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.

Background and aims: Currently there is considerable interest in ketone metabolism owing to recently reported benefits of ketosis for human health. Traditionally, ketosis has been achieved by following a high-fat, low-carbohydrate “ketogenic” diet, but adherence to such diets can be difficult. An alternative way to increase blood D-β-hydroxybutyrate (D-βHB) concentrations is ketone drinks, but the metabolic effects of exogenous ketones are relatively unknown. Here, healthy human volunteers took part in three randomized metabolic studies of drinks containing a ketone ester (KE); (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, or ketone salts (KS); sodium plus potassium βHB.Methods and Results: In the first study, 15 participants consumed KE or KS drinks that delivered ~12 or ~24 g of βHB. Both drinks elevated blood D-βHB concentrations (D-βHB Cmax: KE 2.8 mM, KS 1.0 mM, P < 0.001), which returned to baseline within 3–4 h. KS drinks were found to contain 50% of the L-βHB isoform, which remained elevated in blood for over 8 h, but was not detectable after 24 h. Urinary excretion of both D-βHB and L-βHB was <1.5% of the total βHB ingested and was in proportion to the blood AUC. D-βHB, but not L-βHB, was slowly converted to breath acetone. The KE drink decreased blood pH by 0.10 and the KS drink increased urinary pH from 5.7 to 8.5. In the second study, the effect of a meal before a KE drink on blood D-βHB concentrations was determined in 16 participants. Food lowered blood D-βHB Cmax by 33% (Fed 2.2 mM, Fasted 3.3 mM, P < 0.001), but did not alter acetoacetate or breath acetone concentrations. All ketone drinks lowered blood glucose, free fatty acid and triglyceride concentrations, and had similar effects on blood electrolytes, which remained normal. In the final study, participants were given KE over 9 h as three drinks (n = 12) or a continuous nasogastric infusion (n = 4) to maintain blood D-βHB concentrations greater than 1 mM. Both drinks and infusions gave identical D-βHB AUC of 1.3–1.4 moles.min.Conclusion: We conclude that exogenous ketone drinks are a practical, efficacious way to achieve ketosis.

ObjectiveThe ketones d‐β‐hydroxybutyrate (BHB) and acetoacetate are elevated during prolonged fasting or during a “ketogenic” diet. Although weight loss on a ketogenic diet may be associated with decreased appetite and altered gut hormone levels, it is unknown whether such changes are caused by elevated blood ketones. This study investigated the effects of an exogenous ketone ester (KE) on appetite.MethodsFollowing an overnight fast, subjects with normal weight (n = 15) consumed 1.9 kcal/kg of KE, or isocaloric dextrose (DEXT), in drinks matched for volume, taste, tonicity, and color. Blood samples were analyzed for BHB, glucose, insulin, ghrelin, glucagon‐like peptide 1 (GLP‐1), and peptide tyrosine tyrosine (PYY), and a three‐measure visual analogue scale was used to measure hunger, fullness, and desire to eat.ResultsKE consumption increased blood BHB levels from 0.2 to 3.3 mM after 60 minutes. DEXT consumption increased plasma glucose levels between 30 and 60 minutes. Postprandial plasma insulin, ghrelin, GLP‐1, and PYY levels were significantly lower 2 to 4 hours after KE consumption, compared with DEXT consumption. Temporally related to the observed suppression of ghrelin, reported hunger and desire to eat were also significantly suppressed 1.5 hours after consumption of KE, compared with consumption of DEXT.ConclusionsIncreased blood ketone levels may directly suppress appetite, as KE drinks lowered plasma ghrelin levels, perceived hunger, and desire to eat.

Background— Patients with treated HIV infection have clear survival benefits although with increased cardiac morbidity and mortality. Mechanisms of heart disease may be partly related to untreated chronic inflammation. Cardiovascular magnetic resonance imaging allows a comprehensive assessment of myocardial structure, function, and tissue characterization. We investigated, using cardiovascular magnetic resonance, subclinical inflammation and myocardial disease in asymptomatic HIV-infected individuals. Methods and Results— Myocardial structure and function were assessed using cardiovascular magnetic resonance at 1.5-T in treated HIV-infected individuals without known cardiovascular disease (n=103; mean age, 45±10 years) compared with healthy controls (n=92; mean age, 44±10 years). Assessments included left ventricular volumes, ejection fraction, strain, regional systolic, diastolic function, native T1 mapping, edema, and gadolinium enhancement. Compared with controls, subjects with HIV infection had 6% lower left ventricular ejection fraction ( P <0.001), 7% higher myocardial mass ( P =0.02), 29% lower peak diastolic strain rate ( P <0.001), 4% higher short-tau inversion recovery values ( P =0.02), and higher native T1 values (969 versus 956 ms in controls; P =0.01). Pericardial effusions and myocardial fibrosis were 3 and 4× more common, respectively, in subjects with HIV infection (both P <0.001). Conclusions— Treated HIV infection is associated with changes in myocardial structure and function in addition to higher rates of subclinical myocardial edema and fibrosis and frequent pericardial effusions. Chronic systemic inflammation in HIV, which involves the myocardium and pericardium, may explain the high rate of myocardial fibrosis and increased cardiac dysfunction in people living with HIV.

Ketone bodies acetoacetate (AcAc) and D-β-hydroxybutyrate (βHB) may provide an alternative carbon source to fuel exercise when delivered acutely in nutritional form. The metabolic actions of ketone bodies are based on sound evolutionary principles to prolong survival during caloric deprivation. By harnessing the potential of these metabolic actions during exercise, athletic performance could be influenced, providing a useful model for the application of ketosis in therapeutic conditions. This article examines the energetic implications of ketone body utilisation with particular reference to exercise metabolism and substrate energetics.

Purpose: Ketosis, achieved through ingestion of ketone esters, may influence endurance exercise capacity by altering substrate metabolism. However, the effects of ketone consumption on acid-base status and subsequent metabolic and respiratory compensations are poorly described. Methods: Twelve athletically trained individuals completed an incremental bicycle ergometer exercise test to exhaustion following the consumption of either a ketone ester [ (R) -3-hydroxybutyrate- (R) -1,3-butanediol] or a taste-matched control drink (bitter flavoured water) in a blinded, cross-over study. Respiratory gases and arterialised blood gas samples were taken at rest and at regular intervals during exercise. Results: Ketone ester consumption increased blood D -β-hydroxybutyrate concentration from 0.2 to 3.7 mM/L ( p < 0.01), causing significant falls versus control in blood pH to 7.37 and bicarbonate to 18.5 mM/L before exercise. To compensate for ketoacidosis, minute ventilation was modestly increased ( p < 0.05) with non-linearity in the ventilatory response to exercise (ventilatory threshold) occurring at a 22 W lower workload ( p < 0.05). Blood pH and bicarbonate concentrations were the same at maximal exercise intensities. There was no difference in exercise performance having consumed the ketone ester or control drink. Conclusion: Athletes compensated for the greater acid load caused by ketone ester ingestion by elevating minute ventilation and earlier hyperventilation during incremental exercise.

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Obesity is linked to a wide variety of cardiac changes, from subclinical diastolic dysfunction to end-stage systolic heart failure. Obesity causes changes in cardiac metabolism, which make ATP production and utilization less efficient, producing functional consequences that are linked to the increased rate of heart failure in this population. As a result of the increases in circulating fatty acids and insulin resistance that accompanies excess fat storage, several of the proteins and genes that are responsible for fatty acid uptake and metabolism are upregulated, and the metabolic machinery responsible for glucose utilization and oxidation are inhibited. The resultant increase in fatty acid metabolism, and the inherent alterations in the proteins of the electron transport chain used to create the gradient needed to drive mitochondrial ATP production, results in a decrease in efficiency of cardiac work and a relative increase in oxygen usage. These changes in cardiac mitochondrial metabolism are potential therapeutic targets for the treatment and prevention of obesity-related heart failure. (2013) Keywords: myocardial metabolism; review; obese INTRODUCTION Cardiac energy metabolism is essentially a four-step process involving the following: (1) myocellular substrate uptake/selection, (2) mitochondrial ATP production and (3) ATP transfer from the site of production (mitochondrion) to (4) the site of ATP utilization (cardiac myofibril; Figure 1). 1 Although glycolysis is an ATP generator, the overall ATP production is controlled largely by the rate at which the Krebs (tricarboxylic acid) cycle operates. 2 Acetyl co-enzyme A (CoA), which is produced from the oxidation of fatty acids, ketone bodies, or glucose via glycolysis, and the pyruvate dehydrogenase (PDH) enzyme complex 3 enters the Krebs cycle for complete oxidation. During oxidative phosphorylation, electrons, primarily obtained from oxidative metabolism of carbohydrates and fats, are transferred through the electron transport chain, a fourcomplex protein system embedded within the inner membrane of the mitochondria. The major function of the electron transport chain is to produce a proton electrochemical potential difference between two compartments that powers ATP synthase to generate ATP, which is used for all cardiac cellular processes. 4 ATP is the heart's only immediate source of energy for contraction, and as both systole and diastole are ATP-consuming processes, 5,6 cardiac ATP demand is very high. To keep up with this demand for continuous and efficient contraction and relaxation, the heart needs to produce around 20 times its own weight in ATP per day. 1 As a result of this large energy requirement, any impairment in ATP production, transfer or utilization can have detrimental effects on cardiac function. 7 Cardiac metabolism and ATP production is altered in obesity and has emerged as a candidate mechanism to explain the increase in heart failure in this population. 8 Indeed, it has recently been shown that obesity, in the absence of co-morbiditie...