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Metabolic pathways of ketone body metabolism in liver and skeletal muscle Ketogenesis: FFAs are converted to fatty acyl CoA (FA-CoA), enter hepatic mitochondria via CPT1-mediated transport and undergo β-oxidation to acetyl CoA. Sequential reactions of condensation of Ac-CoA molecules to acetoacetyl CoA (AcAc-CoA) by mitochondrial thiolase activity of Ac-CoA acetyltransferase (ACAT), generation of hydroxymethylglutaryl-CoA (HMG-CoA) by hydroxymethylglutaryl CoA synthase (HMGCS), and decomposition of HMG-CoA, liberating AcAc and Ac-CoA, in a reaction catalysed by HMG-CoA lyase (HMGCL). AcAc is the central KB, and some will be exported to the circulation but the majority is reduced to βHB in an NAD + –NADH-coupled near equilibrium reaction catalysed by BDH, in which the equilibrium constant favours βHB formation. Ketolysis: The only metabolic fate of βHB is inter-conversion with AcAc, and upon entry into peripheral tissues it is re-oxidised to AcAc. Covalent activation of AcAc by CoA is catalysed by succinyl-CoA:3-oxoacid CoA transferase (OXCT) resulting in generation of AcAc-CoA. This near equilibrium reaction exchanges CoA between succinate and AcAc, with succinyl-CoA acting as a CoA donor. Because the free energy released by hydrolysis of AcAc-CoA is greater than that of succinyl-CoA, the equilibrium of this reaction thermodynamically favours the formation of AcAc. Two molecules of Ac-CoA are liberated by thiolytic cleavage of AcAc-CoA by ACAT, after which Ac-CoA is incorporated into the TCA cycle. Protein content and enzyme activity that are higher in exercise-trained skeletal muscle are indicated by the green cross (+).
Source publication
![Figure 1. Changes in [βHB] under various physiological states Plasma...](profile/Brendan-Egan/publication/309885871/figure/fig1/AS:436653622861826@1481117744934/Changes-in-bHB-under-various-physiological-states-Plasma-KB-is-01-mM-in-the_Q320.jpg)
Optimising training and performance through nutrition strategies is central to supporting elite sportspeople, much of which has focussed on manipulating the relative intake of carbohydrate and fat and their contributions as fuels for energy provision. The ketone bodies, namely acetoacetate, acetone, and β-hydroxybutyrate (βHB), are produced in the...
Contexts in source publication
Context 1
... ratio and decline in hepatic glycogen concentration, while reduced blood flow to the liver or elevations in [KBs] suppress ketogenesis (Robinson & Williamson, 1980;Laffel, 1999). Ketogenesis involves a series of sequential reactions beginning with acetyl CoA (Ac-CoA) and acetoacetyl CoA (AcAc-CoA), and ending with the liberation of AcAc (Fig. 2). Some AcAc is exported, but the majority is reduced to βHB in an NAD + -NADH-coupled near equilibrium reaction catalysed by 3-hydroxybutyrate dehydrogenase (BDH), in which the equilibrium constant favours βHB formation. These KBs are transported into the circulation via the solute ligand carrier (SLC) protein 16A (SLC16A) family of ...
Context 2
... in extra-hepatic tissues. In peripheral tissues, KBs, primarily in the form of βHB, enter the mitochondrial matrix again via MCT1-mediated 4 M. Evans and others J Physiol 000.00 transport. βHB is re-oxidised to AcAc via BDH after which sequential reactions result in the generation of two molecules of Ac-CoA (Fig. 2). These are incorporated into the TCA cycle via citrate synthase for terminal oxidation and production of ATP, which in skeletal muscle contributes to fuelling muscular work (Fery & Balasse, 1986. Succinyl-CoA:3-oxoacid CoA transferase (OXCT) is essential for ketolysis in extra-hepatic tissues, with very low abundance in hepatocytes ...
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Citations
... Therefore, when the non-carbohydrate substrates are amino acids (during gluconeogenesis), they are derived from the breakdown of skeletal muscle via proteolysis to generate fuel [21]. There is evidence that ketones may promote the synthesis of proteins in muscles [22,23]. The evolutionary adaptation of preferentially using fat stores over protein stores as a fuel source prevents the breakdown of protein stores [24]. ...
Exogenous supplementation with ketone beverages has been shown to reduce plasma glucose levels during acute nutritional ketosis. It remains to be investigated whether growth differentiation factor 15 (GDF-15)—an anorexigenic hormone—is involved in this process. The aim was to investigate the effect of a ketone ester beverage delivering β-hydroxybutyrate (KEβHB) on plasma levels of GDF-15, as well as assess the influence of eating behaviour on it. The study was a randomised controlled trial (registered at clinicaltrials.gov as NCT03889210). Individuals were given a KEβHB beverage or placebo in a cross-over fashion. Blood samples were collected at baseline, 30, 60, 90, 120, and 150 min after ingestion. Eating behaviour was assessed using the three-factor eating questionnaire. GDF-15 levels were not significantly different (p = 0.503) after the KEβHB beverage compared with the placebo. This finding remained consistent across the cognitive restraint, emotional eating, and uncontrolled eating domains. Changes in the anorexigenic hormone GDF-15, irrespective of eating behaviour, do not appear to play a major role in the glucose-lowering effect of exogenous ketones.
... During prolonged aerobic exercise (i.e., running, cycling, or swimming), ketone bodies can make an increasing contribution to performance as an alternative skeletal muscle fuel source. Specifically, the absorption and oxidation of circulating ketones has been shown to increase up to 5-fold during fasted exercise [1][2][3] with higher rates observed in endurance trained muscle likely due to greater transport capacity and enzymatic machinery [3,4]. ...
... During prolonged aerobic exercise (i.e., running, cycling, or swimming), ketone bodies can make an increasing contribution to performance as an alternative skeletal muscle fuel source. Specifically, the absorption and oxidation of circulating ketones has been shown to increase up to 5-fold during fasted exercise [1][2][3] with higher rates observed in endurance trained muscle likely due to greater transport capacity and enzymatic machinery [3,4]. ...
This study investigated the effect of a commercially available ketone supplement on heart rate (HR), perceived exertion (RPE), blood lactate, glucose, and ketone concentrations, along with time to fatigue (TTF) during a running task to voluntary fatigue. Twelve NCAA Division I cross-country athletes took part in this randomized, double-blind, placebo-controlled cross-over study. Bayesian methodologies were employed for all statistical analyses, and point estimates were determined to be statistically significant if the 95% highest-density intervals (HDI) excluded zero. TTF was not significantly different between conditions with a Meandiff = 48.7 ± 6.3 s (95% HDI: −335, 424) and a 0.39 probability derived from the posterior distribution, indicating the likelihood that the supplement would increase TTF compared to the placebo control. Lactate concentrations immediately post-exercise were significantly lower in the supplement trial relative to placebo with an estimated Meandiff = −4.6 ± 1.9 mmol; 95% HDI: −8.3, −0.9. There were no significant interaction effects observed for either blood glucose or ketone concentrations nor HR or RPE. These findings imply that the acute ingestion of ketones before running at lactate threshold pace has a low probability of increasing TTF in highly trained Division I runners.
... The time course of acetoacetate levels aligns with previously reported reductions in plasma acetoacetate levels in response to acute RE [20,49]. Others have shown that 3-hydroxybutyrate and acetoacetate are released into the blood after exercise [20,50,51]. Berton et al. 2017 showed that 3-hydroxybutyrate and 2-hydroxybutyrate increased immediately after resistance exercise in young non-fasting individuals [39]. ...
... Berton et al. 2017 showed that 3-hydroxybutyrate and 2-hydroxybutyrate increased immediately after resistance exercise in young non-fasting individuals [39]. Previous studies have demonstrated that 3-hydroxybutyrate can regulate adaptation mechanisms in skeletal muscle through positive effects on protein synthesis in human skeletal muscle [51,52], so the rise in 3-hydroxybutyrate during exercise likely represents a beneficial adaptive response. ...
Background
The favorable health-promoting adaptations to exercise result from cumulative responses to individual bouts of physical activity. Older adults often exhibit anabolic resistance; a phenomenon whereby the anabolic responses to exercise and nutrition are attenuated in skeletal muscle. The mechanisms contributing to age-related anabolic resistance are emerging, but our understanding of how chronological age influences responsiveness to exercise is incomplete. The objective was to determine the effects of healthy aging on peripheral blood metabolomic response to a single bout of resistance exercise and whether any metabolites in circulation are predictive of anabolic response in skeletal muscle.
Methods
Thirty young (20–35 years) and 49 older (65–85 years) men and women were studied in a cross-sectional manner. Participants completed a single bout of resistance exercise consisting of eight sets of 10 repetitions of unilateral knee extension at 70% of one-repetition maximum. Blood samples were collected before exercise, immediately post exercise, and 30-, 90-, and 180-minutes into recovery. Proton nuclear magnetic resonance spectroscopy was used to profile circulating metabolites at all timepoints. Serial muscle biopsies were collected for measuring muscle protein synthesis rates.
Results
Our analysis revealed that one bout of resistance exercise elicits significant changes in 26 of 33 measured plasma metabolites, reflecting alterations in several biological processes. Furthermore, 12 metabolites demonstrated significant interactions between exercise and age, including organic acids, amino acids, ketones, and keto-acids, which exhibited distinct responses to exercise in young and older adults. Pre-exercise histidine and sarcosine were negatively associated with muscle protein synthesis, as was the pre/post-exercise fold change in plasma histidine.
Conclusions
This study demonstrates that while many exercise-responsive metabolites change similarly in young and older adults, several demonstrate age-dependent changes even in the absence of evidence of sarcopenia or frailty.
... Myofiber glycogen is the main energetic substrate for muscle work during intense exercise [1]. In this context, carbohydrate (CHO) supplementation before and/or during endurance exercise has proven to serve as an additional fuel source to muscle energy production when glycogen levels are diminishing in this tissue, and thus to prevent premature fatigue [2]. ...
... In recent years, it has been proposed that ketone supplementation might also enhance endurance exercise performance [3]. Plasma concentration of ketone bodies can be increased (i.e., ketosis) either naturally (e.g., during periods of energy deficiency) or exogenously (through dietary supplementation), thereby serving as an additional energy substrate for extrahepatic tissues including the brain, heart, and skeletal muscle [1]. Ketone bodies have been reported to inhibit muscle glycolytic flux [4], and therefore acute ketone supplementation before and/or during exercise might represent an extra energy supply for muscle work, potentially sparing muscle glycogen stores [1,5]. ...
... Plasma concentration of ketone bodies can be increased (i.e., ketosis) either naturally (e.g., during periods of energy deficiency) or exogenously (through dietary supplementation), thereby serving as an additional energy substrate for extrahepatic tissues including the brain, heart, and skeletal muscle [1]. Ketone bodies have been reported to inhibit muscle glycolytic flux [4], and therefore acute ketone supplementation before and/or during exercise might represent an extra energy supply for muscle work, potentially sparing muscle glycogen stores [1,5]. ...
... Ketones enter into the cancer cell via the monocarboxylate transporters (MCTs) that is responsible for lactate export, leading to competitively inhibit lactate export and shorten cancer survival time (135) ( Figure 4D). Finally, some studies have reported the KD exerts anti-tumor effects by hindering systematic inflammation mediated by NLRP3 inflammasome (136,137), with the consequent reduction of inflammatory markers in cancers (124,138,139) (Figure 4E). ...
Due to rapid research expansion on dietary factors and development of cancer prevention guidelines, the field of dietary pattern and its relationship to cancer risk has gained more focus. Numerous epidemiology studies have reported associations between Gastric Cancer (GC) and both data-driven posteriori dietary pattern and priori dietary pattern defined by predetermined dietary indexes. As dietary patterns have evolved, a series of patterns based on biological markers has advanced, offering deeper insights into the relationship between diet and the risk of cancer. Although researches on dietary patterns and cancer risk are booming, there is limited body of literature focusing specifically on GC. In this study, we compare the similarities and differences among the specific components of dietary patterns and indices, summarize current state of knowledge regarding dietary patterns related to GC and illustrate their potential mechanisms for GC prevention. In conclusion, we offer suggestions for future research based on the emerging themes within this rapidly evolving field.
... In addition, the serum BHB concentration was analyzed to confirm whether KD feeding induced nutritional ketosis. There was no difference in the BHB concentration between CON and DM groups, and KD feeding increased the serum BHB concentration to a level associated with nutritional ketosis (0.5-3.0 mmol/L) [32]. Moreover, other related metabolic parameters were analyzed in serum and GA muscles. ...
Diabetes is often associated with reduced muscle mass and function. The ketogenic diet (KD) may improve muscle mass and function via the induction of nutritional ketosis. To test whether the KD is able to preserve muscle mass and strength in a mouse model of type 2 diabetes (T2DM), C57BL/6J mice were assigned to lean control, diabetes control, and KD groups. The mice were fed a standard diet (10% kcal from fat) or a high-fat diet (HFD) (60% kcal from fat). The diabetic condition was induced by a single injection of streptozotocin (STZ; 100 mg/kg) and nicotinamide (NAM; 120 mg/kg) into HFD-fed mice. After 8-week HFD feeding, the KD (90% kcal from fat) was fed to the KD group for the following 6 weeks. After the 14-week experimental period, an oral glucose tolerance test and grip strength test were conducted. Type 2 diabetic condition induced by HFD feeding and STZ/NAM injection resulted in reduced muscle mass and grip strength, and smaller muscle fiber areas. The KD nutritional intervention improved these effects. Additionally, the KD altered the gene expression of nucleotide-binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome- and endoplasmic reticulum (ER) stress-related markers in the muscles of diabetic mice. Collectively, KD improved muscle mass and function with alterations in NLRP3 inflammasome and ER stress.
... This rise may be explained by the glucose-sparing effects of blood ketones, which can serve as an alternative fuel for tissues, including the brain and skeletal muscles. The association between higher serum ketones and hyperglycemia has been demonstrated in other studies and may result from impaired insulin secretion and altered gluconeogenesis pathways [16][17][18][19][20]. Although there was a modest increase in HbA1c after three months of statin therapy in our study, it was not statistically significant, possibly due to the small sample size. ...
Introduction: Statins, by inhibiting cholesterol synthesis, may cause an accumulation of acetyl-CoA in hepatocytes, leading to its diversion towards ketogenesis. Ketone bodies can serve as an alternative energy source, potentially sparing blood glucose and contributing to hyperglycemia. This study aimed to evaluate the impact of Atorvastatin therapy on blood ketone levels, glycemic control and lipd profile in patients with Type 2 Diabetes Mellitus (T2DM). Methods: The study included 45 individuals with T2DM who had not previously used statins. They were prescribed Atorvastatin tablets at a daily dose of 10 mg before bedtime, while their ongoing anti-diabetic medications remained unchanged. Measurements of blood ketones, urine ketones, fasting plasma glucose (FPG), post-prandial plasma glucose (PPG), glycated hemoglobin (HbA1c), and lipid parameters were conducted at baseline and after three months of Atorvastatin therapy. Results: After three months of Atorvastatin therapy, there was a moderate yet significant increase in blood ketones, FPG, and PPG. Concurrently, there was a significant reduction in serum total cholesterol and low-density lipoprotein cholesterol levels. Conclusion: A three-month therapy with Atorvastatin at a dose of 10 mg daily at bedtime among patients with T2DM led to a moderate increase in blood ketone levels, FPG, and PPG, alongside improvements in lipid parameters.
... During periods of prolonged fasting or a low-carbohydrate diet, the liver produces ketone bodies (acetoacetate and β-hydroxybutyrate) from fatty acids. Ketone bodies can be used by muscle cells as an alternative energy source, particularly during prolonged endurance exercise, thereby helping in sparing glycogen and potentially delaying the onset of muscle fatigue during prolonged or intense exercise by decreasing the lactic acid buildup during exercise [33]. ...
Metabolic myopathies are a group of genetic disorders that affect the normal functioning of muscles due to abnormalities in metabolic pathways. These conditions result in impaired energy production and utilization within muscle cells, leading to limitations in muscle function with concomitant occurrence of related signs and symptoms, among which fatigue is one of the most frequently reported. Understanding the underlying molecular mechanisms of muscle fatigue in these conditions is challenging for the development of an effective diagnostic and prognostic approach to test targeted therapeutic interventions. This paper outlines the key biomolecules involved in muscle fatigue in metabolic myopathies, including energy substrates, enzymes, ion channels, and signaling molecules. Potential future research directions in this field are also discussed.
... The hepatic metabolism of FAs produces ketones commonly used as substrates for energy: acetoacetate, acetone and beta-hydroxybutyrate (BOHb) [75,76]. Normally, ketones are produced in starvation [77], fasting [78,79], prolonged physical exercises [80], pregnancy [81] and in diets with high-fat and low-carbohydrate rates [82]. Thus, when glucose stores in the body are low, more FAs are made available to the liver for oxidation, leading to the consequent production of energy-rich molecules, mainly acetyl-CoA. ...
Given the remarkable progress in global health and overall quality of life, the significant rise in life expectancy has become intertwined with the surging occurrence of neurodegenerative disorders (NDs). This emerging trend is poised to pose a substantial challenge to the fields of medicine and public health in the years ahead. In this context, Alzheimer’s disease (AD) is regarded as an ND that causes recent memory loss, motor impairment and cognitive deficits. AD is the most common cause of dementia in the elderly and its development is linked to multifactorial interactions between the environment, genetics, aging and lifestyle. The pathological hallmarks in AD are the accumulation of β-amyloid peptide (Aβ), the hyperphosphorylation of tau protein, neurotoxic events and impaired glucose metabolism. Due to pharmacological limitations and in view of the prevailing glycemic hypometabolism, the ketogenic diet (KD) emerges as a promising non-pharmacological possibility for managing AD, an approach that has already demonstrated efficacy in addressing other disorders, notably epilepsy. The KD consists of a food regimen in which carbohydrate intake is discouraged at the expense of increased lipid consumption, inducing metabolic ketosis whereby the main source of energy becomes ketone bodies instead of glucose. Thus, under these dietary conditions, neuronal death via lack of energy would be decreased, inasmuch as the metabolism of lipids is not impaired in AD. In this way, the clinical picture of patients with AD would potentially improve via the slowing down of symptoms and delaying of the progression of the disease. Hence, this review aims to explore the rationale behind utilizing the KD in AD treatment while emphasizing the metabolic interplay between the KD and the improvement of AD indicators, drawing insights from both preclinical and clinical investigations. Via a comprehensive examination of the studies detailed in this review, it is evident that the KD emerges as a promising alternative for managing AD. Moreover, its efficacy is notably enhanced when dietary composition is modified, thereby opening up innovative avenues for decreasing the progression of AD.
... Blood levels of ketone bodies in individuals vary, ranging from 1 mM to 5 mM after brief fasting (3 -4 days) to 8 -9.5 mmol after prolonged fasting (17 -24 days) [34] . Individuals typically generate blood ketone body contents of 1 -2 mM after workouts [35] . Plasma concentrations of ketone bodies can exceed 5 mM when individuals consume limited carbohydrates or adhere to KDs [35] . ...
... Individuals typically generate blood ketone body contents of 1 -2 mM after workouts [35] . Plasma concentrations of ketone bodies can exceed 5 mM when individuals consume limited carbohydrates or adhere to KDs [35] . ...
Obesity and diabetes represent two prevalent metabolic challenges intricately linked to poor dietary habits and a sedentary lifestyle. The escalating incidence of both conditions in recent years has approached epidemic proportions, with concomitant associations observed in individuals with excessive body weight, including hypertension and cancer. In response to this growing health concern, treatment approaches such as food therapy are deemed necessary. A pivotal aspect in managing these conditions is the careful selection of an appropriate diet to facilitate effective weight loss while minimizing potential adverse effects. Consequently, the ketogenic diet (KD) has garnered attention and support in the treatment of obesity and diabetes. This review aims to discern the potential advantages and risks associated with the utilization of a low-carbohydrate diet in Type 2 diabetic patients. It is well-established that dietary choices significantly impact the health of diabetic patients, and therefore, adopting an appropriate diet is crucial. The KD has demonstrated positive effects on blood sugar levels and glycosylated hemoglobin (HbA1c) levels, concurrently contributing to a reduction in insulin requirements during medication therapy. Furthermore, short-term experiments have revealed a positive association between nutrition choices and weight management. Beneficial improvements have been noted in the lipid profiles, including high-density lipoprotein, low-density lipoprotein, HbA1c, and triglyceride levels. For individuals grappling with diabetes or obesity, a low-carbohydrate diet emerges as a genuine and potentially beneficial therapy option. This review provides a comprehensive overview of the key concepts influencing the treatment of obesity and Type 2 diabetic patients through low-carbohydrate diets.
