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Sports Medicine (Auckland, N.Z.) Dec 2022The ketone bodies acetoacetate (AcAc) and β-hydroxybutyrate (βHB) have pleiotropic effects in multiple organs including brain, heart, and skeletal muscle by serving as... (Review)
Review
The ketone bodies acetoacetate (AcAc) and β-hydroxybutyrate (βHB) have pleiotropic effects in multiple organs including brain, heart, and skeletal muscle by serving as an alternative substrate for energy provision, and by modulating inflammation, oxidative stress, catabolic processes, and gene expression. Of particular relevance to athletes are the metabolic actions of ketone bodies to alter substrate utilisation through attenuating glucose utilisation in peripheral tissues, anti-lipolytic effects on adipose tissue, and attenuation of proteolysis in skeletal muscle. There has been long-standing interest in the development of ingestible forms of ketone bodies that has recently resulted in the commercial availability of exogenous ketone supplements (EKS). These supplements in the form of ketone salts and ketone esters, in addition to ketogenic compounds such as 1,3-butanediol and medium chain triglycerides, facilitate an acute transient increase in circulating AcAc and βHB concentrations, which has been termed 'acute nutritional ketosis' or 'intermittent exogenous ketosis'. Some studies have suggested beneficial effects of EKS to endurance performance, recovery, and overreaching, although many studies have failed to observe benefits of acute nutritional ketosis on performance or recovery. The present review explores the rationale and historical development of EKS, the mechanistic basis for their proposed effects, both positive and negative, and evidence to date for their effects on exercise performance and recovery outcomes before concluding with a discussion of methodological considerations and future directions in this field.
Topics: Humans; Ketones; Ketone Bodies; Ketosis; Acetoacetates; 3-Hydroxybutyric Acid; Dietary Supplements
PubMed: 36214993
DOI: 10.1007/s40279-022-01756-2 -
Journal of Diabetes Science and... May 2024Ketone bodies are an energy substrate produced by the liver and used during states of low carbohydrate availability, such as fasting or prolonged exercise. High ketone... (Review)
Review
Ketone bodies are an energy substrate produced by the liver and used during states of low carbohydrate availability, such as fasting or prolonged exercise. High ketone concentrations can be present with insulin insufficiency and are a key finding in diabetic ketoacidosis (DKA). During states of insulin deficiency, lipolysis increases and a flood of circulating free fatty acids is converted in the liver into ketone bodies-mainly beta-hydroxybutyrate and acetoacetate. During DKA, beta-hydroxybutyrate is the predominant ketone in blood. As DKA resolves, beta-hydroxybutyrate is oxidized to acetoacetate, which is the predominant ketone in the urine. Because of this lag, a urine ketone test might be increasing even as DKA is resolving. Point-of-care tests are available for self-testing of blood ketones and urine ketones through measurement of beta-hydroxybutyrate and acetoacetate and are cleared by the US Food and Drug Administration (FDA). Acetone forms through spontaneous decarboxylation of acetoacetate and can be measured in exhaled breath, but currently no device is FDA-cleared for this purpose. Recently, technology has been announced for measuring beta-hydroxybutyrate in interstitial fluid. Measurement of ketones can be helpful to assess compliance with low carbohydrate diets; assessment of acidosis associated with alcohol use, in conjunction with SGLT2 inhibitors and immune checkpoint inhibitor therapy, both of which can increase the risk of DKA; and to identify DKA due to insulin deficiency. This article reviews the challenges and shortcomings of ketone testing in diabetes treatment and summarizes emerging trends in the measurement of ketones in the blood, urine, breath, and interstitial fluid.
Topics: Humans; Diabetic Ketoacidosis; Ketones; Ketone Bodies; Acetoacetates; 3-Hydroxybutyric Acid; Breath Tests; Point-of-Care Testing
PubMed: 36794812
DOI: 10.1177/19322968231152236 -
Advanced Science (Weinheim,... Sep 2023Ketone bodies have long been known as a group of lipid-derived alternative energy sources during glucose shortages. Nevertheless, the molecular mechanisms underlying...
Ketone bodies have long been known as a group of lipid-derived alternative energy sources during glucose shortages. Nevertheless, the molecular mechanisms underlying their non-metabolic functions remain largely elusive. This study identified acetoacetate as the precursor for lysine acetoacetylation (Kacac), a previously uncharacterized and evolutionarily conserved histone post-translational modification. This protein modification is comprehensively validated using chemical and biochemical approaches, including HPLC co-elution and MS/MS analysis using synthetic peptides, Western blot, and isotopic labeling. Histone Kacac can be dynamically regulated by acetoacetate concentration, possibly via acetoacetyl-CoA. Biochemical studies show that HBO1, traditionally known as an acetyltransferase, can also serve as an acetoacetyltransferase. In addition, 33 Kacac sites are identified on mammalian histones, depicting the landscape of histone Kacac marks across species and organs. In summary, this study thus discovers a physiologically relevant and enzymatically regulated histone mark that sheds light on the non-metabolic functions of ketone bodies.
Topics: Animals; Histones; Lysine; Acetoacetates; Tandem Mass Spectrometry; Protein Processing, Post-Translational; Mammals
PubMed: 37382194
DOI: 10.1002/advs.202300032 -
Nutrients Mar 2020Ketone bodies (KBs), comprising β-hydroxybutyrate, acetoacetate and acetone, are a set of fuel molecules serving as an alternative energy source to glucose. KBs are... (Review)
Review
Modulation of Cellular Biochemistry, Epigenetics and Metabolomics by Ketone Bodies. Implications of the Ketogenic Diet in the Physiology of the Organism and Pathological States.
Ketone bodies (KBs), comprising β-hydroxybutyrate, acetoacetate and acetone, are a set of fuel molecules serving as an alternative energy source to glucose. KBs are mainly produced by the liver from fatty acids during periods of fasting, and prolonged or intense physical activity. In diabetes, mainly type-1, ketoacidosis is the pathological response to glucose malabsorption. Endogenous production of ketone bodies is promoted by consumption of a ketogenic diet (KD), a diet virtually devoid of carbohydrates. Despite its recently widespread use, the systemic impact of KD is only partially understood, and ranges from physiologically beneficial outcomes in particular circumstances to potentially harmful effects. Here, we firstly review ketone body metabolism and molecular signaling, to then link the understanding of ketone bodies' biochemistry to controversies regarding their putative or proven medical benefits. We overview the physiological consequences of ketone bodies' consumption, focusing on (i) KB-induced histone post-translational modifications, particularly β-hydroxybutyrylation and acetylation, which appears to be the core epigenetic mechanisms of activity of β-hydroxybutyrate to modulate inflammation; (ii) inflammatory responses to a KD; (iii) proven benefits of the KD in the context of neuronal disease and cancer; and (iv) consequences of the KD's application on cardiovascular health and on physical performance.
Topics: 3-Hydroxybutyric Acid; Acetoacetates; Animals; Diabetes Mellitus, Type 1; Diet, Ketogenic; Epigenesis, Genetic; Epigenomics; Humans; Ketone Bodies; Ketosis; Metabolomics; Neoplasms; Nervous System Diseases
PubMed: 32192146
DOI: 10.3390/nu12030788 -
Biochimica Et Biophysica Acta.... Jun 2020The ketone bodies, d-β-hydroxybutyrate and acetoacetate, are soluble 4-carbon compounds derived principally from fatty acids, that can be metabolised by many oxidative... (Review)
Review
The ketone bodies, d-β-hydroxybutyrate and acetoacetate, are soluble 4-carbon compounds derived principally from fatty acids, that can be metabolised by many oxidative tissues, including heart, in carbohydrate-depleted conditions as glucose-sparing energy substrates. They also have important signalling functions, acting through G-protein coupled receptors and histone deacetylases to regulate metabolism and gene expression including that associated with anti-oxidant activity. Their concentration, and hence availability, increases in diabetes mellitus and heart failure. Whilst known to be substrates for ATP production, especially in starvation, their role(s) in the heart, and in heart disease, is uncertain. Recent evidence, reviewed here, indicates that increased ketone body metabolism is a feature of heart failure, and is accompanied by other changes in substrate selection. Whether the change in myocardial ketone body metabolism is adaptive or maladaptive is unknown, but it offers the possibility of using exogenous ketones to treat the failing heart.
Topics: Acetoacetates; Fatty Acids; Glucose; Heart Failure; Humans; Ketone Bodies; Ketones; Myocardium
PubMed: 32084511
DOI: 10.1016/j.bbadis.2020.165739 -
Metabolism: Clinical and Experimental Jan 2023Glucagon-like peptide-1 receptor agonists (GLP-1RA) and bariatric surgery have proven to be effective treatments for obesity and cardiometabolic conditions. We aimed to... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Glucagon-like peptide-1 receptor agonists (GLP-1RA) and bariatric surgery have proven to be effective treatments for obesity and cardiometabolic conditions. We aimed to explore the early metabolomic changes in response to GLP-1RA (liraglutide) therapy vs. placebo and in comparison to bariatric surgery.
METHODS
Three clinical studies were conducted: a bariatric surgery cohort study of participants with morbid obesity who underwent either Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) studied over four and twelve weeks, and two randomized placebo-controlled, crossover double blind studies of liraglutide vs. placebo administration in participants with type 2 diabetes (T2D) and participants with obesity studied for three and five weeks, respectively. Nuclear magnetic resonance spectroscopy-derived metabolomic data were assessed in all eligible participants who completed all the scheduled in-clinic visits. The primary outcome of the study was to explore the changes of the metabolome among participants with obesity with and without T2D receiving the GLP-1RA liraglutide vs. placebo and participants with obesity undergoing bariatric surgery during the three to five-week study period. In addition, we assessed the bariatric surgery effects longitudinally over the twelve weeks of the study and the differences between the bariatric surgery subgroups on the metabolome. The trials are registered with ClinicalTrials.gov, numbers NCT03851874, NCT01562678 and NCT02944500.
RESULTS
Bariatric surgery had a more pronounced effect on weight and body mass index reduction (-14.19 ± 5.27 kg and - 5.19 ± 5.27, respectively, p < 0.001 for both) and resulted in more pronounced metabolomic and lipidomic changes compared to liraglutide therapy at four weeks postoperatively. Significant changes were observed in lipoprotein parameters, inflammatory markers, ketone bodies, citrate, and branched-chain amino acids after the first three to five weeks of intervention. After adjusting for the amount of weight loss, a significant difference among the study groups remained only for acetoacetate, β-hydroxybutyrate, and citrate (p < 0.05 after FDR correction). Glucose levels were significantly reduced in all intervention groups but mainly in the T2D group receiving GLP-1RA treatment. After adjusting for weight loss, only glucose levels remained significant (p = 0.001 after FDR correction), mainly due to the glucose change in the T2D group receiving GLP-1RA. Similar results with those observed at four weeks were observed in the surgical group when delta changes at twelve weeks were assessed. Comparing the two types of bariatric surgery, an intervention effect was more pronounced in the RYGB subgroup regarding total triglycerides, triglyceride-rich lipoprotein size, and trimethylamine-N-oxide (p for intervention: 0.031, 0.028, 0.036, respectively). However, after applying FDR correction, these changes deemed to be only suggestive; only time effects remained significant with no significant changes persisting in relation to the types of bariatric surgery.
CONCLUSIONS
The results of this study suggest that the early metabolomic, lipid and lipoprotein changes observed between liraglutide treatment and bariatric surgery are similar and result largely from the changes in patients' body weight. Specific changes observed in the short-term post-surgical period between bariatric vs. nonsurgical treated participants, i.e., acetoacetate, β-hydroxybutyrate, and citrate changes, may reflect changes in patient diets and calorie intake indicating potential calorie and diet-driven metabolomics/lipidomic effects in the short-term postoperatively. Significant differences observed between SG and RYGB need to be confirmed and extended by future studies.
Topics: Humans; 3-Hydroxybutyric Acid; Acetoacetates; Citrates; Cohort Studies; Diabetes Mellitus, Type 2; Gastrectomy; Gastric Bypass; Glucose; Lipoproteins; Liraglutide; Obesity, Morbid; Weight Loss
PubMed: 36375643
DOI: 10.1016/j.metabol.2022.155346 -
Nature Communications Dec 2021Lactic acidosis, the extracellular accumulation of lactate and protons, is a consequence of increased glycolysis triggered by insufficient oxygen supply to tissues....
Lactic acidosis, the extracellular accumulation of lactate and protons, is a consequence of increased glycolysis triggered by insufficient oxygen supply to tissues. Macrophages are able to differentiate from monocytes under such acidotic conditions, and remain active in order to resolve the underlying injury. Here we show that, in lactic acidosis, human monocytes differentiating into macrophages are characterized by depolarized mitochondria, transient reduction of mitochondrial mass due to mitophagy, and a significant decrease in nutrient absorption. These metabolic changes, resembling pseudostarvation, result from the low extracellular pH rather than from the lactosis component, and render these cells dependent on autophagy for survival. Meanwhile, acetoacetate, a natural metabolite produced by the liver, is utilized by monocytes/macrophages as an alternative fuel to mitigate lactic acidosis-induced pseudostarvation, as evidenced by retained mitochondrial integrity and function, retained nutrient uptake, and survival without the need of autophagy. Our results thus show that acetoacetate may increase tissue tolerance to sustained lactic acidosis.
Topics: Acetoacetates; Acidosis, Lactic; Cellular Reprogramming; Energy Metabolism; Gene Expression; Humans; Hydrogen-Ion Concentration; Lactic Acid; Macrophages; Metabolic Engineering; Mitochondria; Mitophagy; Protective Agents; Tumor Microenvironment
PubMed: 34880237
DOI: 10.1038/s41467-021-27426-x -
Cell Metabolism Feb 2019Metabolic plasticity has been linked to polarized macrophage function, but mechanisms connecting specific fuels to tissue macrophage function remain unresolved. Here we...
Metabolic plasticity has been linked to polarized macrophage function, but mechanisms connecting specific fuels to tissue macrophage function remain unresolved. Here we apply a stable isotope tracing, mass spectrometry-based untargeted metabolomics approach to reveal the metabolome penetrated by hepatocyte-derived glucose and ketone bodies. In both classically and alternatively polarized macrophages, [C]acetoacetate (AcAc) labeled ∼200 chemical features, but its reduced form D-[C]β-hydroxybutyrate (D-βOHB) labeled almost none. [C]glucose labeled ∼500 features, and while unlabeled AcAc competed with only ∼15% of them, the vast majority required the mitochondrial enzyme succinyl-coenzyme A-oxoacid transferase (SCOT). AcAc carbon labeled metabolites within the cytoplasmic glycosaminoglycan pathway, which regulates tissue fibrogenesis. Accordingly, livers of mice lacking SCOT in macrophages were predisposed to accelerated fibrogenesis. Exogenous AcAc, but not D-βOHB, ameliorated diet-induced hepatic fibrosis. These data support a hepatocyte-macrophage ketone shuttle that segregates AcAc from D-βOHB, coordinating the fibrogenic response to hepatic injury via mitochondrial metabolism in tissue macrophages.
Topics: 3-Hydroxybutyric Acid; Acetoacetates; Animals; Hepatocytes; Liver Cirrhosis, Experimental; Macrophages; Mice; Mice, Inbred C57BL; Mitochondria
PubMed: 30449686
DOI: 10.1016/j.cmet.2018.10.015 -
Journal of Internal Medicine Sep 1997To assess whether blood ketone bodies are increased in congestive heart failure (CHF).
OBJECTIVE
To assess whether blood ketone bodies are increased in congestive heart failure (CHF).
METHODS
Thirteen patients with CHF and 11 cardiac patients without CHF took part in the study. Blood acetoacetate and b-hydroxybutyrate levels and the pertinent metabolic and hormonal milieu were measured during 20 h fast and after 2 h glucose infusion.
RESULTS
The averaged blood ketone body and free fatty acid levels were significantly higher during the fast and also remained higher after glucose infusion in patients with CHF than in the control group. The areas under ketone body concentration time curve over the last 8 h of the fast were 3522 +/- 662 mumol L-1 h-1 (SE) and 1789 +/- 192 mumol L-1 h-1 in patients with and without CHF, respectively (P = 0.022). Circulating noradrenaline and growth hormone were higher but glucagon lower in patients with CHF than in the controls (P < 0.05 for all differences) whereas the glucose and insulin concentrations were comparable in the study groups. At the time of peak ketonaemia the glucagon-to-insulin ratio was lower in patients with CHF than in patients without CHF (P = 0.04).
CONCLUSIONS
These data suggest that severe CHF is a ketosis-prone state. Augmented supply of free fatty acids for ketogenesis due to increased stress hormone-related lipolysis is one likely mechanism.
Topics: 3-Hydroxybutyric Acid; Acetoacetates; Heart Failure; Humans; Hydroxybutyrates; Ketone Bodies; Ketosis; Middle Aged
PubMed: 9350168
DOI: 10.1046/j.1365-2796.1997.00187.x -
Frontiers in Endocrinology 2022Ketogenesis takes place in hepatocyte mitochondria where acetyl-CoA derived from fatty acid catabolism is converted to ketone bodies (KB), namely β-hydroxybutyrate... (Review)
Review
Ketogenesis takes place in hepatocyte mitochondria where acetyl-CoA derived from fatty acid catabolism is converted to ketone bodies (KB), namely β-hydroxybutyrate (β-OHB), acetoacetate and acetone. KB represent important alternative energy sources under metabolic stress conditions. Ketogenic diets (KDs) are low-carbohydrate, fat-rich eating strategies which have been widely proposed as valid nutritional interventions in several metabolic disorders due to its substantial efficacy in weight loss achievement. Carbohydrate restriction during KD forces the use of FFA, which are subsequently transformed into KB in hepatocytes to provide energy, leading to a significant increase in ketone levels known as "nutritional ketosis". The recent discovery of KB as ligands of G protein-coupled receptors (GPCR) - cellular transducers implicated in a wide range of body functions - has aroused a great interest in understanding whether some of the clinical effects associated to KD consumption might be mediated by the ketone/GPCR axis. Specifically, anti-inflammatory effects associated to KD regimen are presumably due to GPR109A-mediated inhibition of NLRP3 inflammasome by β-OHB, whilst lipid profile amelioration by KDs could be ascribed to the actions of acetoacetate GPR43 and of β-OHB GPR109A on lipolysis. Thus, this review will focus on the effects of KD-induced nutritional ketosis potentially mediated by specific GPCRs in metabolic and endocrinological disorders. To discriminate the effects of ketone bodies , independently of weight loss, only studies comparing ketogenic isocaloric non-ketogenic diets will be considered as well as short-term tolerability and safety of KDs.
Topics: Humans; Ketone Bodies; Acetoacetates; Diet, Ketogenic; 3-Hydroxybutyric Acid; Ketosis; Receptors, G-Protein-Coupled; Ketones; Carbohydrates; Weight Loss
PubMed: 36339405
DOI: 10.3389/fendo.2022.972890