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Review
. 2021 Dec 9;19(1):313.
doi: 10.1186/s12916-021-02185-0.

Ketone bodies: from enemy to friend and guardian angel

Affiliations
Review

Ketone bodies: from enemy to friend and guardian angel

Hubert Kolb et al. BMC Med. .

Abstract

During starvation, fasting, or a diet containing little digestible carbohydrates, the circulating insulin levels are decreased. This promotes lipolysis, and the breakdown of fat becomes the major source of energy. The hepatic energy metabolism is regulated so that under these circumstances, ketone bodies are generated from β-oxidation of fatty acids and secreted as ancillary fuel, in addition to gluconeogenesis. Increased plasma levels of ketone bodies thus indicate a dietary shortage of carbohydrates. Ketone bodies not only serve as fuel but also promote resistance to oxidative and inflammatory stress, and there is a decrease in anabolic insulin-dependent energy expenditure. It has been suggested that the beneficial non-metabolic actions of ketone bodies on organ functions are mediated by them acting as a ligand to specific cellular targets. We propose here a major role of a different pathway initiated by the induction of oxidative stress in the mitochondria during increased ketolysis. Oxidative stress induced by ketone body metabolism is beneficial in the long term because it initiates an adaptive (hormetic) response characterized by the activation of the master regulators of cell-protective mechanism, nuclear factor erythroid 2-related factor 2 (Nrf2), sirtuins, and AMP-activated kinase. This results in resolving oxidative stress, by the upregulation of anti-oxidative and anti-inflammatory activities, improved mitochondrial function and growth, DNA repair, and autophagy. In the heart, the adaptive response to enhanced ketolysis improves resistance to damage after ischemic insults or to cardiotoxic actions of doxorubicin. Sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors may also exert their cardioprotective action via increasing ketone body levels and ketolysis. We conclude that the increased synthesis and use of ketone bodies as ancillary fuel during periods of deficient food supply and low insulin levels causes oxidative stress in the mitochondria and that the latter initiates a protective (hormetic) response which allows cells to cope with increased oxidative stress and lower energy availability. KEYWORDS: Ketogenic diet, Ketone bodies, Beta hydroxybutyrate, Insulin, Obesity, Type 2 diabetes, Inflammation, Oxidative stress, Cardiovascular disease, SGLT2, Hormesis.

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Conflict of interest statement

S. Martin has received non-restricted support for the conduct of trials of lifestyle change in persons at risk or with type 2 diabetes from Novartis Pharma GmbH, Boehringer Ingelheim Pharma GmbH & Co. KG, Almased Wellness GmbH, Nintendo of Europe GmbH, HMM Holding AG, and Gesellschaft von Freunden und Förderern der Heinrich-Heine-Universität Düsseldorf e.V. H. Kolb, K. Kempf, M. Röhling, and M. Lenzen-Schulte have nothing to disclose. N. C. Schloot is currently employed by Lilly Germany and a stockholder of Lilly.

Figures

Fig. 1
Fig. 1
Overview of the ketogenesis and ketolysis pathways. In cases of limited availability of oxaloacetate, beta oxidation of fatty acids in hepatocytes leads to the accumulation of acetyl-CoA which is channeled into the ketogenic pathway and converted to acetoacetate, the majority of which is reduced to βOHB, another part spontaneously decarboxylates to acetone. Secreted βOHB and acetoacetate are taken up by extrahepatic cells and converted back to acetyl-CoA. The latter can be entered into the TCA cycle after conjugation with oxaloacetate by citrate synthase because there is no gluconeogenesis that would drain local pools of pyruvate and oxaloacetate. FFA, free fatty acids; mThiolase, mitochondrial thiolase; HMGCS2, hydroxy methylglutaryl-CoA synthase; HMGCL, HMG-CoA lyase; BDH1, mitochondrial βOHB dehydrogenase; MCT1/2, monocarboxylate transporter 1 and 2; SCOT, succinyl-CoA:3-oxoacid-CoA transferase; CS, citrate synthase
Fig. 2
Fig. 2
Scheme of cell-protective functions of ketone bodies. The metabolic shift towards fat oxidation and ketolysis during starvation or ketogenic diet is associated with mitochondrial stress characterized by increased levels of ROS and increased ratios of NAD+/NADH and AMP/ATP as well as AMP/ADP. These “danger signals” cause a protective adaptive (hormetic) cellular response, via the activation of Nrf2, SIRT1, SIRT3, and AMPK, respectively. Ketone bodies also activate ROS production from NOX4, and βOHB alters the gene expression pattern by promoting histone acetylation via inhibiting class I and II HDACs and possibly by direct β-hydroxybutyrylation of histones. Long-term consequences of the initial moderate metabolic stress include upregulation of anti-oxidative and anti-inflammatory activities and improved mitochondrial function. ROS, radical oxygen species; Nrf2, nuclear factor erythroid 2-related factor 2; SIRT, sirtuin, silent information regulator; AMPK, AMP-activated kinase; NFkB, nuclear factor kappa B; NOX, NADPH oxidase; HDAC, histone deacetylase; FOXO, forkhead box O
Fig. 3
Fig. 3
Ketone bodies preserve cardiological functions in animal studies. Increasing ketone body utilization by cardiomyocytes via fasting, ketogenic diet, or supplementing βOHB causes mitochondrial stress which is followed by an adaptive cellular response which is characterized by improved mitochondrial function and anti-oxidative defense. This leads to less cell damage and fibrosis in ischemia-reperfusion experiments and less cardiotoxic effects of doxorubicin. FFA, free fatty acids
Fig. 4
Fig. 4
Suggested mechanism for the cardioprotective action of SGLT2 inhibitors. The lowering of blood glucose levels because of suppressed reabsorption in the kidney leads to lower systemic insulin and higher glucagon levels and resurgence of lipolysis resulting in substantial ketogenesis. Increased ketolysis in the heart causes mitochondrial stress followed by a protective (hormetic) response leading to improved mitochondrial function and anti-oxidative capacity which provides significant cardioprotection. SGLT, sodium-glucose co-transporter. (1), (2), (3), see references [129, 155]; (4) and (5), see references [128, 129]; (6), see references [14, 136]; (7), see references [–25, 156]; (8) and (9), see references [, –34]; and (10), see references [–127]

References

    1. Kolb H, Stumvoll M, Kramer W, Kempf K, Martin S. Insulin translates unfavourable lifestyle into obesity. BMC Med. 2018;16:232. - PMC - PubMed
    1. Kolb H, Kempf K, Rohling M, Martin S. Insulin: too much of a good thing is bad. BMC Med. 2020;18:224. - PMC - PubMed
    1. Owen OE, Reichard GA, Jr, Patel MS, Boden G. Energy metabolism in feasting and fasting. Adv Exp Med Biol. 1979;111:169. - PubMed
    1. Laffel L. Ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes. Diabetes Metab Res Rev. 1999;15:412. - PubMed
    1. McPherson PA, McEneny J. The biochemistry of ketogenesis and its role in weight management, neurological disease and oxidative stress. J Physiol Biochem. 2012;68:141. - PubMed