Article

Nutritional Ketosis Alters Fuel Preference and Thereby Endurance Performance in Athletes

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Abstract

Ketosis, the metabolic response to energy crisis, is a mechanism to sustain life by altering oxidative fuel selection. Often overlooked for its metabolic potential, ketosis is poorly understood outside of starvation or diabetic crisis. Thus, we studied the biochemical advantages of ketosis in humans using a ketone ester-based form of nutrition without the unwanted milieu of endogenous ketone body production by caloric or carbohydrate restriction. In five separate studies of 39 high-performance athletes, we show how this unique metabolic state improves physical endurance by altering fuel competition for oxidative respiration. Ketosis decreased muscle glycolysis and plasma lactate concentrations, while providing an alternative substrate for oxidative phosphorylation. Ketosis increased intramuscular triacylglycerol oxidation during exercise, even in the presence of normal muscle glycogen, co-ingested carbohydrate and elevated insulin. These findings may hold clues to greater human potential and a better understanding of fuel metabolism in health and disease.

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... Ketone bodies are synthesized from FA oxidation (FAO)-derived acetyl-coenzyme A, and then are transported to key extrahepatic oxidative tissues such as the heart and brain for oxidation [4,5]. Myocardial ketone body delivery is particularly increased under physiological conditions such as fasting, starvation, post-exercise, the neonatal period, pregnancy, and also during pathological conditions, such as uncontrolled diabetes [6][7][8]. The circulating concentration of ketone bodies in healthy individuals normally exhibits circadian oscillations between around 100 µM and 250 µM but can rise to ∼1 mM after prolonged exercise, 5-7 mM after prolonged fasting, and as high as 20 mM in pathological states (e.g., untreated insulin-deficient diabetes) [7,9]. ...
... Dietary supplementation of ketone bodies has been shown to have multiple beneficial effects on both health and disease. For example, ketone bodies serve as an alternative fuel in trained athletes [8] and were reported to be beneficial in animal models and patients with heart failure [4,[10][11][12][13]. Additionally, ketone body infusion specifically improved cognitive parameters in patients with type 2 diabetes [14]. ...
... Ketone bodies have been reported to exert beneficial actions in rodents and humans with heart failure [4,7,8,[10][11][12][13][14][15][16]. On the other hand, ketones can induce myocellular insulin resistance [17][18][19]. ...
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The heart is metabolically flexible. Under physiological conditions, it mainly uses lipids and glucose as energy substrates. In uncontrolled diabetes, the heart switches towards predominant lipid utilization, which over time is detrimental to cardiac function. Additionally, diabetes is accompanied by high plasma ketone levels and increased utilization of energy provision. The administration of exogenous ketones is currently being investigated for the treatment of cardiovascular disease. Yet, it remains unclear whether increased cardiac ketone utilization is beneficial or detrimental to cardiac functioning. The mechanism of lipid-induced cardiac dysfunction includes disassembly of the endosomal proton pump (named vacuolar-type H+-ATPase; v-ATPase) as the main early onset event, followed by endosomal de-acidification/dysfunction. The de-acidified endosomes can no longer serve as a storage compartment for lipid transporter CD36, which then translocates to the sarcolemma to induce lipid accumulation, insulin resistance, and contractile dysfunction. Lipid-induced v-ATPase disassembly is counteracted by the supply of specific amino acids. Here, we tested the effect of ketone bodies on v-ATPase assembly status and regulation of lipid uptake in rodent/human cardiomyocytes. 3-β-hydroxybutyrate (3HB) exposure induced v-ATPase disassembly and the entire cascade of events leading to contractile dysfunction and insulin resistance, similar to conditions of lipid oversupply. Acetoacetate addition did not induce v-ATPase dysfunction. The negative effects of 3HB could be prevented by addition of specific amino acids. Hence, in sedentary/prediabetic subjects ketone bodies should be used with caution because of possible aggravation of cardiac insulin resistance and further loss of cardiac function. When these latter maladaptive conditions would occur, specific amino acids could potentially be a treatment option.
... In addition, KB can increase the expression of the protein Brain Derived Neurotropic Factor (BDNF), an important molecule for brain plasticity/regulation of cognitive function [13,14]. Recently, ketone supplements have emerged as an alternative to a ketogenic diet to induce hyperketonemia acutely [15,16] and are available commercially in two forms, ketone salts (KS) and ketone esters (KE). These supplements have been shown to help spare CHO [15] and to provide an alternative fuel for the brain [17]. ...
... Recently, ketone supplements have emerged as an alternative to a ketogenic diet to induce hyperketonemia acutely [15,16] and are available commercially in two forms, ketone salts (KS) and ketone esters (KE). These supplements have been shown to help spare CHO [15] and to provide an alternative fuel for the brain [17]. However, only a few studies have evaluated the efficacy of ketone supplements on cognitive function during exercise with some studies showing positive effects [18,19] while others found no benefits [20][21][22] when compared to CHO or a non-caloric placebo. ...
... The greatest value achieved over a 20 s collection period was considered max whenever a plateau in . VO 2 occurred (<50% of the expected increase in oxygen uptake for the increased workload) or when two of the following three criterion measures were attained (±10 bpm of age predicted maximum HR, RER > 1. 15 [RER = volume of CO 2 produced/volume of O 2 consumed] or volitional fatigue). Further, peak sprint speed was determined using a 10-15 s all-out effort on a non-motorized treadmill (Desmo Pro, Woodway ® , Waukesha, WI, USA). ...
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Ketone supplementation has been proposed to enhance cognition during exercise. To assess whether any benefits are due to reduced cognitive fatigue during the latter portions of typical sport game action, we induced cognitive fatigue, provided a ketone monoester supplement (KME) vs. a non-caloric placebo (PLAC), and assessed cognitive performance during a simulated soccer match (SSM). In a double-blind, balanced, crossover design, nine recreationally active men (174.3 ± 4.2 cm, 76.6 ± 7.4 kg, 30 ± 3 y, 14.2 ± 5.5 % body fat, V˙O2 max = 55 ± 5 mL·kg BM−1·min−1; mean ± SD) completed a 45-min SSM (3 blocks of intermittent, variable intensity exercise) consuming either KME (25 g) or PLAC, after a 40-min mental fatiguing task. Cognitive function (Stroop and Choice Reaction Task [CRT]) and blood metabolites were measured throughout the match. KME reduced concentrations of both blood glucose (block 2: 4.6 vs. 5.2 mM, p = 0.02; block 3: 4.7 vs. 5.3 mM, p = 0.01) and blood lactate (block 1: 4.7 vs. 5.4 mM, p = 0.05; block 2: 4.9 vs. 5.9 mM, p = 0.01) during the SSM vs. PLAC, perhaps indicating a CHO sparing effect. Both treatments resulted in impaired CRT performance during the SSM relative to baseline, but KME displayed a reduced (p < 0.05) performance decrease compared to PLAC (1.3 vs. 3.4% reduction in correct answers, p = 0.02). No other differences in cognitive function were seen. These data suggest that KME supplementation attenuated decrements in CRT during repeated, high intensity, intermittent exercise. More study is warranted to assess fully the potential cognitive/physical benefits of KME for athletes.
... Rights reserved. (R)-3-hydroxybutyl (R)-3-hydroxybutyrate (R-BD R-βHB) ketone monoester (KME) A ketone monoester produced by synthesis of R-βhydroxybutyrate and R-1, 3-butanediol This ketone ester is salt-free, has 99% chiral purity and therefore only provides the R form of βHB [34,100,319] Ingestion in the fasted state produces a rapid and dose-responsive increase in whole blood [R-βHB], e. when ingested fed at rest [34], and ~ 2:1 during exercise when ingested fed [38] R,S-1,3-butanediol acetoacetate (R,S-BD AcAc) ketone diester (KDE) a A ketone diester produced by transesterification of t-butylacetoacetate with R,S-1,3-butanediol [102,320] This ketone ester is a non-ionised sodium-free and pH-neutral precursor of AcAc Only one human study has reported circulating [KB] esters have been prominent in the exercise science literature [35, 38, 42, 44, 47-49, 54, 58-60, 66-68, 70-72, 78, 81, 86, 87, 99], and include the R-3-hydroxybutyl R-3-hydroxybutyrate (R-BD R-βHB) ketone monoester (KME) [34,44,100], originally developed to improve the physical and cognitive performance in warfighters [101], and the R,S-1,3-butanediol acetoacetate (R,S-BD AcAc) ketone diester (KDE) [35,102,103]. Other ketone esters that have been reported in the peer-reviewed literature to date include a compound of βHB and the short chain fatty acid butyrate (βHB-BA) [104], and a diester of hexanoic acid (a ketogenic MCFA) and R-1,3 butanediol (BH-BD) [39,105,106]. ...
... Given the numerous possible combinations of AcAc and βHB with ketogenic precursors (including BD, MCFAs, glycerol, and ketogenic amino acids), it is likely that additional forms of EKS will be developed in the future. In the time since 2016 when the first peer-reviewed article detailing the effects of acute ingestion of EKS in humans on exercise metabolism and endurance performance was published [44], there has been a dramatic increase in the number of articles investigating the effects in humans of acute ingestion of EKS of various types on exercise metabolism, physical and cognitive performance, and recovery from exercise [21, 35-38, 42, 44-49, 51, 52, 54, 56-62, 64, 66-73, 78, 81, 82, 84-86], and in other studies investigating short-term (~ 10 d to 6 weeks) daily consumption [74,83,87,99,[107][108][109][110]. Therefore, this review provides an update on investigations into the effects of EKS on exercise performance and recovery outcomes relevant to athletic performance, as well as discussion of methodological considerations and future directions in this field. ...
... R-βHB is preferred to AcAc for measuring circulating [KB] as an indicator of ketosis, and therefore the use of POC is preferable to urinary ketone measurement due to the inability of nitroprusside in the urinary sticks to detect βHB [114], especially during mild ketosis [120]. Other studies have used laboratory methods, including reagent and colorimetric kits for measurement of plasma or serum [R-βHB] from venous blood samples [35,36,44,47,49,54], whereas S-βHB has been determined alongside R-βHB using gas chromatography-mass spectrometry with a chiral column [34], hydrophilic interaction liquid chromatography (HILIC) coupled to electrospray tandem mass spectrometry [65], and the combination of ultraperformance liquid chromatography and electrospray ionisation mass spectrometry [21]. ...
Article
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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.
... Therefore, they do not need carbohydrate restriction [3,13]. So far, three ketone donors have been identified: 3HB, ketone ester (KE) [30,31], and PHB [3,13]. Just as PHB can induce ketobiotics since it passes through the small intestine and donates 3HB to microbiota to change its structure [3,13], 3HB and KE can also donate 3HB to mammals since they are absorbed in the small intestine and cannot reach the large intestine [20,30]. ...
... So far, three ketone donors have been identified: 3HB, ketone ester (KE) [30,31], and PHB [3,13]. Just as PHB can induce ketobiotics since it passes through the small intestine and donates 3HB to microbiota to change its structure [3,13], 3HB and KE can also donate 3HB to mammals since they are absorbed in the small intestine and cannot reach the large intestine [20,30]. I summerized the differential actions of ketone donators in Table 1. ...
... KE is an ester compound between 3HB and 1,3-butandiol [30,31]. However, this ester bond can be easily hydrolysed by a digestive enzyme (esterase) in the small intestine to produce 3HB and 1,3-butandiol in the small intestine. ...
... Ketone bodies can modulate several of the key pathologic processes involved in both obese and allergic asthma. [16][17][18] As an energy source, ketone bodies make cells less reliant on glycolysis, 14,[19][20][21][22][23] as a result of which they produce less lactic acid, a catabolite implicated as a causal factor in the pathogenesis of allergic asthma. [24][25][26][27][28] Ketone bodies have been reported to function through cell surface receptors, including the G proteincoupled receptors hydroxycarboxylic acid receptor 2 (HCAR2/ GPR109a) and free fatty acid receptor 3 (FFAR3/ GPR41). ...
... 66 Elevating ketone bodies is safe both in animal models of disease and in human subjects. 22,23,40,[67][68][69][70][71][72][73] In our studies, feeding a ketogenic diet, adding 1,3-BD to chow, or supplementing with KE augmented circulating BHB levels, but not to remarkably high concentrations and not nearly to those used in our in vitro studies or in those of other investigators. A ketogenic diet contains sufficient protein, reduced amounts of carbohydrates, and an abundance of fat that serves as a substrate for ketone body formation. ...
... KEs are considered a dietary supplement and have shown benefits to elite athletes and in patients with chronic disease. 22,23,40,67,68 As used in our studies, the KE (R)-1,3-BHB (R)-1,3-BD 23,67,68 augments circulating BHB levels and was incorporated into mouse food at a concentration of 20% of weight (and approximately 20% of calories) to promote protracted consumption. KE supplementation elicited the most consistent and substantial effects to decrease methacholine hyperresponsiveness in each of the mouse models of allergic asthma, which we speculate is a consequence of its capacity to most markedly elevate circulating BHB levels. ...
Article
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Background Allergic asthmatics exhibit lung inflammation and remodeling accompanied by methacholine hyperresponsiveness manifesting in proximal airway narrowing and distal lung tissue collapsibility, and can present with a range of mild to severe disease amenable or resistant to therapeutic intervention, respectively. There remains a need for alternatives or complements to existing treatments that could control the physiological manifestations of allergic asthma. Objectives Eliciting anti-inflammatory activity and effective in mitigating the methacholine hyperresponsiveness associated with obese asthma, we hypothesized that increasing the systemic concentrations of ketone bodies would diminish pathological outcomes in asthma-relevant cell types and in mouse models of allergic asthma. Methods We explored in vitro the effects of ketone bodies on allergic asthma-relevant cell types (macrophages, airway epithelial cells, CD4 T cells, and bronchial smooth muscle) and in vivo using preclinical models representative of several endotypes of allergic asthma whether promotion of ketosis through feeding a ketogenic diet or providing a ketone precursor or a ketone ester dietary supplement could affect immune and inflammatory parameters as well as methacholine hyperresponsiveness. Results The ketone bodies, acetoacetate (AcAc) and β-hydroxybutyrate (BHB), dose-dependently decreased pro-inflammatory cytokine secretion from mouse macrophages and airway epithelial cells, decreased house dust mite (HDM) extract-induced IL-8 secretion from human airway epithelial cells, and decreased cytokine production from polyclonally- and HDM-activated T cells. Feeding a ketogenic diet, providing a ketone body precursor, or supplementing the diet with a ketone ester increased serum BHB concentrations and decreased methacholine hyperresponsiveness in several acute HDM sensitization and challenge allergic asthma models. Ketogenic diet feeding or ketone ester supplementation decreased methacholine hyperresponsiveness in a HDM rechallenge model of chronic allergic asthma. Ketone ester supplementation synergized with corticosteroid treatment to decrease methacholine hyperresponsiveness in an HDM-driven model of mixed-granulocytic severe asthma. HDM-induced morphological changes in bronchial smooth muscle cells were dose-dependently inhibited by BHB, as was HDM protease activity. Conclusions Increasing systemic BHB concentrations through dietary interventions could provide symptom relief for several endotypes of allergic asthmatics through effects on multiple asthma-relevant cells.
... It is an energy contributor for cellular activities [25,[29][30][31][32]. 3HB utilization is increased in atrophic cardiomyocyte [33,34], and exogenous 3HB exerts the obvious hemodynamic effects for patients with chronic heart failure (HF) [35,36]. The conventional ketogenic diet (KD) body supplement and 3HB supplemented to foods or drinks gradually have found applications for treating neurodegenerative disease such as epilepsy [37,38], Alzheimer's disease [39,40], cancer [41,42], aging [43], atherosclerosis [44], colonic inflammation and carcinogenesis [45], NLRP3-mediated inflammation [46], osteoporosis [47] and enhanced exercise performance [48]. ...
... Although 3HB is an important fuel molecule with high energetic efficiency, the current approach is not precise enough to observe the reallocation of energy substrates in terms of glycolysis (Additional file 1: Fig. S5j), fatty acid oxidation (Additional file 3: Table S2), and TCA cycle (Additional file 1: Fig. S5e-i). These results further revealed that 3HB regulates muscle protein via different mechanisms during exercises under healthy and muscle atrophy conditions [48]. ...
... From an endogenous small-molecule point of view, these results indicate that 3HB can attenuate disuse-induced muscle atrophy and provide an option for possible nutritional supplements to increase prognosis and life expectancy. 3HB may also pose tractable implementation for the weight loss ones to save muscle mass in the fat-only loss condition and those bodybuilders desiring to get stronger muscular fitness and more muscle mass [48,84]. Our mouse model was found simulating the skeletal muscle atrophy in a weightless environment, which share similar pathophysiological changes and metabolic mechanisms with senescent state [85,86]. ...
Article
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Background Muscle atrophy is an increasingly global health problem affecting millions, there is a lack of clinical drugs or effective therapy. Excessive loss of muscle mass is the typical characteristic of muscle atrophy, manifesting as muscle weakness accompanied by impaired metabolism of protein and nucleotide. (D)-3-hydroxybutyrate (3HB), one of the main components of the ketone body, has been reported to be effective for the obvious hemodynamic effects in atrophic cardiomyocytes and exerts beneficial metabolic reprogramming effects in healthy muscle. This study aims to exploit how the 3HB exerts therapeutic effects for treating muscle atrophy induced by hindlimb unloaded mice. Results Anabolism/catabolism balance of muscle protein was maintained with 3HB via the Akt/FoxO3a and the mTOR/4E-BP1 pathways; protein homeostasis of 3HB regulation includes pathways of ubiquitin–proteasomal, autophagic-lysosomal, responses of unfolded-proteins, heat shock and anti-oxidation. Metabolomic analysis revealed the effect of 3HB decreased purine degradation and reduced the uric acid in atrophied muscles; enhanced utilization from glutamine to glutamate also provides evidence for the promotion of 3HB during the synthesis of proteins and nucleotides. Conclusions 3HB significantly inhibits the loss of muscle weights, myofiber sizes and myofiber diameters in hindlimb unloaded mouse model; it facilitates positive balance of proteins and nucleotides with enhanced accumulation of glutamate and decreased uric acid in wasting muscles, revealing effectiveness for treating muscle atrophy. Graphical Abstract
... When sufficiently elevated, the ketone bodies-βhydroxybutyrate (βHB) and acetoacetate (AcAc)-may provide a supplementary oxidative substrate for skeletal muscle (Balasse & Fery, 1989). Given this, it is hypothesized that inducing hyperketonemia may enhance exercise capacity by reducing muscles reliance on CHO (Cox et al., 2016;Phinney et al., 1983). However, the estimated contribution of ketone oxidation to overall energy expenditure during exercise varies widely from 0% to 18% (Balasse & Fery, 1989;Cox et al., 2016;Wahren et al., 1975), meaning the utility of this substrate is debated (Petrick et al., 2020). ...
... Given this, it is hypothesized that inducing hyperketonemia may enhance exercise capacity by reducing muscles reliance on CHO (Cox et al., 2016;Phinney et al., 1983). However, the estimated contribution of ketone oxidation to overall energy expenditure during exercise varies widely from 0% to 18% (Balasse & Fery, 1989;Cox et al., 2016;Wahren et al., 1975), meaning the utility of this substrate is debated (Petrick et al., 2020). Ketones also have a range of metabolic signaling effects (Newman & Verdin, 2017), including altering the availability and utilization of carbohydrate and fat, which could acutely modulate exercise capacity and alter adaptative responses to exercise training (Evans et al., 2017). ...
... Here, blood ketone levels rise rapidly and transiently in a dosedependent fashion , without the need for dietary CHO restriction. The combination of hyperketonemia with replete CHO stores may enhance acute endurance exercise capacity (Cox et al., 2016;Poffé et al., 2021), although both null (Dearlove et al., 2019;Evans & Egan, 2018;Evans et al., 2019;Poffé et al., 2020) and negative effects (Leckey et al., 2017) have also been reported. Moreover, prolonged supplementation of ketones during high-intensity exercise training may prevent the deleterious effects of overreaching (Poffé et al., 2019), and has been hypothesized to influence the adaptive response to exercise training (Evans et al., 2017). ...
Article
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Elevating blood ketones may enhance exercise capacity and modulate adaptations to exercise training; however, these effects may depend on whether hyperketonemia is induced endogenously through dietary carbohydrate restriction, or exogenously through ketone supplementation. To determine this, we compared the effects of endogenously‐ and exogenously‐induced hyperketonemia on exercise capacity and adaptation. Trained endurance athletes undertook 6 days of laboratory based cycling (“race”) whilst following either: a carbohydrate‐rich control diet (n = 7; CHO); a carbohydrate‐rich diet + ketone drink four‐times daily (n = 7; Ex Ket); or a ketogenic diet (n = 7; End Ket). Exercise capacity was measured daily, and adaptations in exercise metabolism, exercise physiology and postprandial insulin sensitivity (via an oral glucose tolerance test) were measured before and after dietary interventions. Urinary β‐hydroxybutyrate increased by ⁓150‐fold and ⁓650‐fold versus CHO with Ex Ket and End Ket, respectively. Exercise capacity was increased versus pre‐intervention by ~5% on race day 1 with CHO (p < 0.05), by 6%–8% on days 1, 4, and 6 (all p < 0.05) with Ex Ket and decreased by 48%–57% on all race days (all p > 0.05) with End Ket. There was an ⁓3‐fold increase in fat oxidation from pre‐ to post‐intervention (p < 0.05) with End Ket and increased perceived exercise exertion (p < 0.05). No changes in exercise substrate metabolism occurred with Ex Ket, but participants had blunted postprandial insulin sensitivity (p < 0.05). Dietary carbohydrate restriction and ketone supplementation both induce hyperketonemia; however, these are distinct physiological conditions with contrasting effects on exercise capacity and adaptation to exercise training. Exercise performance and adaptive responses to an endogenously‐ and exogenously‐induced hyperketonemia are markedly different.
... The KD, defined as restricting carbohydrates to <10% of daily energy [5], is used to achieve ketosis, the metabolic state in which the body increases ketone body production and relies on fat as its primary energy source [6]. Specifically, endurance athletes employ the KD to shift the body toward greater fat utilization, otherwise known as "fat adaptation", in situations where the body would typically and predominately rely on glycogen utilization [7]. ...
... Specifically, endurance athletes employ the KD to shift the body toward greater fat utilization, otherwise known as "fat adaptation", in situations where the body would typically and predominately rely on glycogen utilization [7]. The fat-adapted state can occur within five-to-six days on the KD [8,9] and is thought to be associated with increased improved performance and glycogen sparing [6,10,11]. Additionally, it is common for endurance athletes to follow a KD to promote weight loss and improve performance through increases in speed or power. ...
Article
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Extreme carbohydrate deficits during a ketogenic diet (KD) may result in metabolic adaptations reflective of low energy availability; however, the manifestation of these adaptations outside of exercise have yet to be elucidated in cyclists and triathletes. The purpose of this study is to investigate the chronic and postprandial metabolic responses to a KD compared to a high-carbohydrate diet (HCD) and habitual diet (HD) in trained competitive cyclists and triathletes. For this randomized crossover trial, six trained competitive cyclist and triathletes (F: 4, M: 2) followed an ad libitum KD and HCD for 14 d each after their HD. Fasting energy expenditure (EE), respiratory exchange ratio (RER), and fat and carbohydrate oxidation (FatOx and CarbOx, respectively) were collected during their HD and after 14 d on each randomly assigned KD and HCD. Postprandial measurements were collected on day 14 of each diet following the ingestion of a corresponding test meal. There were no significant differences in fasting EE, RER, FatOx, or CarbOx among diet conditions (all p > 0.050). Although postprandial RER and CarbOx were consistently lower following the KD meal, there were no differences in peak postprandial RER (p = 0.452), RER incremental area under the curve (iAUC; p = 0.416) postprandial FatOx (p = 0.122), peak FatOx (p = 0.381), or FatOx iAUC (p = 0.164) between the KD and HD meals. An ad libitum KD does not significantly alter chronic EE or substrate utilization compared to a HCD or HD; postprandial FatOx appears similar between a KD and HD; this is potentially due to the high metabolic flexibility of cyclists and triathletes and the metabolic adaptations made to habitual high-fat Western diets in practice. Cyclists and triathletes should consider these metabolic similarities prior to a KD given the potential health and performance impairments from severe carbohydrate restriction.
... Tanto el diéster de acetoacetato R,S-1,3-butanodiol como el monoéster de cetona R-3hidroxibutilo R-3-hidroxibutirato se han probado en atletas de élite con resultados variables (Evans y Egan, 2018). La administración oral aguda de monoéster de cetona R-3-hidroxibutilo R-3-hidroxibutirato da como resultado una concentración plasmática de βHB de aproximadamente 3,0 mM a los 20 min y mejora el rendimiento experimental durante 30 min en un 2 % (Cox et al., 2016). ...
... Por el contrario, el diéster de acetoacetato R, S-1,3-butanodiol oral fue menos eficaz y se incrementaron los niveles séricos de βHB por debajo de 0,4 mM y se produjo un deterioro del 2% del rendimiento en una contrarreloj de 31,2 km. El consumo de monoéster de cetona R-3-hidroxibutilo R-3 hidroxibutirato aumenta el aporte de los cuerpos cetónicos como combustible durante el ejercicio y supone hasta un 16-18 % de la cantidad total de energía suministrada, además se producen efectos metabólicos significativos entre los que se encuentran: reducción de los niveles de glucosa y lactato en sangre, incremento del glucógeno muscular y mayor utilización intramuscular de triglicéridos (Cox et al., 2016). ...
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Los cuerpos cetónicos son pequeñas moléculas derivadas de la grasa que proporcionan energía a los tejidos cuando hay escasez de glucosa, como durante la inanición o el ejercicio prolongado y se transportan a través del torrente sanguíneo hacia los tejidos metabólicamente activos, como los músculos o el cerebro. El betahidroxibutirato (βHB) es un sustrato eficiente, que produce un 31 % más de energía en concreto 243,6 kcal/mol por molécula de carbono, frente a los 185,7 kcal/mol del piruvato. Tanto el diéster de acetoacetato R,S-1,3-butanodiol como el monoéster de cetona R-3-hidroxibutilo R-3-hidroxibutirato se han probado en atletas de élite con resultados variables. Además, la ingesta de sales cetogénicas de βHB produce efectos metabólicos significativos como la reducción de los niveles de glucosa y lactato en sangre, incremento del glucógeno muscular y mayor utilización intramuscular de triglicéridos. Se realizó una revisión sistemática de la literatura científica con el objetivo de englobar toda la evidencia relacionada con los efectos de la ingesta de sales cetogénicas de βHB en la realización de ejercicio de resistencia. Se llevó a cabo una búsqueda en Pubmed y Elsevier siguiendo las directrices PRISMA, seleccionando finalmente 9 artículos que cumplían con los criterios de inclusión establecidos y abordaban la temática de forma específica. Los artículos examinados mostraron que la ingesta de sales cetogénicas de βHB no mejoran el rendimiento en el ejercicio de resistencia. La ingesta de sales cetogénicas de βHB elevan los niveles séricos de βHB. Una dosis mayor o menor de sales cetogénicas de βHB no muestran un resultado diferente en los test físicos de los estudios analizados. La ingesta de sales cetogénicas de βHB podrían tener un efecto negativo en el rendimiento en deportes de resistencia. Se necesitan más estudios que contengan dosis más altas de sales cetogénicas de βHB con la realización de test de resistencia de mayor duración a un nivel de intensidad alto de manera constante.
... Recently, exogenous sources of ketones, such as ketone esters, have been developed for their ability to elevate blood ketone concentrations without the need for changes in dietary macronutrient intake. These ketone esters have been used to test the effects of exogenous ketosis on a variety of end points across states of health and disease, ranging from physical (12)(13)(14)(15) and cognitive (16)(17)(18) performance to blood glucose regulation (19)(20)(21)(22) and cardiac function (23,24). The consumption of exogenous ketone products may replicate a subset of the effects of endogenous ketosis (6,25). ...
... We used standard serving sizes to mimic real world use. The highest weight adjusted serving size in our study was ~460 mg/kg, which is somewhat lower than servings used in functional studies of ketone esters for athletic performance (573 mg/kg) (15), cardiac function (714 mg/kg) (23), and brain function (625 mg/kg) (18), therefore future work should include larger serving sizes of BH-BD to understand if the ketone response to increasing serving size continues, or if there are alterations in BHB kinetics with higher amounts. ...
Article
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Objective: Growing interest in the metabolic state of ketosis has driven development of exogenous ketone products to induce ketosis without dietary changes. Bis hexanoyl (R)-1,3-butanediol (BH-BD) is a novel ketone ester which, when consumed, increases blood beta-hydroxybutyrate (BHB) concentrations. BH-BD is formulated as a powder or ready-to-drink (RTD) beverage; the relative efficacy of these formulations is unknown, but hypothesized to be equivalent. Methods: This randomized, observer-blinded, controlled, crossover decentralized study in healthy adults (n = 15, mean age = 33.7 years, mean BMI = 23.6 kg/m²) aimed to elucidate blood BHB and glucose concentrations before and 15, 30, 45, 60, 90 and 120 minutes following two serving sizes of reconstituted BH-BD powder (POW 25 g, POW 12.5 g), compared to a RTD BH-BD beverage (RTD 12.5 g), and a non-ketogenic control, all taken with a standard meal. Results: All BH-BD products were well tolerated and increased BHB, inducing nutritional ketosis (BHB ≥0.5 mM) after ∼15 minutes, relative to the control. BHB remained elevated 2 h post-consumption. The control did not increase BHB. Ketosis was dose responsive; peak BHB concentration and area under the curve (AUC) were two-fold greater with POW 25 g compared to POW 12.5 g and RTD 12.5 g. There were no differences in peak BHB and AUC between matched powder and RTD formulas. Blood glucose increased in all conditions following the meal but there were neither significant differences in lowest observed concentrations, nor consistent differences at each time point between conditions. These results demonstrate that both powdered and RTD BH-BD formulations similarly induce ketosis with no differences in glucose concentrations in healthy adults.
... Conversely, humans are adopting dietary regimens (e.g., ketogenic diet, intermittent fasting, time-restricted feeding) that lead to increases in BHB levels (Newman & Verdin, 2017). Moreover, human studies have used the ingestion of ketone esters to increase BHB levels and enhance metabolic performance in athletes (Cox et al., 2016). Finally, other cataloged health benefits caused by BHB thus far are diverse and range from improved memory, increased lifespan, and reduction of hypertension (Newman & Verdin, 2017). ...
... Photographs were taken at 63× magnification. intermittent fasting, time-restricted feeding) geared towards improving wellness, athletic performance, and health (Ang et al., 2020;Cox et al., 2016;Patterson & Sears, 2017). In humans, serum levels of BHB are usually in the low micromolar range (50 μmol/L in the normal fed state), but can begin to rise in some physiological and pathological conditions. ...
Article
Besides their canonical roles as energy sources, short‐chain fatty acids act as metabolic regulators of gene expression through histone posttranslational modifications. Ketone body β‐hydroxybutyrate (BHB) causes a novel epigenetic modification, histone lysine β‐hydroxybutyrylation (Kbhb), which is associated with genes upregulated in starvation‐responsive metabolic pathways. Dairy cows increase BHB in early lactation, and the effects of this increase on cellular epigenomes are unknown. We searched for and identified that Kbhb is present in bovine tissues in vivo and confirmed that this epigenetic mark is responsive to BHB in bovine and human fibroblasts cultured in vitro in a dose‐dependent manner. Maturation of cumulus–oocyte complexes with high concentrations of BHB did not affect the competence to complete meiotic maturation or to develop until the blastocyst stage. BHB treatment strongly induced H3K9bhb in cumulus cells, but faintly in oocytes. RNA‐seq analysis in cumulus cells indicated that BHB treatment altered the expression of 345 genes. The downregulated genes were mainly involved in glycolysis and ribosome assembly pathways, while the upregulated genes were involved in mitochondrial metabolism and oocyte development. The genes and pathways altered by BHB will provide entry points to carry out functional experiments aiming to mitigate metabolic disorders and improve fertility in cattle.
... The hepatic BHB is then distributed via blood circulation to metabolically active tissues, including muscle, brain, and heart, then metabolized into Ac-CoA, and eventually ATP in the TCA circle (34) (Figure 1). The liver can produce up to 300 g of ketone bodies per day in human bodies, which provides 5~20% of the total energy expenditure (34,55). In addition, BHB has a higher H: C ratio than pyruvate (2 and 1.3, respectively) and higher reducibility, which means that it yields more free energy per mole of oxygen to fuel ATP production (56) and consequently was thought to produce fewer byproducts of reactive oxygen species (ROS) than glucose or FFAs (57). ...
... The catabolism of BHB increases the level of intracellular Ac-CoA (Figure 1), which was thought to post-transcriptionally modulate gene expression via both enzymatic and nonenzymatic protein acetylation (96). As the alternative energy source, by increasing cytoplasmic citrate and inhibiting the activities of phosphofructokinase (PFK) and pyruvate dehydrogenase (PDH), BHB inhibits glycolysis, the cytoplasmic steps of glucose utilization in many tissues (Figure 1), such as the heart, brain, skeletal muscle, and tumours (6,55,71,75), maintaining blood glucose at a necessary level. Besides, Ac-FIGURE 1 | Diagrammatic sketch of endogenous generation and consumption of BHB. ...
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Ketone bodies are crucial intermediate metabolites widely associated with treating metabolic diseases. Accumulating evidence suggests that ketone bodies may act as immunoregulators in humans and animals to attenuate pathological inflammation through multiple strategies. Although the clues are scattered and untrimmed, the elevation of these ketone bodies in the circulation system and tissues induced by ketogenic diets was reported to affect the immunological barriers, an important part of innate immunity. Therefore, beta-hydroxybutyrate, a key ketone body, might also play a vital role in regulating the barrier immune systems. In this review, we retrospected the endogenous ketogenesis in animals and the dual roles of ketone bodies as energy carriers and signal molecules focusing on beta-hydroxybutyrate. In addition, the research regarding the effects of beta-hydroxybutyrate on the function of the immunological barrier, mainly on the microbiota, chemical, and physical barriers of the mucosa, were outlined and discussed. As an inducible endogenous metabolic small molecule, beta-hydroxybutyrate deserves delicate investigations focusing on its immunometabolic efficacy. Comprehending the connection between ketone bodies and the barrier immunological function and its underlining mechanisms may help exploit individualised approaches to treat various mucosa or skin-related diseases.
... Concomitantly, we have also noticed decreases in serum metabolites (acetate, butyrate). Ketone oxidation (e.g., β-hydroxybutyrate (βHB)) might provide an alternative, energetically advantageous fuel for skeletal muscle contraction [35]. However, βHB oxidation contributes minimally to energy expenditure, although the large relative contribution of exogenous βHB oxidation occurs during light exercise [36]. ...
... The acute exogenous intake of ketone ester can even slightly impair short high-intensity endurance exercise performance [40]. The production of ketone bodies, while providing an alternative substrate for oxidative phosphorylation, actually decreases muscle glycolysis and plasma lactate concentrations [35]. Here, we report an increased intensity of exercise accompanied by a higher rate of anaerobic glycolysis during the peak period. ...
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Background Physical exercise has favorable effects on the structure of gut microbiota and metabolite production in sedentary subjects. However, little is known whether adjustments in an athletic program impact overall changes of gut microbiome in high-level athletes. We therefore characterized fecal microbiota and serum metabolites in response to a 7-week, high-intensity training program and consumption of probiotic Bryndza cheese. Methods Fecal and blood samples and training logs were collected from young competitive male ( n = 17) and female ( n = 7) swimmers. Fecal microbiota were categorized using specific primers targeting the V1–V3 region of 16S rDNA, and serum metabolites were characterized by NMR-spectroscopic analysis and by multivariate statistical analysis, Spearman rank correlations, and Random Forest models. Results We found higher α-diversity, represented by the Shannon index value (HITB-pre 5.9 [± 0.4]; HITB-post 6.4 [± 0.4], p = 0.007), (HIT-pre 5.5 [± 0.6]; HIT-post 5.9 [± 0.6], p = 0.015), after the end of the training program in both groups independently of Bryndza cheese consumption. However, Lactococcus spp . increased in both groups, with a higher effect in the Bryndza cheese consumers (HITB-pre 0.0021 [± 0.0055]; HITB-post 0.0268 [± 0.0542], p = 0.008), (HIT-pre 0.0014 [± 0.0036]; HIT-post 0.0068 [± 0.0095], p = 0.046). Concomitant with the increase of high-intensity exercise and the resulting increase of anaerobic metabolism proportion, pyruvate ( p [HITB] = 0.003; p [HIT] = 0.000) and lactate ( p [HITB] = 0.000; p [HIT] = 0.030) increased, whereas acetate ( p [HITB] = 0.000; p [HIT] = 0.002) and butyrate ( p [HITB] = 0.091; p [HIT] = 0.019) significantly decreased. Conclusions Together, these data demonstrate a significant effect of high-intensity training (HIT) on both gut microbiota composition and serum energy metabolites. Thus, the combination of intensive athletic training with the use of natural probiotics is beneficial because of the increase in the relative abundance of lactic acid bacteria.
... Among other mimetics are ketone body precursors. These include 1,3-butanediol metabolizing in the liver to ketone bodies [149,156] and esters such as (R)-3-hydroxybutyl-(R)-3-hydroxybutyrate and R,S-1,3-butanediol AcAc diester [157][158][159][160]. Acute ingestion of either ketone ester leads to a short-term (from 0.5 to 6 h) nutritional ketosis, indicated by a serum BHB concentration increase over 1 mM [161,162]. Nutritional ketosis in this case is achieved without fasting or a KD and prevents problems with salt or the non-bioactive form of BHB overloading; those will be discussed below in the "Limitations of KD Mimetics Administration" section. ...
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The ketogenic diet (KD) has been used as a treatment for epilepsy since the 1920s, and its role in the prevention of many other diseases is now being considered. In recent years, there has been an intensive investigation on using the KD as a therapeutic approach to treat acute pathologies, including ischemic ones. However, contradictory data are observed for the effects of the KD on various organs after ischemic injury. In this review, we provide the first systematic analysis of studies conducted from 1980 to 2022 investigating the effects and main mechanisms of the KD and its mimetics on ischemia–reperfusion injury of the brain, heart, kidneys, liver, gut, and eyes. Our analysis demonstrated a high diversity of both the composition of the used KD and the protocols for the treatment of animals, which could be the reason for contradictory effects in different studies. It can be concluded that a true KD or its mimetics, such as β-hydroxybutyrate, can be considered as positive exposure, protecting the organ from ischemia and its negative consequences, whereas the shift to a rather similar high-calorie or high-fat diet leads to the opposite effect.
... Although the glucose-lowering properties of β-OHB were observed in infusion studies early-on (Neptune, 1956), initial research employing modern-day exogenous ketone supplements mostly focused on testing the potential of ketosis to enhance exercise performance (Cox et al., 2016;O'Malley et al., 2017). Informed by the serendipitous observation that blood glucose was lowered during exercise after ingestion of exogenous ketones compared to a non-carbohydratecontaining comparator in these studies, evidence supporting (Nakagata et al., 2021). ...
Article
New findings: What is the topic of this review? The integrative physiological response to exogenous ketone supplementation. What advances does it highlight? The physiological effects and therapeutic potential of exogenous ketones on metabolic health, cardiovascular function, cognitive processing, and modulation of inflammatory pathways and immune function. Also highlighted are current challenges and future directions of the field. Abstract: Exogenous oral ketone supplements, primarily in form of ketone salts or esters, have emerged as a useful research tool for manipulating metabolism with potential therapeutic application targeting various aspects of several common chronic diseases. Recent literature has investigated the effects of exogenously induced ketosis on metabolic health, cardiovascular function, cognitive processing, and modulation of inflammatory pathways and immune function. This narrative review provides an overview of the integrative physiological effects of exogenous ketone supplementation and highlights current challenges and future research directions. Much of the existing research on therapeutic applications - particularly mechanistic studies - has involved pre-clinical rodent and/or cellular models, requiring further validation in human clinical studies. Existing human studies report that exogenous ketones can lower blood glucose and improve some aspects of cognitive function, highlighting the potential therapeutic application of exogenous ketones for type 2 diabetes and neurological diseases. There is also support for the ability of exogenous ketosis to improve cardiac metabolism in rodent models of heart failure with supporting human studies emerging; long-terms effects of exogenous ketone supplementation on the human cardiovascular system and lipid profiles are needed. An important avenue for future work is provided by research accelerating technologies that enable continuous ketone monitoring and/or the development of more palatable ketone mixtures that optimize plasma ketone kinetics to enable sustained ketosis. Lastly, research exploring the physiological interactions between exogenous ketones and varying metabolic states (e.g., exercise, fasting, metabolic disease) should yield important insights that can be used to maximize the health benefits of exogenous ketosis.
... Another possible reason for the observation of reduced levels of lactate during exercise is an alteration of energy supply. Ketosis decreases muscle glycolysis and plasma lactate levels, while increasing intramuscular triacylglycerol oxidation during exercise, providing an alternative substrate for oxidative phosphorylation [59]. Further investigations are necessary to understand the effects of both viable and heat-killed TWK10 on energy metabolism during exercise. ...
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Lactiplantibacillus plantarum TWK10, a probiotic strain, has been demonstrated to improve exercise performance, regulate body composition, and ameliorate age-related declines. Here, we performed a comparative analysis of viable and heat-killed TWK10 in the regulation of exercise performance, body composition, and gut microbiota in humans. Healthy adults (n = 53) were randomly divided into three groups: Control, TWK10 (viable TWK10, 3 × 1011 colony forming units/day), and TWK10-hk (heat-killed TWK10, 3 × 1011 cells/day) groups. After six-week administration, both the TWK10 and TWK10-hk groups had significantly improved exercise performance and fatigue-associated features and reduced exercise-induced inflammation, compared with controls. Viable TWK10 significantly promoted improved body composition, by increasing muscle mass proportion and reducing fat mass. Gut microbiota analysis demonstrated significantly increasing trends in the relative abundances of Akkermansiaceae and Prevotellaceae in subjects receiving viable TWK10. Predictive metagenomic profiling revealed that heat-killed TWK10 administration significantly enhanced the signaling pathways involved in amino acid metabolisms, while glutathione metabolism, and ubiquinone and other terpenoid-quinone biosynthesis pathways were enriched by viable TWK10. In conclusion, viable and heat-killed TWK10 had similar effects in improving exercise performance and attenuating exercise-induced inflammatory responses as probiotics and postbiotics, respectively. Viable TWK10 was also highly effective in regulating body composition. The differences in efficacy between viable and heat-killed TWK10 may be due to differential impacts in shaping gut microbiota.
... While differences in ketone levels were not significantly different between all of the IF groups compared to AL groups (Fig 1), higher ketone levels, whether induced by diet or the IF regimen, were correlated with increased distance traveled during OF, indicating a resistance to physical fatigue. Ketones provide an alternative fuel for oxidative phosphorylation and makes oxidation a preferential process, which minimizes glycolysis [47]. Increased ketone levels have been associated with improved physical performance and decreased fatigue in previous studies [23,24]. ...
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Intermittent fasting (IF) is an alternating pattern of restricting eating. This study evaluated mental and physical fatigue secondary to IF (daily 18-hour fast, 7-days-a-week) in the high-fat diet (HFD)-induced male obese Sprague Dawley rats. Fifty-four rats were randomly assigned to a HFD (n = 28) or a standard diet (SD; n = 26). After six weeks, the HFD rats were divided into one of four groups: obese HFD ad libitum (OB-HFD-AL), obese HFD-IF (OB-HFD-IF), obese SD-AL (OB-SD-AL), and obese SD-IF (OB-SD-IF). Similarly, non-obese controls were grouped into HFD-AL (C-HFD-AL), non-obese HFD-IF (C-HFD-IF), non-obese SD-AL (C-SD-AL), and non-obese SD-IF (C-SD-IF). After 2 weeks of IF, mental and physical fatigue were measured using open field (OF) and novel object recognition (NOR) tests. Rats on IF gained weight at a slower pace ( p< 0.05) and had lower glucose levels ( p <0.01) compared to the AL group. In non-obese rats, ketone levels were higher in the IF-HFD group than IF-SD (p<0.05) and AL-SD ( p <0.01) animals. Obese rats exhibited elevated blood ketone levels in IF-SD conditions versus AL-SD rats ( p <0.01). AL-HFD rats had higher ketone levels than AL-SD animals in both obese and non-obese groups ( p <0.05). In conclusion, rats with higher blood ketone levels, whether they were on IF or AL, traveled a greater distance during OF suggesting a lack of physical fatigue. There was no significant difference between IF and AL during NOR indicating a lack of mental fatigue. Thus, IF results in reduced body weight and blood glucose levels but does not induce physical or mental fatigue.
... Systemic presence of ketone molecules is known to promote resistance to oxidative and inflammatory stress and control transcription of genes associated with aging [32][33][34][35][36]38,39,41,42]. Although the effects of a ketogenic diet on exercise performance are controversial, administration of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate ketone ester to trained cyclists has been shown to increase performance [43,44]. ...
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TCN006, a formulation of (R)-3-Hydroxybutyrate glycerides, is a promising ingredient for enhancing ketone intake of humans. Ketones have been shown to have beneficial effects on human health. To be used by humans, TCN006 must be determined safe in appropriately designed safety studies. The results of a bacterial reverse mutation assay, an in vitro mammalian micronucleus study, and 14-and 90-day repeat dose toxicity studies in rats are reported herein. In the 14- and 90-day studies, male and female Wistar rats had free access to drinking water containing 0, 75,000, 125,000 or 200,000 ppm TCN006 for 92 and 93 days, respectively. TCN006 tested negative for genotoxicity and the no observed adverse effect level (NOAEL) for toxicity in the 14- and 90-day studies was 200,000 ppm, the highest dose administered. In the longer term study, the mean overall daily intake of TCN006 in the 200,000 ppm groups was 14,027.9 mg/kg bw/day for males and 20,507.0 mg/kg bw/day for females. At this concentration, palatability of water was likely affected, which led to a decrease in water consumption in both males and females compared to respective controls. This had no effect on the health of the animals. Although the rats were administered very high levels of (R)-3-Hydroxybutyrate glycerides, there were no signs of ketoacidosis.
... Interestingly, we observed higher labeling in citrate M + 2 following metabolism of [U-13 C]βHB in the human brain slices. As ketone bodies can compete with glucose for ace-tylCoA generation, the higher M + 2 labeling in citrate likely reflects a higher entry of βHB-derived acetylCoA into the TCA cycle [67,68]. Furthermore, metabolism of [U-13 C] βHB was not reduced to the same extent as [U-13 C]glucose in the human slices, indicating that the human brain retains a larger basal capacity for ketone body metabolism and that ketones may serve as an important neuronal substrate in the human cerebral cortex. ...
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Disruptions of brain energy and neurotransmitter metabolism are associated with several pathological conditions including neurodegenerative diseases such as Alzheimer’s disease. Transgenic rodent models, and in vitro preparations hereof, are often applied for studying pathological aspects of brain metabolism. However, despite the conserved cerebral development across mammalian species, distinct differences in cellular composition and structure may influence metabolism of the rodent and human brain. To address this, we investigated the metabolic function of acutely isolated brain slices and non-synaptic mitochondria obtained from the cerebral cortex of mice and neurosurgically resected neocortical tissue of humans. Utilizing dynamic isotope labeling with 13C-enriched metabolic substrates, we show that metabolism of glucose, acetate, β-hydroxybutyrate, and glutamine operates at lower rates in human cerebral cortical slices when compared to mouse slices. In contrast, human cerebral cortical slices display a higher capacity for converting exogenous glutamate into glutamine, which subsequently supports neuronal GABA synthesis, whereas mouse slices primarily convert glutamate into aspartate. In line with the reduced metabolic rate of the human brain slices, isolated non-synaptic mitochondria of the human cerebral cortex have a lower oxygen consumption rate when provided succinate as substrate. However, when provided pyruvate and malate, human mitochondria display a higher coupled respiration and lower proton leak, signifying a more efficient mitochondrial coupling compared to mouse mitochondria. This study reveals key differences between mouse and human brain metabolism concerning both neurons and astrocytes, which must be taken into account when applying in vitro rodent preparations as a model system of the human brain.
... However, ketone concentrations within human and rodent reproductive fluids remain to be determined. Ketones are readily consumed and utilized by extra-hepatic tissues for ATP production via oxidative metabolism, concurrently supressing glycolysis (Cox et al., 2016;Hunter et al., 1987;Laffel, 1999;Patel and Owen, 1977;Randle et al., 1964). Further, ketones can epigenetically regulate gene expression by promoting histone lysine acetylation (Newman and Verdin, 2017) and histone lysine β-hydroxybutyrylation (Xie et al., 2016). ...
Article
Research question : Does the ketone acetoacetate (AcAc) alone, or combined with β-hydroxybutyrate (βOHB), impact mouse embryo development, metabolism, histone acetylation, and viability? Design : Pronucleate mouse oocytes were cultured in vitro in G1/G2 media supplemented with ketones (AcAc or AcAc + βOHB) at concentrations representing maternal serum levels during pregnancy (0.04 mM AcAc, 0.1 mM βOHB), standard diet consumption (0.1 mM AcAc, 0.25 mM βOHB), ketogenic diet consumption (0.8 mM AcAc, 2 mM βOHB), and diabetic ketoacidosis (2 mM AcAc, 4 mM βOHB). Day 5 blastocysts were assessed for cell allocation, glucose metabolism, and histone acetylation. Day 4 blastocysts exposed to 0.8 mM AcAc + 2 mM βOHB were transferred to standard-fed recipient females, and E14.5 fetal and placental development assessed. Results : Exposure to 2 mM AcAc or 0.8 mM AcAc + 2 mM βOHB did not impair blastocyst development, but significantly increased glucose consumption (P < 0.01), lowered glycolytic flux (P < 0.01), and elevated trophectoderm (TE) histone 3 lysine 27 acetylation (H3K27ac; P < 0.001) compared with unexposed controls. Preimplantation AcAc + βOHB exposure further reduced post-implantation fetal development by 25% (P < 0.05), and delayed female-specific fetal limb development (P < 0.05) and estimated fetal age (P < 0.05) compared with controls. Conclusion : Preimplantation exposure to ketones affects underlying metabolism and histone acetylation in blastocysts that are associated with persistent, female-specific perturbations in fetal development. A periconceptional diet that elevates ketone levels may impair human embryonic viability.
... In addition to local synthesis, lactate is also imported into the brain via endothelial MCT1 transporters (42) and there partially replaces glucose as energy metabolite during ketosis (3). Circulating lactate remains at control levels in human subjects following a KD (43). In mice, KD increased MCT1 abundance in brain vessels and, despite reduced astrocyte synthesis, maintained cortical lactate levels, contributing to the sustained mitochondrial OXPHOS in cortical neurons of KD-fed mice. ...
Article
To maintain homeostasis, the body, including the brain, reprograms its metabolism in response to altered nutrition or disease. However, the consequences of these challenges for the energy metabolism of the different brain cell types remain unknown. Here, we generated a proteome atlas of the major central nervous system (CNS) cell types from young and adult mice, after feeding the therapeutically relevant low-carbohydrate, high-fat ketogenic diet (KD) and during neuroinflammation. Under steady-state conditions, CNS cell types prefer distinct modes of energy metabolism. Unexpectedly, the comparison with KD revealed distinct cell type–specific strategies to manage the altered availability of energy metabolites. Astrocytes and neurons but not oligodendrocytes demonstrated metabolic plasticity. Moreover, inflammatory demyelinating disease changed the neuronal metabolic signature in a similar direction as KD. Together, these findings highlight the importance of the metabolic cross-talk between CNS cells and between the periphery and the brain to manage altered nutrition and neurological disease.
... Some small clinical trials have compared the two different forms of the same molecule, concluding that the ketone esters were able to increase free BHB levels 50% higher than ketone salts [34]. Recently, supplementation with ketone body esters has shown an improvement in exercise performance [35,36]. ...
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Ketone bodies are small compounds derived from fatty acids that behave as an alternative mitochondrial energy source when insulin levels are low, such as during fasting or strenuous exercise. In addition to the metabolic function of ketone bodies, they also have several signaling functions separate from energy production. In this perspective, we review the main current data referring to ketone bodies in correlation with nutrition and metabolic pathways as well as to the signaling functions and the potential impact on clinical conditions. Data were selected following eligibility criteria accordingly to the reviewed topic. We used a set of electronic databases (Medline/PubMed, Scopus, Web of Sciences (WOS), Cochrane Library) for a systematic search until July 2022 using MeSH keywords/terms (i.e., ketone bodies, BHB, acetoacetate, inflammation, antioxidant, etc.). The literature data reported in this review need confirmation with consistent clinical trials that might validate the results obtained in in vitro and in vivo in animal models. However, the data on exogenous ketone consumption and the effect on the ketone bodies’ brain uptake and metabolism might spur the research to define the acute and chronic effects of ketone bodies in humans and pursue the possible implication in the prevention and treatment of human diseases. Therefore, additional studies are required to examine the potential systemic and metabolic consequences of ketone bodies.
... Certainly, the association is subject to modulatory effects of different states like exercise or fed and fasted states. Whether nutritional ketosis is beneficial or not to exercise capacity is yet undetermined (Valenzuela et al., 2020) even though BHB is readily extracted from circulation in both resting and working striated muscle (Cox et al., 2016). The resting muscles and therefore lower energy needs may, at least in part, explain the lack of protein-sparing effect of BHB as also indicated by the minute glucose extraction and comparable lipolysis rates as evaluated by palmitate flux. ...
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Systemic administration of beta‐hydroxybutyrate (BHB) decreases whole‐body protein oxidation and muscle protein breakdown in humans. We aimed to determine any direct effect of BHB on skeletal muscle protein turnover when administered locally in the femoral artery. Paired design with each subject being investigated on one single occasion with one leg being infused with BHB and the opposing leg acting as a control. We studied 10 healthy male volunteers once with bilateral femoral vein and artery catheters. One artery was perfused with saline (Placebo) and one with sodium‐BHB. Labelled phenylalanine and palmitate were used to assess local leg fluxes. Femoral vein concentrations of BHB were significantly higher in the intervention leg (3.4 (3.2, 3.6) mM) compared with the placebo‐controlled leg (1.9 (1.8, 2.1) mM) with a peak difference of 1.4 (1.1, 1.7) mM, p < 0.0005. Net loss of phenylalanine for BHB vs Placebo −6.7(−10.8, −2.7) nmol/min vs −8.7(−13.8, −3.7) nmol/min, p = 0.52. Palmitate flux and arterio‐venous difference of glucose did not differ between legs. Under these experimental conditions, we failed to observe the direct effects of BHB on skeletal muscle protein turnover. This may relate to a combination of high concentrations of BHB (close to 2 mM) imposed systemically by spillover leading to high BHB concentrations in the saline‐infused leg and a lack of major differences in concentration gradients between the two sides—implying that observations were made on the upper part of the dose–response curve for BHB and the relatively small number of subjects studied. Investigation of direct effects on skeletal muscle protein turnover of beta‐hydroxybutyrate infused in one leg when opposing leg acts as control. Due to spill‐over and low number of participants no significant effects were observed. Caution to spillover effects are warranted in futures studies.
... Although skeletal muscles have a high affinity for ketone bodies, they provide less than 5% of the fuel substrates in healthy, resting muscles [183]. During exercise, however, ketone bodies can become the preferred fuel source in skeletal muscle [185,186]. In a healthy mouse model treated with intravenous infusion of ketone bodies, it was shown that sensitivity to ketone bodies was higher in skeletal muscle with a glycolytic phenotype [187]. ...
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Despite the constant improvement of therapeutical options, heart failure (HF) remains associated with high mortality and morbidity. While new developments in guideline-recommended therapies can prolong survival and postpone HF hospitalizations, impaired exercise capacity remains one of the most debilitating symptoms of HF. Exercise intolerance in HF is multifactorial in origin, as the underlying cardiovascular pathology and reactive changes in skeletal muscle composition and metabolism both contribute. Recently, sodium-related glucose transporter 2 (SGLT2) inhibitors were found to improve cardiovascular outcomes significantly. Whilst much effort has been devoted to untangling the mechanisms responsible for these cardiovascular benefits of SGLT2 inhibitors, little is known about the effect of SGLT2 inhibitors on exercise performance in HF. This review provides an overview of the pathophysiological mechanisms that are responsible for exercise intolerance in HF, elaborates on the potential SGLT2-inhibitor-mediated effects on these phenomena, and provides an up-to-date overview of existing studies on the effect of SGLT2 inhibitors on clinical outcome parameters that are relevant to the assessment of exercise capacity. Finally, current gaps in the evidence and potential future perspectives on the effects of SGLT2 inhibitors on exercise intolerance in chronic HF are discussed.
... A reduction in total protein and fibrosis-associated proteins in BALF, as well as a decrease in collagen deposition, tissue density and lung injury score, indicated a faster resolution of inflammation in mice that were fed a ketogenic diet (Extended Data Fig. 8g-i). Furthermore, increasing the availability of circulating BHB by supplying esterified BHB in the drinking water 44 (Extended Data Fig. 9a,b) enhanced the responses of T H 1 cells (Extended Data Fig. 9c), while reducing lung damage (Extended Data Fig. 9d) and the expression of genes and proteins associated with fibrosis in IAV-infected mice (Extended Data Fig. 9e,f). Treatment with ketone ester also diminished the dependency of CD4 + T cells on glucose but promoted their potential to oxidize amino acids and fatty acids (Extended Data Fig. 9g). ...
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Anorexia and fasting are host adaptations to acute infection, inducing a metabolic switch towards ketogenesis and the production of ketone bodies, including β-hydroxybutyrate (BHB) 1-6. However, whether ketogenesis metabolically influences the immune response in pulmonary infections remains unclear. Here we report impaired production of BHB in humans with SARS-CoV-2-induced but not influenza-induced acute respiratory distress syndrome (ARDS). CD4+ T cell function is impaired in COVID-19 and BHB promotes both survival and production of Interferon-γ from CD4+ T cells. Using metabolic tracing analysis, we uncovered that BHB provides an alternative carbon source to fuel oxidative phosphorylation (OXPHOS) and the production of bioenergetic amino acids and glutathione, which is important for maintaining the redox balance. T cells from patients with SARS-CoV-2-induced ARDS were exhausted and skewed towards glycolysis, but can be metabolically reprogrammed by BHB to perform OXPHOS, thereby increasing their functionality. Finally, we demonstrate that ketogenic diet (KD) and delivery of BHB as ketone ester drink restores CD4+ T cell metabolism and function in respiratory infections, ultimately reducing the mortality of SARS-CoV-2 infected mice. Altogether, our data reveal BHB as alternative carbon source promoting T cell responses in pulmonary viral infections, highlighting impaired ketogenesis as a potential confounder of severe COVID-19.
... Studies have shown that ketogenic body supplementation is a way to induce ketosis and provide sustainable sources of fuel for energy generation and enhanced exercise performance [45]. In addition to the use of the ketogenic diet for weight loss, the ketogenic diet is also prominent within the athletic community as a superior source of energy [46]. The contribution of lipids to oxidation metabolic changes depending on the duration and strengthening exercises. ...
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The use of the ketogenic diet is a safe and effective process to reduce the health complications of obesity, thus losing weight while preventing weight regain at the same time. Humans have metabolic flexibility and the potential to utilize ketones as an energy source by reducing carbohydrate intake in the diet, this reduces insulin levels, and ketogenesis occurs. These conditions promote the release of excess stored fat, avoid muscle weakness, and improve insulin sensitivity. Losing weight by diet causes appetite feeling and a rise in ghrelin release, that raises the likelihood of regaining weight and is thus counterproductive to goals for weight reduction. The study's aim is to review evidence on a ketogenic diet for weight loss and metabolic illnesses like insulin resistance, lipid disorders, cardiovascular disease, fatty liver disease development, and Polycystic Ovarian Syndrome and exercise and delay aging, in addition to addressing the side effects of the ketogenic diet, and thus we provide basic information about nutritional ketones and the mechanism of their generation.
... Exogenous ketones, in the form of either ketone monoester or ketone salts, have recently been designed as a possible alternative to ketogenic diets. In particular, ketone monoester drink containing D-β-hydroxybutyrate-R-1.3-butanediol (KEβHB) was shown to elevate the circulating levels of βHB to as high as 5 mmol/L within 30 min of ingestion in healthy individuals [8,9] as well as those with metabolic disorders [10,11]. ...
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Background: Ketone monoester β-hydroxybutyrate (KEβHB) ingestion has emerged as an effective method of inducing acute ketosis. Although evidence suggests that KEβHB can offer several therapeutic benefits, whether KEβHB affects lipid profile is still unknown. Aims: The primary aim was to study the effect of KEβHB on plasma lipid profile in individuals with prediabetes. The secondary aim was to investigate the role of saturated fat intake in that effect. Methods: This study was a randomized controlled trial with cross-over design. Following an overnight fast, 18 adults (six women and 12 men) with prediabetes (diagnosed based on the American Diabetes Association criteria) ingested a single dose of KEβHB drink or placebo drink. Blood samples were collected every 30 min, from baseline to 150 min. Outcome variables included changes in total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, remnant cholesterol, triglycerides, and the triglycerides to HDL cholesterol ratio. The area under the curve (AUC) over 150 min was calculated for each outcome following ingestion of the drinks. Habitual saturated fat intake was ascertained using the EPIC-Norfolk food frequency questionnaire. Results: Significant elevation of blood β-hydroxybutyrate from 0.2 mmol/L to 3.5 mmol/L (p < 0.001) was achieved within 30 min. Acute ketosis resulted in significantly lower AUCs for remnant cholesterol (p = 0.022) and triglycerides (p = 0.022). No statistically significant differences in the AUCs for total cholesterol, HDL cholesterol, LDL cholesterol, and the triglycerides to HDL cholesterol ratio were found. The changes in remnant cholesterol and triglycerides were statistically significant in individuals with high, but not low, habitual saturated fat intake. Conclusion: Acute ketosis had no untoward effect on plasma lipid profile. Moreover, it led to significantly reduced circulating levels of remnant cholesterol and triglycerides. This paves the way for investigating whether exogenous ketone supplementation reduces cardiovascular disease risk (via its actions on triglyceride-rich lipoproteins) in at-risk populations. Trial registration: ClinicalTrials.gov, NCT03889210.
... Post-compaction, the embryo relies heavily on glycolytic metabolism to support the production of biosynthetic precursors, cytosolic redox state, and to ensure lactate efflux for maternal-embryo signalling during implantation (Hewitson and Leese, 1993;Gardner, 1998;Harvey et al., 2002;Gardner, 2015;Gardner and Harvey, 2015;Ma et al., 2020;Gurner et al., 2022). However, bOHB promotes oxidative phosphorylation (Laffel, 1999) while suppressing glycolysis (Randle et al., 1964;Patel and Owen, 1977;Cox et al., 2016). This is of significance given that aberrant glucose uptake and glycolytic metabolism is a well-characterized biomarker of poor embryonic viability (Lane and Gardner, 1996;Gardner and Wale, 2013). ...
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STUDY QUESTION What is the effect of the ketone β-hydroxybutyrate (βOHB) on preimplantation mouse embryo development, metabolism, epigenetics and post-transfer viability? SUMMARY ANSWER In vitro βOHB exposure at ketogenic diet (KD)-relevant serum concentrations significantly impaired preimplantation mouse embryo development, induced aberrant glycolytic metabolism and reduced post-transfer fetal viability in a sex-specific manner. WHAT IS KNOWN ALREADY A maternal KD in humans elevates gamete and offspring βOHB exposure during conception and gestation, and in rodents is associated with an increased time to pregnancy, and altered offspring organogenesis, post-natal growth and behaviour, suggesting a developmental programming effect. In vitro exposure to βOHB at supraphysiological concentrations (8–80 mM) perturbs preimplantation mouse embryo development. STUDY DESIGN, SIZE, DURATION A mouse model of embryo development and viability was utilized for this laboratory-based study. Embryo culture media were supplemented with βOHB at KD-relevant concentrations, and the developmental competence, physiology, epigenetic state and post-transfer viability of in vitro cultured βOHB-exposed embryos was assessed. PARTICIPANTS/MATERIALS, SETTING, METHODS Mouse embryos were cultured in vitro with or without βOHB at concentrations representing serum levels during pregnancy (0.1 mM), standard diet consumption (0.25 mM), KD consumption (2 mM) and diabetic ketoacidosis (4 mM). The impact of βOHB exposure on embryo development (blastocyst formation rate, morphokinetics and blastocyst total, inner cell mass and trophectoderm (TE) cell number), physiology (redox state, βOHB metabolism, glycolytic metabolism), epigenetic state (histone 3 lysine 27 β-hydroxybutyrylation, H3K27bhb) and post-transfer viability (implantation rate, fetal and placental development) was assessed. MAIN RESULTS AND THE ROLE OF CHANCE All βOHB concentrations tested slowed embryo development (P < 0.05), and βOHB at KD-relevant serum levels (2 mM) delayed morphokinetic development, beginning at syngamy (P < 0.05). Compared with unexposed controls, βOHB exposure reduced blastocyst total and TE cell number (≥0.25 mM; P < 0.05), reduced blastocyst glucose consumption (2 mM; P < 0.01) and increased lactate production (0.25 mM; P < 0.05) and glycolytic flux (0.25 and 2 mM; P < 0.01). Consumption of βOHB by embryos, mediated via monocarboxylate transporters, was detected throughout preimplantation development. Supraphysiological (20 mM; P < 0.001), but not physiological (0.25–4 mM) βOHB elevated H3K27bhb levels. Preimplantation βOHB exposure at serum KD levels (2 mM) reduced post-transfer viability. Implantation and fetal development rates of βOHB-treated embryos were 50% lower than controls (P < 0.05), and resultant fetuses had a shorter crown-rump length (P < 0.01) and placental diameter (P < 0.05). A strong sex-specific effect of βOHB was detected, whereby female fetuses from βOHB-treated embryos weighed less (P < 0.05), had a shorter crown-rump length (P < 0.05), and tended to have accelerated ear development (P < 0.08) compared with female control fetuses. LIMITATIONS, REASONS FOR CAUTION This study only assessed embryo development, physiology and viability in a mouse model utilizing in vitro βOHB exposure; the impact of in vivo exposure was not assessed. The concentrations of βOHB utilized were modelled on blood/serum levels as the true oviduct and uterine concentrations are currently unknown. WIDER IMPLICATIONS OF THE FINDINGS These findings indicate that the development, physiology and viability of mouse embryos is detrimentally impacted by preimplantation exposure to βOHB within a physiological range. Maternal diets which increase βOHB levels, such as a KD, may affect preimplantation embryo development and may therefore impair subsequent viability and long-term health. Consequently, our initial observations warrant follow-up studies in larger human populations. Furthermore, analysis of βOHB concentrations within human and rodent oviduct and uterine fluid under different nutritional states is also required. STUDY FUNDING/COMPETING INTEREST(S) This work was funded by the University of Melbourne and the Norma Hilda Schuster (nee Swift) Scholarship. The authors have no conflicts of interest. TRIAL REGISTRATION NUMBER N/A.
... The levels of ketone bodies, AcAc and βOHB are abundant compared to acetone (Laffel, 1999). Under physiological conditions, ketone bodies contribute 5-20% of total energy metabolism (Cox et al., 2016). Ketone body generation and utilization are influenced by various physiological cues, including nutrient deprivation, exercise, and calorie restriction, where their serum concentrations could rise from 100-250μM to 1 mM (Fery and Balasse, 1983;Fèry and Balasse, 1988;Balasse and Féry, 1989). ...
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Non-alcoholic fatty liver disease (NAFLD), the most common chronic liver diseases, arise from non-alcoholic fatty liver (NAFL) characterized by excessive fat accumulation as triglycerides. Although NAFL is benign, it could progress to non-alcoholic steatohepatitis (NASH) manifested with inflammation, hepatocyte damage and fibrosis. A subset of NASH patients develops end-stage liver diseases such as cirrhosis and hepatocellular carcinoma. The pathogenesis of NAFLD is highly complex and strongly associated with perturbations in lipid and glucose metabolism. Lipid disposal pathways, in particular, impairment in condensation of acetyl-CoA derived from β-oxidation into ketogenic pathway strongly influence the hepatic lipid loads and glucose metabolism. Current evidence suggests that ketogenesis dispose up to two-thirds of the lipids entering the liver, and its dysregulation significantly contribute to the NAFLD pathogenesis. Moreover, ketone body administration in mice and humans shows a significant improvement in NAFLD. This review focuses on hepatic ketogenesis and its role in NAFLD pathogenesis. We review the possible mechanisms through which impaired hepatic ketogenesis may promote NAFLD progression. Finally, the review sheds light on the therapeutic implications of a ketogenic diet in NAFLD.
... This hypothesis is supported by the improved performance observed in healthy athletes following the ingestion of ketones, which substantiates their proposed functioning as an alternative energy source. 15,16 The therapeutic use of ketones in the form of ketone salts (KSs) in metabolic disorders has been previously described, most extensively in children suffering from multiple acyl-CoA dehydrogenase deficiency (MADD, OMIM #231680). 12,17,18 Ketone salts are comprised of beta-hydroxybutyrate (βHB) and a mineral (calcium, sodium, potassium, magnesium, or a mixture of these) and are only available as food supplements. ...
Article
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Recent studies have reported the potential for the therapeutic use of ketones in the form of ketone salts (KSs) in pediatric patients with fatty acid oxidation disorders (FAODs). We report a case of ketone salt administration in an adult patient with mitochondrial trifunctional protein deficiency (MTPD), an ultra‐rare inborn error of the fatty acid metabolism. This patient was treated with oral KSs during an episode of sepsis of unknown origin. Before KS supplementation was initiated, he had developed severe rhabdomyolysis as well as a respiratory insufficiency that did not respond to emergency treatment aimed at stabilizing the metabolic decompensation by promoting anabolism. Therefore, KS supplementation was attempted twice to support his energy production and help regain metabolic stability. In both instances, KS supplementation led to a considerable metabolic alkalosis, which prompted its discontinuation. This adverse event could have been caused by an increase in extracellular sodium load due to KS administration. Therefore, the clinical applicability of KSs in adults may be limited. Alternative chemical forms of beta‐hydroxybutyrate (βHB), such as ketone esters, might provide a more acceptable safety profile for future research into the therapeutic benefits of ketone body supplementation in adult patients with FAODs.
... A potentially safer alternative for ketone salts is the ketone ester 3-hydroxybutyl-3-hydroxybutanoate (3HHB, Fig. 1a) which is endogenously converted to two 3HB − molecules 11 . Sustained nutritional ketosis through oral ingestion of 3HHB has previously shown to be safe in healthy adults 12 and has been extensively studied in elite athletes for its potential to improve exercise performance and endurance [13][14][15] . ...
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In septic mice, 3-hydroxybutyrate-sodium-salt has shown to partially prevent sepsis-induced muscle weakness. Although effective, the excessive sodium load was toxic. We here investigated whether ketone ester 3-hydroxybutyl-3-hydroxybutanoate (3HHB) was a safer alternative. In a mouse model of abdominal sepsis, the effects of increasing bolus doses of 3HHB enantiomers on mortality, morbidity and muscle force were investigated (n = 376). Next, plasma 3HB- clearance after bolus d-3HHB was investigated (n = 27). Subsequently, in septic mice, the effect on mortality and muscle force of a continuous d,l-3HHB infusion was investigated (n = 72). In septic mice, as compared with placebo, muscle force was increased at 20 mmol/kg/day l-3HHB and at 40 mmol/kg/day d- and d,l-3HHB. However, severity of illness and mortality was increased by doubling the effective bolus doses. Bolus 3HHB caused a higher 3HB− plasma peak and slower clearance with sepsis. Unlike bolus injections, continuous infusion of d,l-3HHB did not increase severity of illness or mortality, while remaining effective in improving muscle force. Treatment of septic mice with the ketone ester 3HHB partly prevented muscle weakness. Toxicity of 3HHB administered as bolus was completely avoided by continuous infusion of the same dose. Whether continuous infusion of ketone esters represents a promising intervention to also prevent ICU-acquired weakness in human patients should be investigated.
... Se ha descrito que la suplementación con ésteres de cetonas mejora el rendimiento. Aunque el efecto observado fue de un 2% en la mejora del rendimiento en una prueba contrarreloj de 30 minutos, se demostró que el éster de cetona causaba cetosis (altas concentraciones de cuerpos cetónicos en la sangre) y se sugirió que esto podría haber resultado en una reducción de glucógeno en el músculo (Cox et al. 2016). No obstante, hay evidencia contradictoria donde no han encontrado efecto sobre el rendimiento con ésteres de cetonas (Evans et al. 2019). ...
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RESUMEN Introducción. El reciente interés del uso de la dieta cetogénica como alternativa al tratamiento de obesidad, ha despertado la necesidad en los profesionales de la salud de volver a examinar los posibles beneficios de este estilo de alimentación. Objetivo: Resumir los antecedentes y sintetizar las diferentes aplicaciones de dietas cetogénicas en el tratamiento de la obesidad a través de las publicaciones científicas. Material y Método: Se usaron tres bases de datos (PubMed, Google Scholar y Clinical Trials). Los términos usados en la búsqueda fueron dieta cetogénica, obesidad, cuerpos cetónicos, entre otros. Se combinaron con operadores lógicos como cetólisis, oxidación de ácidos grasos, regulación hormonal, saciedad, ejercicio, entre otros. Resultados: Se consideraron para la revisión un total de 23 artículos de reciente publicación con ensayos clínicos y aplicados en modelos animales. Los artículos excluidos no cumplieron con criterios de los niveles de evidencia y de la guía PRISMA. Conclusión: Aunque se han demostrado los numerosos beneficios de las dietas cetogénicas, la utilización debe ir acompañada de un asesoramiento dietético y no abusar de su uso. El modelo de evolución de la nutrición es integrar e individualizar los diversos factores dietéticos que puedan contribuir a mejorar el estilo de vida a largo plazo. ABSTRACT Introduction: There is great interest in the use of the ketogenic diet as an alternative to the treatment of obesity, which has raised the need for health professionals to reexamine the possible benefits of this eating style. Objective: To evaluate the information of the different applications of ketogenic diets in the treatment of obesity through scientific publications. Material and method: Three databases were used (PubMed, Google Scholar, and Clinical Trials). They were combined with logical operators and terms such as ketogenic diet, obesity, ketone bodies, among others. They were combined with logical operators such as ketolysis, fatty acid oxidation, hormonal regulation, satiety and exercise. Results: Twenty-three articles containing randomized clinical trials and animal experiments were considered for the review. The excluded articles did not meet the criteria for levels of evidence and the PRISMA guideline. Conclusions: Although the many benefits of ketogenic diets have been demonstrated, the use should be accompanied by dietary advice and not overuse. The evolutionary model of nutrition is to integrate and individualize the various dietary factors that can contribute to improving the long-term lifestyle.
... Such therapeutic strategies have been authoritatively reviewed by Camberos-Luna and Massieu (2020), but can be summarized into three main categories, which are namely the use of a ketogenic diet (KD), feeding augmentation (including calorie restriction and intermittent fasting), and exogenous supplementation of ketone bodies, KB derivatives, and medium chain triglycerides (MCTs). Generally, endogenously induced ketosis requires the use of extended treatments before ketogenesis is observed, while the use of exogenous supplementation can increase plasma ketones in a matter of hours but require ongoing dosing to maintain the effect (Cox et al., 2016;Stubbs et al., 2017;Evans et al., 2018;Koppel and Swerdlow, 2018). ...
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Metabolic dysfunction is a ubiquitous underlying feature of many neurological conditions including acute traumatic brain injuries and chronic neurodegenerative conditions. A central problem in neurological patients, in particular those with traumatic brain injuries, is an impairment in the utilization of glucose, which is the predominant metabolic substrate in a normally functioning brain. In such patients, alternative substrates including ketone bodies and lactate become important metabolic candidates for maintaining brain function. While the potential neuroprotective benefits of ketosis have been recognized for up to almost a century, the majority of work has focused on the use of ketogenic diets to induce such a state, which is inappropriate in cases of acute disease due to the prolonged periods of time (i.e., weeks to months) required for the effects of a ketogenic diet to be seen. The following review seeks to explore the neuroprotective effects of exogenous ketone and lactate preparations, which have more recently become commercially available and are able to induce a deep ketogenic response in a fraction of the time. The rapid response of exogenous preparations makes their use as a therapeutic adjunct more feasible from a clinical perspective in both acute and chronic neurological conditions. Potentially, their ability to globally moderate long-term, occult brain dysfunction may also be relevant in reducing lifetime risks of certain neurodegenerative conditions. In particular, this review explores the association between traumatic brain injury and contusion-related dementia, assessing metabolic parallels and highlighting the potential role of exogenous ketone and lactate therapies.
... 3,4 Existing literature suggests that prompting a state of ketosis, through either a KD and/or ketone supplementation may improve exercise performance, thus serving as an effective ergogenic aid based on its capacity to contribute ketones as an alternative oxidative fuel source. 5,6 Exogenous ketone supplements have since become a practical approach to inducing rapid ketosis. More current studies have found no performance effects on an incremental bicycle exercise test to exhaustion or a 5k running time trial when supplementing with exogenous ketones compared to a placebo. ...
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Background: Ketosis may improve exercise performance, thus serving as an effective ergogenic aid based on its capacity to contribute ketones as an alternative oxidative fuel source. Objective: The effects of a single dose of exogenous ketone salt supplementation on anaerobic and cardiorespiratory fitness, cognitive performance, and substrate levels were investigated in 19 healthy male and female subjects. Methods: In this triple-blinded, randomized, cross-over designed study, participants received one serving of exogenous ketone salts (KS) and one isocaloric serving of Gatorade G2 sports drink (SD) with a one-week washout period between supplements. Anaerobic performance was determined by a 30-second Wingate test and cardiorespiratory fitness was determined by a VO2peak test. In a time-sensitive order, blood measures to assess glucose, ketone, and lactate levels were taken at four time points including baseline, 30-minutes post-supplement consumption, post-Wingate test, and post- VO2peak test. A cognitive performance battery was administered at the same time points. Results: Paired-samples t-tests showed no significant difference (p = .25) in relative VO2peak between KS (40.91 ± 8.14 ml*kg-1*min-1) and SD (40.07 ± 7.01 ml*kg-1*min-1). There were no significant differences (p > .05 for all) between KS and SD for Wingate test variables peak power (671.58 ± 210.01 vs 674.68 ± 202.94 W), mean power (490.21 ± 139.02 vs 500.74 ± 146.00 W), or fatigue index (12.00 ± 5.35 vs 11.47 ± 5.20 W*s-1). Although cognitive assessment values varied between time points, no significant interaction effect between supplement and time was observed for cognitive performance indices (p > .05 for all). Blood glucose and ketone levels both demonstrated a significant time by condition interaction (p < 0.00). KS attenuated glucose increase and elevated ketones compared to SD. Conclusions: An acute dose of exogenous ketones had a similar effect on anaerobic performance and cardiorespiratory fitness as the sports drink Gatorade G2.
... In untreated individuals with insulin-deficient diabetes, plasma ketone body levels may increase to more than 20 mM, causing massive metabolic disturbances [13,14]. In the postabsorptive state, ketone bodies supply 5% of total energy consumption, but this may increase to 10-18% during exercise or fasting [18]. ...
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The ketogenic diet (KD) entails a high intake of fat, moderate intake of protein, and a very limited intake of carbohydrates. Ketogenic dieting has been proposed as an effective intervention for type 2 diabetes and obesity since glycemic control is improved and sustained weight loss can be achieved. Interestingly, hyperketonemia is also associated with beneficial cardiovascular effects, possibly caused by improved cardiac energetics and reduced oxygen use. Therefore, the KD has the potential to both treat and prevent cardiovascular disease. However, the KD has some adverse effects that could counteract the beneficial cardiovascular properties. Of these, hyperlipidemia with elevation of triglycerides and LDL cholesterol levels are the most important. In addition, poor diet adherence and lack of knowledge regarding long-term effects may also reduce the broader applicability of the KD. The objective of this narrative review is to provide insights into the KD and its effects on myocardial ketone body utilization and, consequently, cardiovascular health.
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Yüksek yoğunluklu egzersiz sırasında (örneğin, laktat eşiğinin üzerinde çalışmak) kasılan iskelet kasları, önemli miktarda hidrojen (H+) iyonu birikimine sebep olur. Bu H+ iyonları, egzersize bağlı metabolik asidozun gelişmesine ve asit-baz homeostazının bozulmasına sebep olabilir. Dolayısıyla bu çalışmanın amacı (a) egzersize bağlı vücut pH seviyesinde meydana gelen değişimlerin fizyolojik mekanizmasını ve sportif performansa etkisini, (b) egzersize bağlı asit-baz homeostazında görülen değişimlerin fizyolojik mekanizmasını ve sportif performansa etkisini ve (c) bahsedilen fizyolojik olayların olumsuz etkilerinin minimize edilmesi için kullanılabilecek besin takviyelerini güncel literatür ışığında incelemeyi amaçlamıştır. Bu derleme çalışmasında egzersiz ve asit-baz dengesi, egzersize bağlı asit-baz bozuklukları ile ilgili konuları içeren bilimsel metinler ve kitaplar incelenmiştir. Pub Med, Web of Science, Medline, Cochrane Library, Google Scholar ve ULAKBİM elektronik veri tabanları “exercise and pH balance”, “acidosis and exercise”, “exercise and acid-base balance”, “athletic performance and fluid balance”, “sport supplements for asid-base balance”, “sports beverage for athletes’’ ve “nutritional strategies for acid-base balance” anahtar kelimeleri kullanılarak taranmıştır. Metabolik asidozla birlikte sporcularda yorgunluk hissi, kaslardaki mekanik performansın azalması gibi etmenler dolayısıyla egzersiz performansını da olumsuz etkiler. Bu nedenle sporcular tarafından yüksek şiddetli egzersizlerde bozulabilecek asit-baz homeostazı için destekleyici besinsel takviyelerin kullanılması (sodyum bikarbonat, sodyum sitrat, beta alanin vb.) sportif performansın optimal biçimde sürdürülebilmesi, oluşabilecek yorgunluğun geciktirilebilmesi ve performansın artırılması için tavsiye edilen alternatiflerdir.
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Scope: The primary aim of the present study was to study the effect of acute ketosis on parameters of appetite regulation in prediabetes. The secondary aim was to investigate whether the effect is influenced by eating behaviours. Methods and results: This was a randomised controlled trial. After an overnight fast, 18 adults with prediabetes (defined in line with the American Diabetes Association criteria) were assigned to consume either a ketone monoester (D-β-hydroxybutyrate-(R)-1,3 butanediol) drink (energy content 123 kcal) or a placebo drink (containing virtually no calories) in cross-over fashion. Blood samples were collected every 30 mins, from baseline to 150 minutes. Paired t-test was used to compare the total area under the curve (AUC) for the changes in parameters of appetite regulation (acylated ghrelin, peptide YY (PYY), and hunger) following both drinks. Eating behaviours were determined with the use of the three-factor eating questionnaire. Significant elevation in blood β-hydroxybutyrate from 0.2 mmol/L to 3.5 mmol/L (p < 0.001) was achieved within 30 minutes. Acute ketosis did not result in statistically significant differences in the AUCs for ghrelin, PYY, and hunger. No statistically significant difference in the AUCs was also observed when participants were stratified by their eating behaviours. Conclusion: Acute ketosis consistently did not affect both objective and subjective parameters of appetite regulation in prediabetes. No subset of people with prediabetes according to eating behaviours had a significant effect of acute ketosis on appetite regulation. This article is protected by copyright. All rights reserved.
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Inflammatory bowel disease (IBD) is a chronic persistent intestinal disorder, with ulcerative colitis and Crohn's disease being the most common. However, the physio‐pathological development of IBD is still unknown. Therefore, research on the etiology and treatment of IBD has been conducted using a variety of approaches. Short‐chain fatty acids such as 3‐hydroxybutyrate (3‐HB) are known to have various physiological activities. In particular, the production of 3‐HB by the intestinal microflora is associated with the suppression of various inflammatory diseases. In this study, we investigated whether poly‐D‐3‐hydroxybutyric acid (PHB), a polyester of 3‐HB, is degraded by intestinal microbiota and works as a slow‐release agent of 3‐HB. Further, we examined whether PHB suppresses the pathogenesis of IBD models. As long as a PHB diet increased 3‐HB concentrations in the feces and blood, PHB suppressed weight loss and histological inflammation in a dextran sulfate sodium‐induced IBD model. Furthermore, PHB increased the accumulation of regulatory T cells in the rectum without affecting T cells in the spleen. These results indicate that PHB has potential applications in treating diseases related to the intestinal microbiota as a sustained 3‐HB donor. We show for the first time that biodegradable polyester exhibits intestinal bacteria‐mediated bioactivity toward IBD. The use of bioplastics, which are essential materials for sustainable social development, represents a novel approach to diseases related to dysbiosis, including IBD.
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The prevalence of neonatal hypoxic-ischemic encephalopathy (HIE), a devastating neurological injury, is increasing; thus, effective treatments and preventions are urgently needed. The underlying pathology of HIE remains unclear; recent research has focused on elucidating key features of the disease. A variety of diseases can be alleviated by consuming a ketogenic diet (KD) despite differences in pathogenesis and features, given the common mechanisms of KD-induced effects. Dietary modification is the most translatable, cost-efficient, and safest approach to treat acute or chronic neurological disorders and reduces reliance on pharmaceutical treatments. Evidence suggests that the KD can exert beneficial effects in animal models and in humans with brain injuries. The efficacy of the KD in preventing neuronal damage, motor alterations, and cognitive decline varies. Moreover, the KD may provide an alternative source of energy, enhance mitochondrial function, and reduce the expression of inflammatory and apoptotic mediators. Thus, this diet has attracted interest as a potential therapy for HIE. This review examined the role of the KD in HIE treatment and described the mechanisms by which ketone bodies (KBs) exert effects under pathological conditions and protect against brain damage; the evidence supports the implementation of dietary interventions as a therapeutic strategy for HIE. Future research should aim to elucidate the underlying mechanisms of the KD in patients with HIE and determine whether the effect of the KD on clinical outcomes can be reproduced in humans.
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Intravenous ketone body infusion can increase erythropoietin (EPO) concentrations, but responses to ketone monoester ingestion post-exercise are currently unknown. The purpose of this study was to assess the effect of ketone monoester ingestion on post-exercise erythropoietin (EPO) concentrations. Nine healthy men completed two trials in a randomized, crossover design (one-week washout). During trials, participants performed a one-hour of cycling (initially alternating between 50% and 90% of maximal aerobic capacity for 2 min each interval, and then 50% and 80%, and 50% and 70% when the higher intensity was unsustainable). Participants ingested 0.8 g·kg ⁻¹ sucrose with 0.4 g·kg ⁻¹ protein immediately after exercise, and at 1, 2, and 3 hours post-exercise. During the control trial (CONTROL), no further nutrition was provided, whereas on the ketone monoester trial (KETONE), participants also ingested 0.29 g·kg ⁻¹ of the ketone monoester (R)‐3‐hydroxybutyl (R)‐3‐hydroxybutyrate immediately post-exercise and at 1 and 2 hours post-exercise. Blood was sampled immediately post-exercise, every 15 min in the first hour, and hourly thereafter for 4 hours. Serum EPO concentrations increased to a greater extent in KETONE than CONTROL (time x condition interaction: p = 0.046). Peak serum EPO concentrations were higher with KETONE (mean ± SD: 9.0 ± 2.3 IU·L ⁻¹ ) compared with CONTROL (7.5 ± 1.5 IU·L ⁻¹ , p < 0.01). Serum beta-hydroxybutyrate concentrations were also higher, and glucose concentrations lower, with KETONE vs CONTROL (both p < 0.01). In conclusion, ketone monoester ingestion increases post-exercise erythropoietin concentrations, revealing a new avenue for orally ingestible ketone monoesters to potentially alter haemoglobin mass.
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Ketogenic diets and orally administered exogenous ketone supplements are strategies to increase serum ketone bodies serving as an alternative energy fuel for high energy demanding tissues, such as the brain, muscles, and the heart. The ketogenic diet is a low-carbohydrate and fat-rich diet, whereas ketone supplements are usually supplied as esters or salts. Nutritional ketosis, defined as serum ketone concentrations of ≥ 0.5 mmol/L, has a fasting-like effect and results in all sorts of metabolic shifts and thereby enhancing the health status. In this review, we thus discuss the different interventions to reach nutritional ketosis, and summarize the effects on heart diseases, epilepsy, mitochondrial diseases, and neurodegenerative disorders. Interest in the proposed therapeutic benefits of nutritional ketosis has been growing the past recent years. The implication of this nutritional intervention is becoming more evident and has shown interesting potential. Mechanistic insights explaining the overall health effects of the ketogenic state, will lead to precision nutrition for the latter diseases.
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Patients with heart failure (HF) usually present with skeletal muscle diseases of varying severity, ranging from early fatigue on exercise to sarcopenia, sarcopenic obesity or cachexia, and frailty, which are significant predictors of HF prognosis. Abnormal mitochondrial metabolism has been identified as one of the earliest signs of skeletal muscle injury in HF and is associated with pathological alterations in muscle, manifested as muscle wasting, myocyte atrophy and apoptosis, fiber type shift, impaired contractile coupling, and muscle fat infiltration. In this review, we update the evidence for skeletal muscle mitochondrial remodeling in HF patients or animal models, including the impairments in mitochondrial ultrastructure, oxidative metabolism, electron transport chain (ETC), phosphorylation apparatus, phosphotransfer system, and quality control. We also focus on molecular regulatory mechanisms upstream of mitochondria, including circulating factors (e.g., RAAS, TNF-α IL-6, IGF-1, GH, ghrelin, adiponectin, NO) and molecular signals within myocytes (e.g., PGC-1α, PPARs, AMPK, SIRT1/3, ROS, and MuRF1). Besides the therapies targeting the signaling pathways mentioned above, such as AdipoRon and elamipretide, we further summarize other potential pharmacological approaches like inhibitors of sodium-glucose cotransporter 2 (SGLT2) and dipeptidyl peptidase-4 (DPP-4), as well as some natural products, which may have the beneficial effects on improving the skeletal muscle mitochondrial function of HF. Targeting myocyte mitochondrial biogenesis, oxidative metabolism, oxidative phosphorylation, and reduction of oxidative stress injury are promising future opportunities for the prevention and management of skeletal muscle myopathy in HF.
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As humans age, we lose skeletal muscle mass, even in the absence of disease (sarcopenia), increasing the risk of death. Low mitochondrial mass and activity contributes to sarcopenia. It is our hypothesis that, a ketogenic diet improves skeletal muscle mitochondrial mass and function when they have declined due to aging or disease, but not in athletes where mitochondrial quality is high.
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Glucose metabolism is impaired in brain aging and several neurological conditions. Beneficial effects of ketones have been reported in the context of protecting the aging brain, however, their neurophysiological effect is still largely uncharacterized, hurdling their development as a valid therapeutic option. In this report, we investigate the neurochemical effect of the acute administration of a ketone d-beta-hydroxybutyrate (d-βHB) monoester in fasting healthy participants with ultrahigh-field proton magnetic resonance spectroscopy (MRS). In two within-subject metabolic intervention experiments, 7 T MRS data were obtained in fasting healthy participants (1) in the anterior cingulate cortex pre- and post-administration of d-βHB (N = 16), and (2) in the posterior cingulate cortex pre- and post-administration of d-βHB compared to active control glucose (N = 26). Effect of age and blood levels of d-βHB and glucose were used to further explore the effect of d-βHB and glucose on MRS metabolites. Results show that levels of GABA and Glu were significantly reduced in the anterior and posterior cortices after administration of d-βHB. Importantly, the effect was specific to d-βHB and not observed after administration of glucose. The magnitude of the effect on GABA and Glu was significantly predicted by older age and by elevation of blood levels of d-βHB. Together, our results show that administration of ketones acutely impacts main inhibitory and excitatory transmitters in the whole fasting cortex, compared to normal energy substrate glucose. Critically, such effects have an increased magnitude in older age, suggesting an increased sensitivity to ketones with brain aging.
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Aims Sepsis is a life-threatening condition of organ dysfunction caused by dysregulated inflammation which predisposes patients to developing cardiovascular diseases. The ketone β-hydroxybutyrate is reported to be cardioprotective in cardiovascular diseases and this may be due to their signaling properties that contribute to reducing inflammation. While exogenous ketone esters (KE) increase blood ketone levels, it remains unknown whether KEs can reduce an enhanced inflammatory response and multi-organ dysfunction that is observed in sepsis. Thus, this study assesses whether a recently developed and clinically safe KE can effectively improve the inflammatory response and organ dysfunction in sepsis. Methods and results To assess the anti-inflammatory effects of a KE, we utilized a model of lipopolysaccharide (LPS)-induced sepsis in which an enhanced inflammatory response results in multi-organ dysfunction. Oral administration of KE for three days prior to LPS-injection significantly protected mice against the profound systemic inflammation compared to their vehicle-treated counterparts. In assessing organ dysfunction, KE protected mice from sepsis-induced cardiac dysfunction as well as renal dysfunction and fibrosis. Furthermore, KE administration attenuated the sepsis-induced inflammation in the heart, kidney, and liver. Moreover, these protective effects occurred independent of changes to enzymes involved in ketone metabolism. Conclusion These data show that using an exogenous KE attenuates the dysregulated systemic and organ inflammation as well as organ dysfunction in a model of severe inflammation. We postulate that this exogenous KE is an appealing and promising approach to capitalize on the protective anti-inflammatory effects of ketones in sepsis and/or other inflammatory responses.
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We have previously demonstrated that exogenous ketosis reduces urine production during exercise. However, the underlying physiological mechanism of this anti-diuretic effect remained unclear. Therefore, we investigated whether acute exogenous ketosis by oral ingestion of ketone ester (KE) during a simulated cycling race (RACE) affects the hormonal pathways implicated in fluid balance regulation during exercise. In a double-blind crossover design, 11 well-trained male cyclists participated in RACE consisting of a 3-h submaximal intermittent cycling (IMT 180' ) bout followed by a 15-minute time trial (TT 15' ) in an environmental chamber set at 28 °C and 60 % relative humidity. Fluid intake was adjusted to maintain euhydration. Before and during RACE, the subjects received either a control drink (CON) or the ketone ester (R)-3-hydroxybutyl (R)-3-hydroxybutyrate (KE), which elevated blood β-hydroxybutyrate to ~2-4 mM. Urine output during IMT 180' was ~20% lower in KE (1172 ± 557 ml) than in CON (1431 ± 548 ml, p < 0.05). Compared with CON, N-terminal pro-atrial natriuretic peptide (NT-pro ANP) concentration during RACE was ~20% lower in KE (p < 0.05). KE also raised plasma noradrenaline concentrations during RACE. Performance in TT 15' was similar between CON and KE. In conclusion, exogenous ketosis suppresses diuresis and downregulates α-natriuretic peptide activity during exercise.
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Objectives Exogenous ketone (monoester or salt) supplements are increasingly being employed for a variety of research purposes and marketed amongst the general public for their ability to raise blood beta-hydroxybutyrate (β-OHB). Emerging research suggests a blood glucose-lowering effect of exogenous ketones. Here, we systematically review and meta-analyze the available evidence of trials reporting on exogenous ketones and blood glucose. Methods We searched 6 electronic databases on December 13, 2021 for trials of any length that reported on the use of exogenous ketones compared to a placebo. We pooled raw mean differences (MD) in (i) blood β-OHB and (ii) blood glucose using random-effects models, and explored differences in the effects of ketone salts compared to ketone monoesters. Publication bias and risk of bias were examined using funnel plots and Cochrane's risk-of-bias tool, respectively. Results Twenty-eight trials including a total of 332 participants met inclusion criteria. There was no evidence for publication bias. Four trials were judged to be at low risk of bias with some concern for risk of bias in the remaining trials. Compared to placebo, consumption of exogenous ketones raised blood β-OHB (MD = 1.98 mM; 95% CI: 1.52 mM, 2.45 mM; P < 0.001) and decreased blood glucose (MD = −0.47 mM; 95% CI: −0.57 mM, −0.36 mM; P < 0.001) across the post-supplementation period of up to 300 minutes. Across both analyses, significantly greater effects were found following ingestion of ketone monoesters compared to ketone salts (P < 0.001). Conclusions Consumption of exogenous ketone supplements leads to acutely increased blood β-OHB and decreased blood glucose. Ketone monoesters exert a more potent β-OHB-raising and glucose-lowering effect as compared to ketone salts. Funding Sources Michael Smith Foundation for Health Research (MSFHR) Scholar Award.
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Ketone ingestion can alter metabolism but effects on exercise performance are unclear, particularly with regard to the impact on intermittent-intensity exercise and team-sport performance. Nine professional male rugby union players each completed two trials in a double-blind, randomized, crossover design. Participants ingested either 90 ± 9 g carbohydrate (CHO; 9% solution) or an energy matched solution containing 20 ± 2 g CHO (3% solution) and 590 mg/kg body mass β-hydroxybutyrate monoester (CHO + BHB-ME) before and during a simulated rugby union-specific match-play protocol, including repeated high-intensity, sprint and power-based performance tests. Mean time to complete the sustained high-intensity performance tests was reduced by 0.33 ± 0.41 s (2.1%) with CHO + BHB-ME (15.53 ± 0.52 s) compared with CHO (15.86 ± 0.80 s) placebo ( p = .04). Mean time to complete the sprint and power-based performance tests were not different between trials. CHO + BHB-ME resulted in blood BHB concentrations that remained >2 mmol/L during exercise ( p < .001). Serum lactate and glycerol concentrations were lower after CHO + BHB-ME than CHO ( p < .05). Coingestion of a BHB-ME with CHO can alter fuel metabolism (attenuate circulating lactate and glycerol concentrations) and may improve high-intensity running performance during a simulated rugby match-play protocol, without improving shorter duration sprint and power-based efforts.
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Recently developed ketone (monoester or salt) supplements acutely elevate blood β-hydroxybutyrate (BHB) exogenously without prolonged periods of fasting or carbohydrate restriction. Previous (small-scale) studies have found a blood glucose-lowering effect of exogenous ketones. This study aimed to systematically review available evidence and conduct meta-analyses of studies reporting on exogenous ketones and blood glucose. We searched 6 electronic databases on December 13, 2021 for randomized and non-randomized trials of any length that reported on the use of exogenous ketones. We calculated raw mean differences (MD) in blood BHB and glucose in two main analyses: (I) after compared to before acute ingestion of exogenous ketones, and (II) following acute ingestion of exogenous ketones compared to a comparator supplement. We pooled effect sizes using random-effects models and performed prespecified subgroup analyses to examine the effect of potential explanatory factors, including study population, exercise, blood BHB, and supplement type, dosing, and timing. Risk of bias was examined using Cochrane's risk-of-bias tools. Studies that could not be meta-analyzed were summarized narratively. Forty-three trials including 586 participants are summarized in this review. Following ingestion, exogenous ketones increased blood BHB (MD = 1.73 mM, 95% CI: 1.26 mM to 2.21 mM, P < 0.001) and decreased mean blood glucose (MD = -0.54 mM, 95% CI: -0.68 mM to -0.40 mM, P < 0.001). Similarly, when compared to placebo, blood BHB increased (MD = 1.98 mM, 95% CI: 1.52 mM to 2.45 mM, P < 0.001) and blood glucose decreased (MD = -0.47 mM, 95% CI: -0.57 mM to -0.36 mM, P < 0.001). Across both analyses, significantly greater effects were seen with ketone monoesters compared to salts (P < 0.001). The available evidence indicates that acute ingestion of exogenous ketones leads to increased blood BHB and decreased blood glucose. Limited evidence on prolonged ketone supplementation was found.
Chapter
The physiologic state of ketosis is characterized by decreased blood glucose, suppression of insulin, and an increase in the blood ketones β‎-hydroxybutyrate (β‎HB) and acetoacetate (AcAc), which serve as alternative sources of ATP in the brain. Ketones are elevated by fasting, caloric restriction, exercise, or the ketogenic diet (KD), and until recently these were the only known methods of inducing and sustaining ketosis in a nonpathologic setting. Many studies have revealed therapeutic effects of the KD, and data suggest that the benefits are mediated largely by ketone body metabolism and signaling. However, the KD often causes reduced patient compliance, which can make the KD a suboptimal long-term treatment. This has led researchers to develop exogenous ketone supplements—compounds that release or are metabolized into β‎HB and/or AcAc. The supplements rapidly elevate blood ketones in a dose-dependent manner, making them a practical method for inducing therapeutic ketosis. Ketone supplementation could potentially be used as stand-alone therapy in certain conditions, or possibly as a way to further augment the efficacy of the KD in the conditions in which it is being used or investigated, and it could increase compliance by allowing patients to maintain a less restrictive diet. Ketone supplements may also serve as an effective preventative medicine due to their potential to protect and enhance mitochondrial function. Preliminary evidence suggests there are several conditions for which ketone supplementation may be beneficial, including epilepsy, Alzheimer’s disease, glucose transporter type 1 deficiency syndrome, cancer, atrophy-related diseases, and metabolic syndrome.
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• Contemporary stable isotope methodology was applied in combination with muscle biopsy sampling to accurately quantify substrate utilisation and study the regulation of muscle fuel selection during exercise. • Eight cyclists were studied at rest and during three consecutive 30 min stages of exercise at intensities of 40, 55 and 75 % maximal workload (Wmax). A continuous infusion of [U-13C]palmitate and [6,6-2H2]glucose was administered to determine plasma free fatty acid (FFA) oxidation and estimate plasma glucose oxidation, respectively. Biopsy samples were collected before and after each exercise stage. • Muscle glycogen and plasma glucose oxidation rates increased with every increment in exercise intensity. Whole-body fat oxidation increased to 32 ± 2 kJ min−1 at 55 % Wmax, but declined at 75 % Wmax (19 ± 2 kJ min−1). This decline involved a decrease in the oxidation rate of both plasma FFA and triacylglycerol fat sources (sum of intramuscular plus lipoprotein-derived triacylglycerol), and was accompanied by increases in muscle pyruvate dehydrogenase complex activation and acetylation of the carnitine pool, resulting in a decline in muscle free carnitine concentration. • We conclude that the most likely mechanism for the reduction in fat oxidation during high-intensity exercise is a downregulation of carnitine palmitoyltransferase I, either by this marked decline in free carnitine availability or by a decrease in intracellular pH.
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The relationship between dietary intake and skeletal-muscle exercise metabolism is central to the interests of exercise physiologists. This area has been examined experimentally for over 100 years. Classic studies with male subjects demonstrated the importance of dietary CHO in maximizing muscle and liver glycogen stores in an attempt to optimize exercise performance. CHO becomes the predominant fuel for exercise at power outputs above 50-60% Vo2max and its availability limits prolonged aerobic exercise at intensities corresponding to 65-85% VO2max. Recent information suggests that female subjects are less able to maximize muscle glycogen stores through dietary means. Contemporary studies have documented in more detail the greater reliance on CHO metabolism following a high-CHO-low-fat and -protein diet and the greater reliance on fat metabolism following a low-CHO-high-fat and protein diet. More emphasis on documenting key enzymic changes in the energy-producing pathways and transport proteins has appeared. However, very little is known regarding the mechanisms that induce these changes over the short or long term in human skeletal muscle. For example, the central role of PDH activity in the selection of intramuscular fuel during exercise and the role of carnitine palmitoyltransferase 1 in the entry of NEFA into the mitochondria, and the effects of diet on these enzymes has received little attention to date. Many research studies have examined extreme diet variations (% total energy; > 85% CHO v. < 5-10% CHO) for short periods of time in an attempt to maximize diet-induced alterations and study the mechanisms responsible for the changes. However, future studies will need to examine less-severe diet alterations for longer periods of time that more accurately reflect what the normal population might experience, such as a diet containing (% total energy) 60 fat, 20 CHO, 20 protein or the recently popular diet with (% total energy) 30 fat, 40 CHO, 30 protein.
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We have previously shown that insulin increases muscle total carnitine (TC) content during acute i.v. l-carnitine infusion. Here we determined the effects of chronic l-carnitine and carbohydrate (CHO; to elevate serum insulin) ingestion on muscle TC content and exercise metabolism and performance in humans. On three visits, each separated by 12 weeks, 14 healthy male volunteers (age 25.9 ± 2.1 years, BMI 23.0 ± 0.8 kg m−2) performed an exercise test comprising 30 min cycling at 50% , 30 min at 80% , then a 30 min work output performance trial. Muscle biopsies were obtained at rest and after exercise at 50% and 80% on each occasion. Following visit one, volunteers ingested either 80 g of CHO (Control) or 2 g of l-carnitine-l-tartrate and 80 g of CHO (Carnitine) twice daily for 24 weeks in a randomised, double blind manner. All significant effects reported occurred after 24 weeks. Muscle TC increased from basal by 21% in Carnitine (P < 0.05), and was unchanged in Control. At 50% , the Carnitine group utilised 55% less muscle glycogen compared to Control (P < 0.05) and 31% less pyruvate dehydrogenase complex (PDC) activation compared to before supplementation (P < 0.05). Conversely, at 80% , muscle PDC activation was 38% higher (P < 0.05), acetylcarnitine content showed a trend to be 16% greater (P < 0.10), muscle lactate content was 44% lower (P < 0.05) and the muscle PCr/ATP ratio was better maintained (P < 0.05) in Carnitine compared to Control. The Carnitine group increased work output 11% from baseline in the performance trial, while Control showed no change. This is the first demonstration that human muscle TC can be increased by dietary means and results in muscle glycogen sparing during low intensity exercise (consistent with an increase in lipid utilisation) and a better matching of glycolytic, PDC and mitochondrial flux during high intensity exercise, thereby reducing muscle anaerobic ATP production. Furthermore, these changes were associated with an improvement in exercise performance.
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The metabolism of millimolar concentrations of R- or S-1,3-butanediol has been studied in perfused livers from fed and starved rats. Protocols were designed to measure in the same experiment (i) uptake of the diol, (ii) the contribution of the diol to ketogenesis, (iii) the contribution of the diol to total fatty acid plus sterol synthesis, and (iv) conversion of S-1,3-butanediol into S-3-hydroxybutyrate. Our data show that R- and S-1,3-butanediol are taken up by the liver at the same rate. Most of the metabolism of R-1,3-butanediol is accounted for by conversion to the physiological ketone bodies R-3-hydroxybutyrate and acetoacetate. Only 29-38% of S-1,3-butanediol uptake is accounted for by conversion into physiological ketone bodies. The balance of S-1,3-butanediol metabolism is conversion to S-3-hydroxybutyrate, lipids and CO2.
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To determine the temporal relationship between changes in contractile performance and flux through the citric acid cycle in hearts oxidizing acetoacetate, we perfused isolated working rat hearts with either glucose or acetoacetate (both 5 mM) and freeze-clamped the tissue at defined times. After 60 min of perfusion, hearts utilizing acetoacetate exhibited lower systolic and diastolic pressures and lower cardiac outputs. The oxidation of acetoacetate increased the tissue content of 2-oxoglutarate and glutamate and decreased the content of succinyl-CoA suggesting inhibition of citric acid cycle flux through 2-oxoglutarate dehydrogenase. Whereas hearts perfused with either acetoacetate or glucose were similar with respect to their function for the first 20 min, changes in tissue metabolites were already observed within 5 min of perfusion at near-physiological workloads. The addition of lactate or propionate, but not acetate, to hearts oxidizing acetoacetate improved contractile performance, although inhibition of 2-oxoglutarate dehydrogenase was probably not diminished. If lactate or propionate were added, malate and citrate accumulated indicating utilization of anaplerotic pathways for the citric acid cycle. We conclude that a decreased rate of flux through 2-oxoglutarate dehydrogenase in hearts oxidizing acetoacetate precedes, and may be responsible for, contractile failure and is not the result of decreased cardiac work. Further, anaplerosis play an important role in the maintenance of contractile function in hearts utilizing acetoacetate.
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The effect of elevated plasma insulin concentration (55 +/- 2 mU/l) on peripheral clearance and production of total ketone bodies was determined using 3-14C-acetoacetate tracer infusions. Nine normal subjects were studied twice, once during insulin infusion (20 mU.m-2.min-1), once during basal plasma insulin concentrations (controls). Blood total ketone body concentrations (sum of acetone, acetoacetate and beta-hydroxybutyrate) were maintained in both studies at 2 mmol/l by feedback-controlled sodium acetoacetate infusions. The coefficient of variation of total ketone body concentrations during the two clamp studies was 10 and 11% respectively. The sodium acetoacetate infusion rate required during the clamp was 55 +/- 4% higher during hyperinsulinaemia than in controls (p less than 0.005). This was due to increased total ketone body clearance (8.4 +/- 0.7 vs 6.7 +/- 0.4 ml.kg-1.min-1, p less than 0.015), and to enhanced suppression of ketone body production (p less than 0.01). Hyperketonaemia alone decreased ketone body production by 42% and diminished ketone body clearance by 46%, the former being enhanced, the latter being in part antagonised by insulin. Since the plasma insulin concentrations were within those observed in patients treated for diabetic ketoacidosis, the data suggest that the antiketotic effect of insulin therapy results in part from an increase in peripheral ketone body disposal.
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The glycogen depletion pattern in human muscle fibers was followed throughout the course of prolonged exercise at a work load requiring 67% of the subjects' maximal aerobic power. Biopsy samples were taken from the vastus lateralis muscle at rest and after 20, 60, 120, and 180 (or when unable to continue at the prescribed load) min of exercise. Muscle fibers were identified as fast twitch (FT) or slow twitch (ST) on the basis of myofibrillar ATPase activity. The glycogen content of muscle samples was determined biochemically. At the end of the exercise total muscle glycogen content was very low. Glycogen was also estimated in the fibers with the PAS stain. ST fibers were the first to become depleted of their glycogen but as the exercise progressed, the FT fibers were also depleted. These data may suggest a preferential utilization of ST fibers during prolonged, intense exercise, with a secondary recruitment of FT occuring as the ST fibers became depleted of their glycogen stores.
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Addition of insulin or a physiological ratio of ketone bodies to buffer with 10 mM glucose increased efficiency (hydraulic work/energy from O2 consumed) of working rat heart by 25%, and the two in combination increased efficiency by 36%. These additions increased the content of acetyl CoA by 9- to 18-fold, increased the contents of metabolites of the first third of the tricarboxylic acid (TCA) cycle 2- to 5-fold, and decreased succinate, oxaloacetate, and aspartate 2- to 3-fold. Succinyl CoA, fumarate, and malate were essentially unchanged. The changes in content of TCA metabolites resulted from a reduction of the free mitochondrial NAD couple by 2- to 10-fold and oxidation of the mitochondrial coenzyme Q couple by 2- to 4-fold. Cytosolic pH, measured using 31P-NMR spectra, was invariant at about 7.0. The total intracellular bicarbonate indicated an increase in mitochondrial pH from 7.1 with glucose to 7.2, 7.5 and 7.4 with insulin, ketones, and the combination, respectively. The decrease in Eh7 of the mitochondrial NAD couple, Eh7NAD+/NADH, from -280 to -300 mV and the increase in Eh7 of the coenzyme Q couple, Eh7Q/QH2, from -4 to +12 mV was equivalent to an increase from -53 kJ to -60 kJ/2 mol e in the reaction catalyzed by the mitochondrial NADH dehydrogenase multienzyme complex (EC 1.6.5.3). The increase in the redox energy of the mitochondrial cofactor couples paralleled the increase in the free energy of cytosolic ATP hydrolysis, delta GATP. The potential of the mitochondrial relative to the cytosolic phases, Emito/cyto, calculated from delta GATP and delta pH on the assumption of a 4 H+ transfer for each ATP synthesized, was -143 mV during perfusion with glucose or glucose plus insulin, and decreased to -120 mV on addition of ketones. Viewed in this light, the moderate ketosis characteristic of prolonged fasting or type II diabetes appears to be an elegant compensation for the defects in mitochondrial energy transduction associated with acute insulin deficiency or mitochondrial senescence.
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Stable isotope tracers and indirect calorimetry were used to evaluate the regulation of endogenous fat and glucose metabolism in relation to exercise intensity and duration. Five trained subjects were studied during exercise intensities of 25, 65, and 85% of maximal oxygen consumption (VO2max). Plasma glucose tissue uptake and muscle glycogen oxidation increased in relation to exercise intensity. In contrast, peripheral lipolysis was stimulated maximally at the lowest exercise intensity, and fatty acid release into plasma decreased with increasing exercise intensity. Muscle triglyceride lipolysis was stimulated only at higher intensities. During 2 h of exercise at 65% VO2max plasma-derived substrate oxidation progressively increased over time, whereas muscle glycogen and triglyceride oxidation decreased. In recovery from high-intensity exercise, although the rate of lipolysis immediately decreased, the rate of release of fatty acids into plasma increased, indicating release of fatty acids from previously hydrolyzed triglycerides. We conclude that, whereas carbohydrate availability is regulated directly in relation to exercise intensity, the regulation of lipid metabolism seems to be more complex.
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The administration of saturating doses of insulin to the glucose perfused, working rat heart acutely increased activity of the glucose transporter 4, GLUT 4, in the plasma membrane (equilibrating extracellular glucose and intracellular [glucose]), activated glycogen synthase (stimulating the rate of glycogen synthesis), and increased mitochondrial acetyl CoA production by the pyruvate dehydrogenase multienzyme complex. Unexpectedly, insulin increased cardiac hydraulic work but decreased net glycolytic flux and O2 consumption, improving net cardiac efficiency by 28%. These improvements in physiologic performance and metabolic efficiency resulted from reduction of the mitochondrial free [NAD+]/[NADH] and oxidation of mitochondrial [coenzyme Q]/[coenzyme QH2], increasing the energy of the proton gradient between cytosolic and mitochondrial phases and leading to a doubling of the cytosolic free [sigmaATP]/[sigmaADP][sigmaPi]. The acute metabolic effects of insulin were qualitatively duplicated by addition of a ratio of 4 mM D-beta-hydroxybutyrate and 1 mM acetoacetate, and the increase in the efficiency was the same as with addition of insulin. Addition of both insulin and ketones to the glucose perfusate increased the efficiency of cardiac hydraulic work by 35%. The ability of a physiologic ratio of ketone bodies to correct most of the metabolic defects of acute insulin deficiency suggests therapeutic roles for these natural substrates during periods of impaired cardiac performance and in insulin-resistant states.
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Malonyl-CoA is an allosteric inhibitor of carnitine palmitoyltransferase (CPT) I, the enzyme that controls the transfer of long-chain fatty acyl (LCFA)-CoAs into the mitochondria where they are oxidized. In rat skeletal muscle, the formation of malonyl-CoA is regulated acutely (in minutes) by changes in the activity of the beta-isoform of acetyl-CoA carboxylase (ACCbeta). This can occur by at least two mechanisms: one involving cytosolic citrate, an allosteric activator of ACCbeta and a precursor of its substrate cytosolic acetyl-CoA, and the other involving changes in ACCbeta phosphorylation. Increases in cytosolic citrate leading to an increase in the concentration of malonyl-CoA occur when muscle is presented with insulin and glucose, or when it is made inactive by denervation, in keeping with a diminished need for fatty acid oxidation in these situations. Conversely, during exercise, when the need of the muscle cell for fatty acid oxidation is increased, decreases in the ATP/AMP and/or creatine phosphate-to-creatine ratios activate an isoform of an AMP-activated protein kinase (AMPK), which phosphorylates ACCbeta and inhibits both its basal activity and activation by citrate. The central role of cytosolic citrate links this malonyl-CoA regulatory mechanism to the glucose-fatty acid cycle concept of Randle et al. (P. J. Randle, P. B. Garland. C. N. Hales, and E. A. Newsholme. Lancet 1: 785-789, 1963) and to a mechanism by which glucose might autoregulate its own use. A similar citrate-mediated malonyl-CoA regulatory mechanism appears to exist in other tissues, including the pancreatic beta-cell, the heart, and probably the central nervous system. It is our hypothesis that by altering the cytosolic concentrations of LCFA-CoA and diacylglycerol, and secondarily the activity of one or more protein kinase C isoforms, changes in malonyl-CoA provide a link between fuel metabolism and signal transduction in these cells. It is also our hypothesis that dysregulation of the malonyl-CoA regulatory mechanism, if it leads to sustained increases in the concentrations of malonyl-CoA and cytosolic LCFA-CoA, could play a key role in the pathogenesis of insulin resistance in muscle. That it may contribute to abnormalities associated with the insulin resistance syndrome in other tissues and the development of obesity has also been suggested. Studies are clearly needed to test these hypotheses and to explore the notion that exercise and some pharmacological agents that increase insulin sensitivity act via effects on malonyl-CoA and/or cytosolic LCFA-CoA.
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Although it is known that carbohydrate (CHO) feedings during exercise improve endurance performance, the effects of different feeding strategies are less clear. Studies using (stable) isotope methodology have shown that not all carbohydrates are oxidised at similar rates and hence they may not be equally effective. Glucose, sucrose, maltose, maltodextrins and amylopectin are oxidised at high rates. Fructose, galactose and amylose have been shown to be oxidised at 25 to 50% lower rates. Combinations of multiple transportable CHO may increase the total CHO absorption and total exogenous CHO oxidation. Increasing the CHO intake up to 1.0 to 1.5 g/min will increase the oxidation up to about 1.0 to 1.1 g/min. However, a further increase of the intake will not further increase the oxidation rates. Training status does not affect exogenous CHO oxidation. The effects of fasting and muscle glycogen depletion are less clear. The most remarkable conclusion is probably that exogenous CHO oxidation rates do not exceed 1.0 to 1.1 g/min. There is convincing evidence that this limitation is not at the muscular level but most likely located in the intestine or the liver. Intestinal perfusion studies seem to suggest that the capacity to absorb glucose is only slightly in excess of the observed entrance of glucose into the blood and the rate of absorption may thus be a factor contributing to the limitation. However, the liver may play an additional important role, in that it provides glucose to the bloodstream at a rate of about 1 g/min by balancing the glucose from the gut and from glycogenolysis/gluconeogenesis. It is possible that when large amounts of glucose are ingested absorption is a limiting factor, and the liver will retain some glucose and thus act as a second limiting factor to exogenous CHO oxidation.
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Analysis of brain metabolites by a wide range of analytical techniques is typically achieved using biochemical extraction methodologies that require either two separate samples or two separate extraction steps to prepare both aqueous and organic metabolite fractions. However there are a number of brain pathologies in which both aqueous metabolite and lipid changes occur so that a simultaneous extraction of both fractions would be valuable. The methanol-chloroform (M/C) technique enables extraction of both aqueous metabolites and lipids simultaneously. It is already well established for lipid extraction of cells and tissue but its efficiency and reproducibility for extraction of aqueous metabolites is unknown. Therefore, we compared the aqueous metabolite yield and the reproducibility of the M/C method to the commonly used perchloric acid (PCA) method, using 1H-NMR spectroscopy of adult rat brain and purified rat astrocyte culture extracts. The results indicate that M/C is a superior technique for aqueous metabolite extraction from both brain tissue and cells when compared to the PCA method. The M/C extraction technique enables the simultaneous extraction of both lipids and aqueous metabolites from a single sample using small solvent-volumes, making it well suited for NMR investigations of both tissues and cells.
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As a treatment for dyslipidemia, oral doses of 1-3 grams of nicotinic acid per day lower serum triglycerides, raise high density lipoprotein cholesterol, and reduce mortality from coronary heart disease (Tavintharan, S., and Kashyap, M. L. (2001) Curr. Atheroscler. Rep. 3, 74-82). These benefits likely result from the ability of nicotinic acid to inhibit lipolysis in adipocytes and thereby reduce serum non-esterified fatty acid levels (Carlson, L. A. (1963) Acta Med. Scand. 173, 719-722). In mice, nicotinic acid inhibits lipolysis via PUMA-G, a Gi/o-coupled seven-transmembrane receptor expressed in adipocytes and activated macrophages (Tunaru, S., Kero, J., Schaub, A., Wufka, C., Blaukat, A., Pfeffer, K., and Offermanns, S. (2003) Nat. Med. 9, 352-355). The human ortholog HM74a is also a nicotinic acid receptor and likely has a similar role in anti-lipolysis. Endogenous levels of nicotinic acid are too low to significantly impact receptor activity, hence the natural ligands(s) of HM74a/PUMA-G remain to be elucidated. Here we show that the fatty acid-derived ketone body (D)-beta-hydroxybutyrate ((D)-beta-OHB) specifically activates PUMA-G/HM74a at concentrations observed in serum during fasting. Like nicotinic acid, (D)-beta-OHB inhibits mouse adipocyte lipolysis in a PUMA-G-dependent manner and is thus the first endogenous ligand described for this orphan receptor. These findings suggests a homeostatic mechanism for surviving starvation in which (D)-beta-OHB negatively regulates its own production, thereby preventing ketoacidosis and promoting efficient use of fat stores.
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The administration of ketones to induce a mild ketosis is of interest for the alleviation of symptoms associated with various neurological disorders. This study aimed to understand the pharmacokinetics (PK) of d-β-hydroxybutyrate (BHB) and quantify the sources of variability following a dose of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate (ketone monoester). Healthy volunteers (n = 37) were given a single drink of the ketone monoester, following which, 833 blood BHB concentrations were measured. Two formulations and five dose levels of ketone monoester were used. A nonlinear mixed effect modelling approach was used to develop a population PK model. A one compartment disposition model with negative feedback effect on endogenous BHB production provided the best description of the data. Absorption was best described by two consecutive first-order inputs and elimination by dual processes involving first-order (CL = 10.9 L/h) and capacity limited elimination (V max = 4520 mg/h). Covariates identified were formulation (on relative oral bioavailable fraction and absorption rate constant) and dose (on relative oral bioavailable fraction). Lean body weight (on first-order clearance) and sex (on apparent volume of distribution) were also significant covariates. The PK of BHB is complicated by complex absorption process, endogenous production and nonlinear elimination. Formulation and dose appear to strongly influence the kinetic profile following ketone monoester administration. Further work is needed to quantify mechanisms of absorption and elimination of ketones for therapeutic use in the form of ketone monoester.
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Although it is known that carbohydrate (CHO) feedings during exercise improve endurance performance, the effects of different feeding strategies are less clear. Studies using (stable) isotope methodology have shown that not all carbohydrates are oxidised at similar rates and hence they may not be equally effective. Glucose, sucrose, maltose, maltodextrins and amylopectin are oxidised at high rates. Fructose, galactose and amylose have been shown to be oxidised at 25 to 50% lower rates. Combinations of multiple transportable CHO may increase the total CHO absorption and total exogenous CHO oxidation. Increasing the CHO intake up to 1.0 to 1.5 g/min will increase the oxidation up to about 1.0 to 1.1 g/min. However, a further increase of the intake will not further increase the oxidation rates. Training status does not affect exogenous CHO oxidation. The effects of fasting and muscle glycogen depletion are less clear. The most remarkable conclusion is probably that exogenous CHO oxidation rates do not exceed 1.0 to 1.1 g/min. There is convincing evidence that this limitation is not at the muscular level but most likely located in the intestine or the liver. Intestinal perfusion studies seem to suggest that the capacity to absorb glucose is only slightly in excess of the observed entrance of glucose into the blood and the rate of absorption may thus be a factor contributing to the limitation. However, the liver may play an additional important role, in that it provides glucose to the bloodstream at a rate of about 1 g/min by balancing the glucose from the gut and from glycogenolysis/gluconeogenesis. It is possible that when large amounts of glucose are ingested absorption is a limiting factor, and the liver will retain some glucose and thus act as a second limiting factor to exogenous CHO oxidation.
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