Ketone Bodies

Abstract

Ketone bodies are water‐soluble equivalents of fatty acids. They can substitute for glucose in peripheral tissues, especially in the brain, when glucose becomes limited in physiological and pathological states. Recent findings demonstrate that they also act as signalling metabolites, thus participating in the organism adaptation to the environment, such as during fasting, calorie restriction or prolonged exercise. Diabetes is the most common pathological cause of elevated blood ketone bodies. Ketone bodies are produced in excess in response to low insulin levels and high levels of counterregulatory hormones, the result being the development of metabolic acidosis that is associated with serious health complications. Yet, ketogenic diets have been used for decades to increase ketone body synthesis for their neuroprotective properties as central signalling metabolites and as main energy‐providing substrate for the brain, in epilepsy and neurodegenerative diseases.

Key Concepts

  • Ketone bodies are key energy substrates and signalling molecules
  • Ketone bodies participate in energy homeostasis
  • Diabetic ketoacidosis is the most common pathological cause of elevated blood ketone bodies and is associated with serious health complications
  • Ketone bodies are neuroprotective
  • Ketone bodies offer promising perspectives in clinical therapy for certain metabolic diseases, neurodegenerative diseases and cancers

Keywords: ketone bodies; energy homeostasis; starvation; exercise; ketoacidosis; neuroprotection

Figure 1. The synthesis of acetoacetate and d‐β‐hydroxybutyrate from acetyl‐CoA in the liver mitochondria.
Figure 2. The metabolic conversion of d‐β‐hydroxybutyrate and acetoacetate to acetyl‐CoA in the mitochondria of peripheral tissues.
Figure 3. Inhibition of the glycolytic pathway by ketone body oxidation. Oxidation of ketone bodies causes acetyl‐CoA and NADH to increase in the mitochondria, thereby inhibiting pyruvate dehydrogenase activity, and thus pyruvate oxidation. As part of the feedback loop, the glycolytic pathway is ultimately inhibited by an increased concentration of citrate and glycolytic intermediates.
Figure 4. Schematic summary of ketone body production, accumulation, utilisation and metabolic effects.
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References

Allen BG , Bhatia SK , Anderson CM , et al. (2014) Ketogenic diets as an adjuvant cancer therapy: history and potential mechanism. Redox Biology 2: 963–970. DOI: 10.1016/j.redox.2014.08.002.

Beylot M (1996) Regulation of in vivo ketogenesis: role of free fatty acids and control by epinephrine, thyroid hormones, insulin and glucagon. Diabetes and Metabolism 22 (5): 299–304.

Blackburn GL , Flatt JP , Clowes GH Jr , et al. (1973) Protein sparing therapy during periods of starvation with sepsis of trauma. Annals of Surgery 177 (5): 588–594.

Drynan L , Quant PA and Zammit VA (1996) Flux control exerted by mitochondrial outer membrane carnitine palmitoyltransferase over β‐oxidation, ketogenesis and tricarboxylic acid cycle activity in hepatocytes isolated from rats in different metabolic states. Biochemical Journal 317 (Pt. 3): 791–795.

Gasior M , Rogawski MA and Hartman AL (2006) Neuroprotective and disease‐modifying effects of the ketogenic diet. Behavioural Pharmacology 17 (5–6): 431–439.

Gibson AA , Seimon RV , Lee CM , et al. (2014) Do ketogenic diets really suppress appetite? A systematic review and meta‐analysis. Obesity Reviews. DOI: 10.1111/obr.12230.

Goodman MN , Larsen PR , Kaplan MM , et al. (1980) Starvation in the rat. II. Effect of age and obesity on protein sparing and fuel metabolism. American Journal of Physiology 239 (4): E277–E286.

Halestrap AP (2013) Monocarboxylic acid transport. Comprehensive Physiology 3 (4): 1611–1643. DOI: 10.1002/cphy.c130008.

Hashim SA and VanItallie TB (2014) Ketone body therapy: from the ketogenic diet to the oral administration of ketone ester. Journal of Lipid Research 55 (9): 1818–1826. DOI: 10.1194/jlr.R046599.

Hegardt FG (1999) Mitochondrial 3‐hydroxy‐3‐methylglutaryl‐CoA synthase: a control enzyme in ketogenesis. Biochemical Journal 338: 569–582.

Kashiwaya Y , Takeshima T , Mori N , et al. (2000) D‐beta‐hydroxybutyrate protects neurons in models of Alzheimer's and Parkinson's disease. Proceedings of the National Academy of Sciences of the United States of America 97 (10): 5440–5444.

Kashiwaya Y , Bergman C , Lee JH , 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. Neurobiology of Aging 34 (6): 1530–1539. DOI: 10.1016/j.neurobiolaging.2012.11.023.

Keller U , Lustenberger M , Muller‐Brand J , et al. (1989) Human ketone body production and utilization studied using tracer techniques: regulation by free fatty acids, insulin, catecholamines, and thyroid hormones. Diabetes/Metabolism Reviews 5 (3): 285–298.

Kimura I , Inoue D , Maeda T , et al. (2011) Short‐chain fatty acids and ketones directly regulate sympathetic nervous system via G protein‐coupled receptor 41 (GPR41). Proceedings of the National Academy of Sciences of the United States of America 108 (19): 8030–8035. DOI: 10.1073/pnas.1016088108.

Klein P , Tyrlikova I and Mathews GC (2014) Dietary treatment in adults with refractory epilepsy: a review. Neurology 83 (21): 1978–1985.

Laffel L (1999) Ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes. Diabetes/Metabolism Research and Reviews 15: 412–426.

Li C , Liu C , Nissim I , et al. (2013) Regulation of glucagon secretion in normal and diabetic human islets by γ‐hydroxybutyrate and glycine. Journal of Biological Chemistry 288 (6): 3938–3951. DOI: 10.1074/jbc.M112.385682.

Newman JC and Verdin E (2014) Ketone bodies as signaling metabolites. Trends in Endocrinology and Metabolism 25 (1): 42–52. DOI: 10.1016/j.tem.2013.09.002.

Owen OE , Felig P , Morgan AP , et al. (1969) Liver and kidney metabolism during prolonged starvation. Journal of Clinical Investigation 48 (3): 574–583.

Paoli A , Rubini A , Volek JS and Grimaldi KA (2013) Beyond weight loss: a review of the therapeutic uses of very‐low‐carbohydrate (ketogenic) diets. European Journal of Clinical Nutrition 67 (8): 789–796. DOI: 10.1038/ejcn.2013.116.

Park H , Kaushik VK , Constant S , et al. (2002) Coordinate regulation of malonyl‐CoA decarboxylase, sn‐glycerol‐3‐phosphate acyltransferase, and acetyl‐CoA carboxylase by AMP‐activated protein kinase in rat tissues in response to exercise. Journal of Biological Chemistry 277 (36): 32571–32577.

Pawan GL and Semple SJ (1983) Effect of 3‐hydroxybutyrate in obese subjects on very‐low‐energy diets and during therapeutic starvation. Lancet 1 (8314–8315): 15–17.

Rardin MJ , He W , Nishida Y , et al. (2013) SIRT5 regulates the mitochondrial lysine succinylome and metabolic networks. Cell Metabolism 18 (6): 920–933. DOI: 10.1016/j.cmet.2013.11.013.

Rasmussen BB and Wolfe RR (1999) Regulation of fatty acid oxidation in skeletal muscle. Annual Review of Nutrition 9: 463–484.

Reger MA , Henderson ST , Hale C , et al. (2004) Effects of beta‐hydroxybutyrate on cognition in memory‐impaired adults. Neurobiology of Aging 25 (3): 311–314.

Ruderman NB , Saha AK , D V , et al. (1998) Malonyl CoA as a metabolic switch and a regulator of insulin sensitivity. Advances in Experimental Medicine and Biology 441: 263–270.

Sengupta S , Peterson TR , Laplante M , et al. (2010) mTORC1 controls fasting‐induced ketogenesis and its modulation by ageing. Nature 468 (7327): 1100–1104. DOI: 10.1038/nature09584.

Shimazu T , Hirschey MD , Newman J , et al. (2013) Suppression of oxidative stress by β‐hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science 339 (6116): 211–214. DOI: 10.1126/science.1227166.

Taggart AK , Kero J , Gan X , et al. (2005) (D)‐beta‐Hydroxybutyrate inhibits adipocyte lipolysis via the nicotinic acid receptor PUMA‐G. Journal of Biological Chemistry 280 (29): 26649–26652.

Takehiro M , Fujimoto S , Shimodahira M , et al. (2005) Chronic exposure to beta‐hydroxybutyrate inhibits glucose‐induced insulin release from pancreatic islets by decreasing NADH contents. American Journal of Physiology, Endocrinology and Metabolism 288 (2): E372–E380.

Thomas LK , Ittmann M and Cooper C (1982) The role of leucine in ketogenesis in starved rats. Biochemical Journal 204 (2): 399–403.

Tieu K , Perier C , Caspersen C , et al. (2003) D‐beta‐hydroxybutyrate rescues mitochondrial respiration and mitigates features of Parkinson disease. Journal of Clinical Investigation 112 (6): 892–901.

Vanitallie TB , Nonas C , Di Rocco A , et al. (2005) Treatment of Parkinson disease with diet‐induced hyperketonemia: a feasibility study. Neurology 64 (4): 728–730.

Van der Auwera I , Wera S , Van Leuven F , et al. (2005) A ketogenic diet reduces amyloid beta 40 and 42 in a mouse model of Alzheimer's disease. Nutrition & Metabolism (London) 2: 28.

Veech RL (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, Leukotrienes, and Essential Fatty Acids 70 (3): 309–319.

Webber J , Simpson E , Parkin H and Macdonald IA (1994) Metabolic effects of acute hyperketonaemia in man before and during an hyperinsulinaemic euglycaemic clamp. Clinical Science (London) 86 (6): 677–687.

Wolfrum C , Asilmaz E , Luca E , et al. (2004) Foxa2 regulates lipid metabolism and ketogenesis in the liver during fasting and in diabetes. Nature 432 (7020): 1027–1032.

Won YJ , Lu VB , Puhl HL III , et al. (2013) β‐hydroxybutyrate modulates N‐type calcium channels in rat sympathetic neurons by acting as an agonist for the G‐protein‐coupled receptor FFA3. Journal of Neuroscience 33 (49): 19314–19325. DOI: 10.1523/JNEUROSCI.3102-13.2013.

Further Reading

Dedkova EN and Blatter LA (2014) Role of β‐hydroxybutyrate, its polymer poly‐β‐hydroxybutyrate and inorganic polyphosphate in mammalian health and disease. Frontiers in Physiology 5: 260. DOI: 10.3389/fphys.2014.00260.

Eaton S , Middleton B and Bartlett K (1998) Control of mitochondrial β‐oxidation: sensitivity of the trifunctional protein to [NAD+]/[NADH] and [acetyl‐CoA]/[CoA]. Biochimica et Biophysica Acta 1429 (1): 230–238.

Freeman JB , Stegink LD , Fry LK , Sherman BM and Denbesten L (1975) Evaluation of amino acid infusions as protein‐sparing agents in normal adult subjects. American Journal of Clinical Nutrition 28 (5): 477–481.

Fukao T , Mitchell G , Sass JO , et al. (2014) Ketone body metabolism and its defects. Journal of Inherited Metabolic Disease 37 (4): 541–551. DOI: 10.1007/s10545-014-9704-9.

Ikeda T , Yoshida T , Ito Y , et al. (1987) Effect of beta‐hydroxybutyrate and acetoacetate on insulin and glucagon secretion from perfused rat pancreas. Archives of Biochemistry and Biophysics 257 (1): 140–143.

Misra S and Oliver NS (2014) Utility of ketone measurement in the prevention, diagnosis and management of diabetic ketoacidosis. Diabetic Medicine. DOI: 10.1111/dme.12604.

Newman JC and Verdin E (2014) β‐hydroxybutyrate: much more than a metabolite. Diabetes Research and Clinical Practice. DOI: 10.1016/j.diabres.2014.08.009.

Quant PA and Eaton S (eds) (1998) Current Views of Fatty Acid Oxidation and Ketogenesis from Organelles to Point Mutations. Advances in Experimental Medicine and Biology. Vol. 441. New York: Kluwer Academic/Plenum.

Spurway TD , Sherratt HA , Pogson CI and Agius L (1997) The flux control coefficient of carnitine palmitoyltransferase I on palmitate β‐oxidation in rat hepatocyte cultures. Biochemical Journal 323 (Pt. 1): 119–122.

Thompson JR and Wu G (1991) The effect of ketone bodies on nitrogen metabolism in skeletal muscle. Comparative Biochemistry and Physiology. B, Comparative Biochemistry 100 (2): 209–216.

Wicklmayr M , Rett K , Dietze G and Mehnert H (1986) Inhibition of muscular triglyceride lipolysis by ketone bodies: a mechanism for energy‐preservation in starvation. Hormone and Metabolic Research 18 (7): 476–478.

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Morio, Beatrice, and Wolfe, Robert R(Apr 2015) Ketone Bodies. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0003819.pub2]