  2011. Obesity, insulin resistance and free fatty acids. Curr. Opin. Endocrinol. Diabetes Obes. 18:139–43 [Google Scholar]
  11. Brown AJ, Goldsworthy SM, Barnes AA, Eilert MM, Tcheang L. 11.  et al. 2003. The orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids. J. Biol. Chem. 278:11312–19 [Google Scholar]
  12. Cahill GF Jr. 12.  2006. Fuel metabolism in starvation. Annu. Rev. Nutr. 26:1–22 [Google Scholar]
  13. Cahill GF Jr., Herrera MG, Morgan AP, Soeldner JS, Steinke J. 13.  et al. 1966. Hormone-fuel interrelationships during fasting. J. Clin. Investig. 45:1751–69 [Google Scholar]
  14. Chen YF, Du JF, Zhao YT, Zhang L, Lv GR. 14.  et al. 2015. Histone deacetylase (HDAC) inhibition improves myocardial function and prevents cardiac remodeling in diabetic mice. Cardiovasc. Diabetol. 14:99 [Google Scholar]
  15. Coll RC, O'Neill LAJ, Schroder K. 15.  2016. Questions and controversies in innate immune research: What is the physiological role of NLRP3?. Cell Death Discov 2:16019 [Google Scholar]
  16. Dahlin M, Elfving A, Ungerstedt U, Amark P. 16.  2005. The ketogenic diet influences the levels of excitatory and inhibitory amino acids in the CSF in children with refractory epilepsy. Epilepsy Res 64:115–25 [Google Scholar]
  17. De Vadder F, Kovatcheva-Datchary P, Goncalves D, Vinera J, Zitoun C. 17.  et al. 2014. Microbiota-generated metabolites promote metabolic benefits via gut-brain neural circuits. Cell 156:84–96 [Google Scholar]
  18. Dedkova EN, Blatter LA. 18.  2014. Role of β-hydroxybutyrate, its polymer poly-β-hydroxybutyrate and inorganic polyphosphate in mammalian health and disease. Front. Physiol. 5:260 [Google Scholar]
  19. Desrochers S, Dubreuil P, Brunet J, Jette M, David F. 19.  et al. 1995. Metabolism of (R,S)-1,3-butanediol acetoacetate esters, potential parenteral and enteral nutrients in conscious pigs. Am. J. Physiol. 268:E660–67 [Google Scholar]
  20. Dobbins R, Byerly R, Gaddy R, Gao F, Mahar K. 20.  et al. 2015. GSK256073 acutely regulates NEFA levels via HCA2 agonism but does not achieve durable glycaemic control in type 2 diabetes. A randomised trial. Eur. J. Pharmacol. 755:95–101 [Google Scholar]
  21. Dobbins RL, Shearn SP, Byerly RL, Gao FF, Mahar KM. 21.  et al. 2013. GSK256073, a selective agonist of G-protein coupled receptor 109A (GPR109A) reduces serum glucose in subjects with type 2 diabetes mellitus. Diabetes Obes. Metab. 15:1013–21 [Google Scholar]
  22. Donevan SD, White HS, Anderson GD, Rho JM. 22.  2003. Voltage-dependent block of N-methyl-d-aspartate receptors by the novel anticonvulsant dibenzylamine, a bioactive constituent of l-(+)-β-hydroxybutyrate. Epilepsia 44:1274–79 [Google Scholar]
  23. Dovey OM, Foster CT, Cowley SM. 23.  2010. Histone deacetylase 1 (HDAC1), but not HDAC2, controls embryonic stem cell differentiation. PNAS 107:8242–47 [Google Scholar]
  24. Edwards C, Canfield J, Copes N, Rehan M, Lipps D, Bradshaw PC. 24.  2014. D-beta-hydroxybutyrate extends lifespan in C. elegans. . Aging 6:621–44 [Google Scholar]
  25. Erecinska M, Nelson D, Daikhin Y, Yudkoff M. 25.  1996. Regulation of GABA level in rat brain synaptosomes: fluxes through enzymes of the GABA shunt and effects of glutamate, calcium, and ketone bodies. J. Neurochem. 67:2325–34 [Google Scholar]
  26. Fajas L, Egler V, Reiter R, Hansen J, Kristiansen K. 26.  et al. 2002. The retinoblastoma-histone deacetylase 3 complex inhibits PPARγ and adipocyte differentiation. Dev. Cell 3:903–10 [Google Scholar]
  27. Feldman N, Rotter-Maskowitz A, Okun E. 27.  2015. DAMPs as mediators of sterile inflammation in aging-related pathologies. Ageing Res. Rev. 24:29–39 [Google Scholar]
  28. Fischer A, Sananbenesi F, Wang X, Dobbin M, Tsai LH. 28.  2007. Recovery of learning and memory is associated with chromatin remodelling. Nature 447:178–82 [Google Scholar]
  29. Freeman LC, Ting JPY. 29.  2016. The pathogenic role of the inflammasome in neurodegenerative diseases. J. Neurochem. 136:29–38 [Google Scholar]
  30. Gaidarov I, Chen XH, Anthony T, Maciejewski-Lenoir D, Liaw C, Unett DJ. 30.  2013. Differential tissue and ligand-dependent signaling of GPR109A receptor: implications for anti-atherosclerotic therapeutic potential. Cell. Signal. 25:2003–16 [Google Scholar]
  31. Galmozzi A, Mitro N, Ferrari A, Gers E, Gilardi F. 31.  et al. 2013. Inhibition of class I histone deacetylases unveils a mitochondrial signature and enhances oxidative metabolism in skeletal muscle and adipose tissue. Diabetes 62:732–42 [Google Scholar]
  32. Gao Z, Yin J, Zhang J, Ward RE, Martin RJ. 32.  et al. 2009. Butyrate improves insulin sensitivity and increases energy expenditure in mice. Diabetes 58:1509–17 [Google Scholar]
  33. Gertz M, Steegborn C. 33.  2010. The lifespan-regulator p66Shc in mitochondria: redox enzyme or redox sensor?. Antioxid. Redox Signal. 13:1417–28 [Google Scholar]
  34. Glozak MA, Sengupta N, Zhang X, Seto E. 34.  2005. Acetylation and deacetylation of non-histone proteins. Gene 363:15–23 [Google Scholar]
  35. Gold M, El Khoury J. 35.  2015. β-amyloid, microglia, and the inflammasome in Alzheimer's disease. Semin. Immunopathol. 37:607–11 [Google Scholar]
  36. Goldberg EL, Asher JL, Molony RD, Shaw AC, Zeiss CJ. 36.  et al. 2017. β-hydroxybutyrate deactivates neutrophil NLRP3 inflammasome to relieve gout flares. Cell Rep 18:2077–87 [Google Scholar]
  37. Goldberg EL, Dixit VD. 37.  2015. Drivers of age-related inflammation and strategies for healthspan extension. Immunol. Rev. 265:63–74 [Google Scholar]
  38. Graff EC, Fang H, Wanders D, Judd RL. 38.  2016. Anti-inflammatory effects of the hydroxycarboxylic acid receptor 2. Metab. Clin. Exp. 65:102–13 [Google Scholar]
  39. Graff J, Rei D, Guan JS, Wang WY, Seo J. 39.  et al. 2012. An epigenetic blockade of cognitive functions in the neurodegenerating brain. Nature 483:222–26 [Google Scholar]
  40. Graff J, Tsai LH. 40.  2013. Histone acetylation: molecular mnemonics on the chromatin. Nat. Rev. Neurosci. 14:97–111 [Google Scholar]
  41. Gregoretti IV, Lee YM, Goodson HV. 41.  2004. Molecular evolution of the histone deacetylase family: functional implications of phylogenetic analysis. J. Mol. Biol. 338:17–31 [Google Scholar]
  42. Guan JS, Haggarty SJ, Giacometti E, Dannenberg JH, Joseph N. 42.  et al. 2009. HDAC2 negatively regulates memory formation and synaptic plasticity. Nature 459:55–60 [Google Scholar]
  43. Gut P, Verdin E. 43.  2013. The nexus of chromatin regulation and intermediary metabolism. Nature 502:489–98 [Google Scholar]
  44. Hakre S, Chavez L, Shirakawa K, Verdin E. 44.  2012. HIV latency: experimental systems and molecular models. FEMS Microbiol. Rev. 36:706–16 [Google Scholar]
  45. Haneklaus M, O'Neill LAJ. 45.  2015. NLRP3 at the interface of metabolism and inflammation. Immunol. Rev. 265:53–62 [Google Scholar]
  46. Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM. 46.  et al. 2009. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460:392–95 [Google Scholar]
  47. Hartman AL, Gasior M, Vining EPG, Rogawski MA. 47.  2007. The neuropharmacology of the ketogenic diet. Pediatr. Neurol. 36:281–92 [Google Scholar]
  48. He W, Newman JC, Wang MZ, Ho L, Verdin E. 48.  2012. Mitochondrial sirtuins: regulators of protein acylation and metabolism. Trends Endocrinol. Metab. 23:467–76 [Google Scholar]
  49. Hegardt FG. 49.  1999. Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase: a control enzyme in ketogenesis. Biochem. J. 338:Pt. 3569–82 [Google Scholar]
  50. Heneka MT, Kummer MP, Stutz A, Delekate A, Schwartz S. 50.  et al. 2013. NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice. Nature 493:674–78 [Google Scholar]
  51. Hirschey MD, Shimazu T, Goetzman E, Jing E, Schwer B. 51.  et al. 2010. SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature 464:121–25 [Google Scholar]
  52. Hugo SE, Cruz-Garcia L, Karanth S, Anderson RM, Stainier DY, Schlegel A. 52.  2012. A monocarboxylate transporter required for hepatocyte secretion of ketone bodies during fasting. Genes Dev 26:282–93 [Google Scholar]
  53. Imai SI, Guarente L. 53.  2014. NAD+ and sirtuins in aging and disease. Trends Cell Biol 24:464–71 [Google Scholar]
  54. Jing H, Lin HN. 54.  2015. Sirtuins in epigenetic regulation. Chem. Rev. 115:2350–75 [Google Scholar]
  55. Johnson SC, Rabinovitch PS, Kaeberlein M. 55.  2013. mTOR is a key modulator of ageing and age-related disease. Nature 493:338–45 [Google Scholar]
  56. Juge N, Gray JA, Omote H, Miyaji T, Inoue T. 56.  et al. 2010. Metabolic control of vesicular glutamate transport and release. Neuron 68:99–112 [Google Scholar]
  57. Kaeberlein M. 57.  2010. Lessons on longevity from budding yeast. Nature 464:513–19 [Google Scholar]
  58. Kashiwaya Y, Bergman C, Lee JH, Wan R, King MT. 58.  et al. 2013. A ketone ester diet exhibits anxiolytic and cognition-sparing properties, and lessens amyloid and tau pathologies in a mouse model of Alzheimer's disease. Neurobiol. Aging 34:1530–39 [Google Scholar]
  59. Kenyon CJ. 59.  2010. The genetics of ageing. Nature 464:504–12 [Google Scholar]
  60. Kim DY, Rho JM. 60.  2008. The ketogenic diet and epilepsy. Curr. Opin. Clin. Nutr. Metab. Care 11:113–20 [Google Scholar]
  61. Kim S, Benguria A, Lai CY, Jazwinski SM. 61.  1999. Modulation of life-span by histone deacetylase genes in Saccharomyces cerevisiae. Mol. Biol. Cell 10:3125–36 [Google Scholar]
  62. Kimura I, Inoue D, Maeda T, Hara T, Ichimura A. 62.  et al. 2011. Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41). PNAS 108:8030–35 [Google Scholar]
  63. Knutson SK, Chyla BJ, Amann JM, Bhaskara S, Huppert SS, Hiebert SW. 63.  2008. Liver-specific deletion of histone deacetylase 3 disrupts metabolic transcriptional networks. EMBO J 27:1017–28 [Google Scholar]
  64. Koeslag JH, Noakes TD, Sloan AW. 64.  1980. Post-exercise ketosis. J. Physiol. 301:79–90 [Google Scholar]
  65. Krebs HA, Gascoyne T. 65.  1968. The redox state of the nicotinamide-adenine dinucleotides in rat liver homogenates. Biochem. J. 108:513–20 [Google Scholar]
  66. Laeger T, Metges CC, Kuhla B. 66.  2010. Role of β-hydroxybutyric acid in the central regulation of energy balance. Appetite 54:450–55 [Google Scholar]
  67. Landgrave-Gómez J, Mercado-Gómez O, Guevara-Guzmán R. 67.  2015. Epigenetic mechanisms in neurological and neurodegenerative diseases. Front. Cell. Neurosci. 9:58 [Google Scholar]
  68. Lardenoije R, Iatrou A, Kenis G, Kompotis K, Steinbusch HWM. 68.  et al. 2015. The epigenetics of aging and neurodegeneration. Prog. Neurobiol. 131:21–64 [Google Scholar]
  69. Lauring B, Taggart AKP, Tata JR, Dunbar R, Caro L. 69.  et al. 2012. Niacin lipid efficacy is independent of both the niacin receptor GPR109A and free fatty acid suppression. Sci. Transl. Med. 4:148ra115 [Google Scholar]
  70. Layden BT, Angueira AR, Brodsky M, Durai V, Lowe WL Jr. 70.  2013. Short chain fatty acids and their receptors: new metabolic targets. Transl. Res.: J. Lab. Clin. Med. 161:131–40 [Google Scholar]
  71. LeRoith D, Taylor SI, Olefsky JM. 71.  2004. Diabetes Mellitus: A Fundamental and Clinical Text Philadelphia: Lippincott Williams & Wilkins
  72. Li H, Gao Z, Zhang J, Ye X, Xu A. 72.  et al. 2012. Sodium butyrate stimulates expression of fibroblast growth factor 21 in liver by inhibition of histone deacetylase 3. Diabetes 61:797–806 [Google Scholar]
  73. Li L, Shi L, Yang SD, Yan RR, Zhang D. 73.  et al. 2016. SIRT7 is a histone desuccinylase that functionally links to chromatin compaction and genome stability. Nat. Commun. 7:12235 [Google Scholar]
  74. Lincoln BC, Des Rosiers C, Brunengraber H. 74.  1987. Metabolism of S-3-hydroxybutyrate in the perfused rat liver. Arch. Biochem. Biophys. 259:149–56 [Google Scholar]
  75. Longo VD, Panda S. 75.  2016. Fasting, circadian rhythms, and time-restricted feeding in healthy lifespan. Cell Metab 23:1048–59 [Google Scholar]
  76. Lund TM, Ploug KB, Iversen A, Jensen AA, Jansen-Olesen I. 76.  2015. The metabolic impact of β-hydroxybutyrate on neurotransmission: Reduced glycolysis mediates changes in calcium responses and KATP channel receptor sensitivity. J. Neurochem. 132:520–31 [Google Scholar]
  77. Lutas A, Birnbaumer L, Yellen G. 77.  2014. Metabolism regulates the spontaneous firing of substantia nigra pars reticulata neurons via KATP and nonselective cation channels. J. Neurosci. 34:16336–47 [Google Scholar]
  78. Ma WY, Berg J, Yellen G. 78.  2007. Ketogenic diet metabolites reduce firing in central neurons by opening KATP channels. J. Neurosci. 27:3618–25 [Google Scholar]
  79. Macia L, Tan J, Vieira AT, Leach K, Stanley D. 79.  et al. 2015. Metabolite-sensing receptors GPR43 and GPR109A facilitate dietary fibre-induced gut homeostasis through regulation of the inflammasome. Nat. Commun. 6:6734 [Google Scholar]
  80. Madiraju P, Pande SV, Prentki M, Madiraju SR. 80.  2009. Mitochondrial acetylcarnitine provides acetyl groups for nuclear histone acetylation. Epigenet.: Off. J. DNA Methylation Soc. 4:399–403 [Google Scholar]
  81. Martin-Montalvo A, Mercken EM, Mitchell SJ, Palacios HH, Mote PL. 81.  et al. 2013. Metformin improves healthspan and lifespan in mice. Nat. Commun. 4:2192 [Google Scholar]
  82. Mattson MP, Longo V, Harvie M. 82.  2016. Impact of intermittent fasting on health and disease processes. Ageing Res. Rev. pii:S1568–16371630251–3 [Google Scholar]
  83. McNally MA, Hartman AL. 83.  2012. Ketone bodies in epilepsy. J. Neurochem. 121:28–35 [Google Scholar]
  84. Melo TM, Nehlig A, Sonnewald U. 84.  2006. Neuronal-glial interactions in rats fed a ketogenic diet. Neurochem. Int. 48:498–507 [Google Scholar]
  85. Mihaylova MM, Shaw RJ. 85.  2013. Metabolic reprogramming by class I and II histone deacetylases. Trends Endocrinol. Metab. 24:48–57 [Google Scholar]
  86. Mihaylova MM, Vasquez DS, Ravnskjaer K, Denechaud PD, Yu RT. 86.  et al. 2011. Class IIa histone deacetylases are hormone-activated regulators of FOXO and mammalian glucose homeostasis. Cell 145:607–21 [Google Scholar]
  87. Milman S, Atzmon G, Huffman DM, Wan JX, Crandall JP. 87.  et al. 2014. Low insulin-like growth factor-1 level predicts survival in humans with exceptional longevity. Aging Cell 13:769–71 [Google Scholar]
  88. Morales CR, Li DL, Pedrozo Z, May HI, Jiang N. 88.  et al. 2016. Inhibition of class I histone deacetylases blunts cardiac hypertrophy through TSC2-dependent mTOR repression. Sci. Signal. 9:ra34 [Google Scholar]
  89. Muoio DM, Noland RC, Kovalik JP, Seiler SE, Davies MN. 89.  et al. 2012. Muscle-specific deletion of carnitine acetyltransferase compromises glucose tolerance and metabolic flexibility. Cell Metab 15:764–77 [Google Scholar]
  90. New M, Olzscha H, La Thangue NB. 90.  2012. HDAC inhibitor-based therapies: Can we interpret the code?. Mol. Oncol. 6:637–56 [Google Scholar]
  91. Newman JC, Milman S, Hashmi SK, Austad SN, Kirkland JL. 91.  et al. 2016. Strategies and challenges in clinical trials targeting human aging. J. Gerontol. A Biol. Sci. Med. Sci 711424–34 [Google Scholar]
  92. Newman JC, Verdin E. 92.  2014. Ketone bodies as signaling metabolites. Trends Endocrinol. Metab. 25:42–52 [Google Scholar]
  93. Newport MT, VanItallie TB, Kashiwaya Y, King MT, Veech RL. 93.  2015. A new way to produce hyperketonemia: use of ketone ester in a case of Alzheimer's disease. Alzheimer's Dement 11:99–103 [Google Scholar]
  94. Nohr MK, Egerod KL, Christiansen SH, Gille A, Offermanns S. 94.  et al. 2015. Expression of the short chain fatty acid receptor Gpr41/Ffar3 in autonomic and somatic sensory ganglia. Neuroscience 290:126–37 [Google Scholar]
  95. Offermanns S, Colletti SL, Lovenberg TW, Semple G, Wise A, IJzerman AP. 95.  2011. International union of basic and clinical pharmacology. LXXXII: nomenclature and classification of hydroxy-carboxylic acid receptors (GPR81, GPR109A, and GPR109B). Pharmacol. Rev. 63:269–90 [Google Scholar]
  96. Offermanns S, Schwaninger M. 96.  2015. Nutritional or pharmacological activation of HCA2 ameliorates neuroinflammation. Trends Mol. Med. 21:245–55 [Google Scholar]
  97. Ogiwara I, Miyamoto H, Morita N, Atapour N, Mazaki E. 97.  et al. 2007. Nav1.1 localizes to axons of parvalbumin-positive inhibitory interneurons: a circuit basis for epileptic seizures in mice carrying an Scn1a gene mutation. J. Neurosci. 27:5903–14 [Google Scholar]
  98. Peleg S, Sananbenesi F, Zovoilis A, Burkhardt S, Bahari-Javan S. 98.  et al. 2010. Altered histone acetylation is associated with age-dependent memory impairment in mice. Science 328:753–56 [Google Scholar]
  99. Pellerin L, Bergersen LH, Halestrap AP, Pierre K. 99.  2005. Cellular and subcellular distribution of monocarboxylate transporters in cultured brain cells and in the adult brain. J. Neurosci. Res. 79:55–64 [Google Scholar]
  100. Penney J, Tsai LH. 100.  2014. Histone deacetylases in memory and cognition. Sci. Signal. 7:re12 [Google Scholar]
  101. Quant PA, Tubbs PK, Brand MD. 101.  1989. Treatment of rats with glucagon or mannoheptulose increases mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase activity and decreases succinyl-CoA content in liver. Biochem. J. 262:159–64 [Google Scholar]
  102. Quant PA, Tubbs PK, Brand MD. 102.  1990. Glucagon activates mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase in vivo by decreasing the extent of succinylation of the enzyme. Eur. J. Biochem. 187:169–74 [Google Scholar]
  103. Rahman M, Muhammad S, Khan MA, Chen H, Ridder DA. 103.  et al. 2014. The β-hydroxybutyrate receptor HCA2 activates a neuroprotective subset of macrophages. Nat. Commun. 5:3944 [Google Scholar]
  104. Rardin MJ, He W, Nishida Y, Newman JC, Carrico C. 104.  et al. 2013. SIRT5 regulates the mitochondrial lysine succinylome and metabolic networks. Cell Metab 18:920–33 [Google Scholar]
  105. Rardin MJ, Newman JC, Held JM, Cusack MP, Sorensen DJ. 105.  et al. 2013. Label-free quantitative proteomics of the lysine acetylome in mitochondria identifies substrates of SIRT3 in metabolic pathways. PNAS 110:6601–6 [Google Scholar]
  106. Rezq S, Abdel-Rahman AA. 106.  2016. Central GPR109A activation mediates glutamate-dependent pressor response in conscious rats. J. Pharmacol. Exp. Ther. 356:456–65 [Google Scholar]
  107. Rho JM. 107.  2015. How does the ketogenic diet induce anti-seizure effects?. Neurosci. Lett. 637:4–10 [Google Scholar]
  108. Robinson AM, Williamson DH. 108.  1980. Physiological roles of ketone bodies as substrates and signals in mammalian tissues. Physiol. Rev. 60:143–87 [Google Scholar]
  109. Rogina B, Helfand SL. 109.  2004. Sir2 mediates longevity in the fly through a pathway related to calorie restriction. PNAS 101:15998–6003 [Google Scholar]
  110. Rogina B, Helfand SL, Frankel S. 110.  2002. Longevity regulation by Drosophila Rpd3 deacetylase and caloric restriction. Science 298:1745 [Google Scholar]
  111. Roopra A, Dingledine R, Hsieh J. 111.  2012. Epigenetics and epilepsy. Epilepsia 53:2–10 [Google Scholar]
  112. Roy M, Beauvieux MC, Naulin J, El Hamrani D, Gallis JL. 112.  et al. 2015. Rapid adaptation of rat brain and liver metabolism to a ketogenic diet: an integrated study using 1H- and 13C-NMR spectroscopy. J. Cereb. Blood Flow Metab. 35:1154–62 [Google Scholar]
  113. Sanchez PE, Zhu L, Verret L, Vossel KA, Orr AG. 113.  et al. 2012. Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer's disease model. PNAS 109:E2895–903 [Google Scholar]
  114. Sato K, Kashiwaya Y, Keon CA, Tsuchiya N, King MT. 114.  et al. 1995. Insulin, ketone bodies, and mitochondrial energy transduction. FASEB J 9:651–58 [Google Scholar]
  115. Sekhavat A, Sun JM, Davie JR. 115.  2007. Competitive inhibition of histone deacetylase activity by trichostatin A and butyrate. Biochem. Cell Biol. 85:751–58 [Google Scholar]
  116. Sengupta S, Peterson TR, Laplante M, Oh S, Sabatini DM. 116.  2010. mTORC1 controls fasting-induced ketogenesis and its modulation by ageing. Nature 468:1100–4 [Google Scholar]
  117. Shimazu T, Hirschey MD, Hua L, Dittenhafer-Reed KE, Schwer B. 117.  et al. 2010. SIRT3 deacetylates mitochondrial 3-hydroxy-3-methylglutaryl CoA synthase 2 and regulates ketone body production. Cell Metab 12:654–61 [Google Scholar]
  118. Shimazu T, Hirschey MD, Newman J, He W, Shirakawa K. 118.  et al. 2013. Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science 339:211–14 [Google Scholar]
  119. Sincennes MC, Brun CE, Rudnicki MA. 119.  2016. Concise review: epigenetic regulation of myogenesis in health and disease. Stem Cells Transl. Med. 5:282–90 [Google Scholar]
  120. Sleiman SF, Henry J, Al-Haddad R, El Hayek L, Abou Haidar E. 120.  et al. 2016. Exercise promotes the expression of brain derived neurotrophic factor (BDNF) through the action of the ketone body β-hydroxybutyrate. eLife pii:e15092 [Google Scholar]
  121. Someya S, Yu W, Hallows WC, Xu JZ, Vann JM. 121.  et al. 2010. Sirt3 mediates reduction of oxidative damage and prevention of age-related hearing loss under caloric restriction. Cell 143:802–12 [Google Scholar]
  122. Somoza JR, Skene RJ, Katz BA, Mol C, Ho JD. 122.  et al. 2004. Structural snapshots of human HDAC8 provide insights into the class I histone deacetylases. Structure 12:1325–34 [Google Scholar]
  123. Stein LR, Imai S. 123.  2012. The dynamic regulation of NAD metabolism in mitochondria. Trends Endocrinol. Metab. 23:420–28 [Google Scholar]
  124. Taggart AK, Kero J, Gan X, Cai TQ, Cheng K. 124.  et al. 2005. (d)-β-Hydroxybutyrate inhibits adipocyte lipolysis via the nicotinic acid receptor PUMA-G. J. Biol. Chem. 280:26649–52 [Google Scholar]
  125. Tang C, Ahmed K, Gille A, Lu S, Grone HJ. 125.  et al. 2015. Loss of FFA2 and FFA3 increases insulin secretion and improves glucose tolerance in type 2 diabetes. Nat. Med. 21:85–89 [Google Scholar]
  126. Thio LL, Wong M, Yamada KA. 126.  2000. Ketone bodies do not directly alter excitatory or inhibitory hippocampal synaptic transmission. Neurology 54:325–31 [Google Scholar]
  127. Thumelin S, Forestier M, Girard J, Pegorier JP. 127.  1993. Developmental changes in mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase gene expression in rat liver, intestine and kidney. Biochem. J. 292:Pt. 2493–96 [Google Scholar]
  128. Trompette A, Gollwitzer ES, Yadava K, Sichelstiel AK, Sprenger N. 128.  et al. 2014. Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis. Nat. Med. 20:159–66 [Google Scholar]
  129. Tunaru S, Kero J, Schaub A, Wufka C, Blaukat A. 129.  et al. 2003. PUMA-G and HM74 are receptors for nicotinic acid and mediate its anti-lipolytic effect. Nat. Med. 9:352–55 [Google Scholar]
  130. Vannini A, Volpari C, Filocamo G, Casavola EC, Brunetti M. 130.  et al. 2004. Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor. PNAS 101:15064–69 [Google Scholar]
  131. Veech RL. 131.  2004. The therapeutic implications of ketone bodies: the effects of ketone bodies in pathological conditions: ketosis, ketogenic diet, redox states, insulin resistance, and mitochondrial metabolism. Prostaglandins Leukot. Essent. Fatty Acids 70:309–19 [Google Scholar]
  132. Veprik A, Laufer D, Weiss S, Rubins N, Walker MD. 132.  2016. GPR41 modulates insulin secretion and gene expression in pancreatic β-cells and modifies metabolic homeostasis in fed and fasting states. FASEB J 30:3860–69 [Google Scholar]
  133. Verdin E. 133.  2015. NAD+ in aging, metabolism, and neurodegeneration. Science 350:1208–13 [Google Scholar]
  134. Verret L, Mann EO, Hang GB, Barth AM, Cobos I. 134.  et al. 2012. Inhibitory interneuron deficit links altered network activity and cognitive dysfunction in Alzheimer model. Cell 149:708–21 [Google Scholar]
  135. von Meyenn F, Porstmann T, Gasser E, Selevsek N, Schmidt A. 135.  et al. 2013. Glucagon-induced acetylation of Foxa2 regulates hepatic lipid metabolism. Cell Metab 17:436–47 [Google Scholar]
  136. Vossel KA, Beagle AJ, Rabinovici GD, Shu HD, Lee SE. 136.  et al. 2013. Seizures and epileptiform activity in the early stages of Alzheimer disease. JAMA Neurol 70:1158–66 [Google Scholar]
  137. Wang DF, Helquist P, Wiech NL, Wiest O. 137.  2005. Toward selective histone deacetylase inhibitor design: homology modeling, docking studies, and molecular dynamics simulations of human class I histone deacetylases. J. Med. Chem 486936–47 [Google Scholar]
  138. Webber RJ, Edmond J. 138.  1977. Utilization of l(+)-3-hydroxybutyrate, d(-)-3-hydroxybutyrate, acetoacetate, and glucose for respiration and lipid synthesis in the 18-day-old rat. J. Biol. Chem. 252:5222–26 [Google Scholar]
  139. Weinert BT, Schölz C, Wagner SA, Iesmantavicius V, Su D. 139.  et al. 2013. Lysine succinylation is a frequently occurring modification in prokaryotes and eukaryotes and extensively overlaps with acetylation. Cell Rep 4:842–51 [Google Scholar]
  140. Wellen KE, Hatzivassiliou G, Sachdeva UM, Bui TV, Cross JR, Thompson CB. 140.  2009. ATP-citrate lyase links cellular metabolism to histone acetylation. Science 324:1076–80 [Google Scholar]
  141. Wilting RH, Yanover E, Heideman MR, Jacobs H, Horner J. 141.  et al. 2010. Overlapping functions of Hdac1 and Hdac2 in cell cycle regulation and haematopoiesis. EMBO J 29:2586–97 [Google Scholar]
  142. Winesett SP, Bessone SK, Kossoff EHW. 142.  2015. The ketogenic diet in pharmacoresistant childhood epilepsy. Expert Rev. Neurother. 15:621–28 [Google Scholar]
  143. Wolfrum C, Asilmaz E, Luca E, Friedman JM, Stoffel M. 143.  2004. Foxa2 regulates lipid metabolism and ketogenesis in the liver during fasting and in diabetes. Nature 432:1027–32 [Google Scholar]
  144. Wolfrum C, Besser D, Luca E, Stoffel M. 144.  2003. Insulin regulates the activity of forkhead transcription factor Hnf-3β/Foxa-2 by Akt-mediated phosphorylation and nuclear/cytosolic localization. PNAS 100:11624–29 [Google Scholar]
  145. Won YJ, Lu VB, Puhl HL 3rd, Ikeda SR. 145.  2013. β-Hydroxybutyrate modulates N-type calcium channels in rat sympathetic neurons by acting as an agonist for the G-protein-coupled receptor FFA3. J. Neurosci. 33:19314–25 [Google Scholar]
  146. Xie ZY, Dai JBA, Dai LZ, Tan MJ, Cheng ZY. 146.  et al. 2012. Lysine succinylation and lysine malonylation in histones. Mol. Cell. Proteom. 11:100–7 [Google Scholar]
  147. Xie ZY, Zhang D, Chung DJ, Tang ZY, Huang H. 147.  et al. 2016. Metabolic regulation of gene expression by histone lysine β-hydroxybutyrylation. Mol. Cell 62:194–206 [Google Scholar]
  148. Yamamoto I, Absalom N, Carland JE, Doddareddy MR, Gavande N. 148.  et al. 2012. Differentiating enantioselective actions of GABOB: a possible role for threonine 244 in the binding site of GABAC ρ1 receptors. ACS Chem. Neurosci. 3:665–73 [Google Scholar]
  149. Yang L, Zhao J, Milutinovic PS, Brosnan RJ, Eger EI, Sonner JM. 149.  2007. Anesthetic properties of the ketone bodies ss-hydroxybutyric acid and acetone. Anesthesia Analgesia 105:673–79 [Google Scholar]
  150. Yang XJ, Seto E. 150.  2008. The Rpd3/Hda1 family of lysine deacetylases: from bacteria and yeast to mice and men. Nat. Rev. Mol. Cell Biol. 9:206–18 [Google Scholar]
  151. Yi C, Ma M, Ran L, Zheng J, Tong J. 151.  et al. 2012. Function and molecular mechanism of acetylation in autophagy regulation. Science 336:474–77 [Google Scholar]
  152. Yoshino J, Mills KF, Yoon MJ, Imai S. 152.  2011. Nicotinamide mononucleotide, a key NAD+ intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell Metab 14:528–36 [Google Scholar]
  153. Youm YH, Nguyen KY, Grant RW, Goldberg EL, Bodogai M. 153.  et al. 2015. The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat. Med. 21:263–69 [Google Scholar]
  154. Yudkoff M, Daikhin Y, Melo TM, Nissim I, Sonnewald U, Nissim I. 154.  2007. The ketogenic diet and brain metabolism of amino acids: relationship to the anticonvulsant effect. Annu. Rev. Nutr. 27:415–30 [Google Scholar]
  155. Yudkoff M, Daikhin Y, Nissim I, Grunstein R, Nissim I. 155.  1997. Effects of ketone bodies on astrocyte amino acid metabolism. J. Neurochem. 69:682–92 [Google Scholar]
  156. Yudkoff M, Daikhin Y, Nissim I, Lazarow A, Nissim I. 156.  2001. Brain amino acid metabolism and ketosis. J. Neurosci. Res. 66:272–81 [Google Scholar]
  157. Zeng Z, Liao R, Yao Z, Zhou W, Ye P. 157.  et al. 2014. Three single nucleotide variants of the HDAC gene are associated with type 2 diabetes mellitus in a Chinese population: a community-based case-control study. Gene 533:427–33 [Google Scholar]
  158. Zhang D, Yang H, Kong X, Wang K, Mao X. 158.  et al. 2011. Proteomics analysis reveals diabetic kidney as a ketogenic organ in type 2 diabetes. Am. J. Physiol. Endocrinol. Metab. 300:E287–95 [Google Scholar]
  159. Zhang HB, Ryu D, Wu YB, Gariani K, Wang X. 159.  et al. 2016. NAD+ repletion improves mitochondrial and stem cell function and enhances life span in mice. Science 352:1436–43 [Google Scholar]
  160. Zhang L, Qin X, Zhao Y, Fast L, Zhuang SG. 160.  et al. 2012. Inhibition of histone deacetylases preserves myocardial performance and prevents cardiac remodeling through stimulation of endogenous angiomyogenesis. J. Pharmacol. Exp. Ther. 341:285–93 [Google Scholar]
  161. Zhang Y, Xie Y, Berglund ED, Coate KC, He TT. 161.  et al. 2012. The starvation hormone, fibroblast growth factor-21, extends lifespan in mice. eLife 1:e00065 [Google Scholar]
  162. Zhao Y, Sun H, Lu J, Li X, Chen X. 162.  et al. 2005. Lifespan extension and elevated hsp gene expression in Drosophila caused by histone deacetylase inhibitors. J. Exp. Biol. 208:697–705 [Google Scholar]
  163. Zimmermann S, Kiefer F, Prudenziati M, Spiller C, Hansen J. 163.  et al. 2007. Reduced body size and decreased intestinal tumor rates in HDAC2-mutant mice. Cancer Res 67:9047–54 [Google Scholar]
/content/journals/10.1146/annurev-nutr-071816-064916
Loading
/content/journals/10.1146/annurev-nutr-071816-064916
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error