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Elevated levels of BCAAs have been associated with heart failure and metabolic disease. The branched-chain ketoacid dehydrogenase kinase (BCKDK) inhibitor BT2 (3,6-dichlorobenzo[b]thiophene-2-carboxylic acid) was designed to induce branched-chain amino acid (BCAA) oxidation to restore levels of BCAAs. BT2 treatment confers cardioprotection and protects from metabolic disease in preclinical models including mice subjected to trans-aortic constriction or LAD ligation, db/db mice, ob/ob mice, and Zucker fatty rats. However, mice with the BCKDK knocked out specifically in the heart or skeletal muscle does not protect from heart failure, suggesting an alternative molecular mechanism by which BT2 is conferring its protective effects. In this study, we provide evidence characterizing BT2 as a mitochondrial uncoupler. Using reductionist systems including respirometry, mitochondrial membrane potential, and patch-clamp electrophysiology, we demonstrate that BT2 is indeed uncoupling mitochondria and is approximately five-fold milder than the well-known chemical uncoupler DNP. Functional assays expose BT2’s protective effects originate from diminishing ROS production and reducing de novo lipogenesis. The evidence provided here more likely solves the long-standing question on BT2’s mechanism by which it is conferring therapeutic effects. Furthermore, these studies establish mild uncouplers of mitochondria as promising pharmacological agents for the treatment of cardiovascular and metabolic disease.

Branched-chain amino acid (BCAA) metabolism is linked to glucose homeostasis, but the underlying signaling mechanisms are unclear. We find that gluconeogenesis is reduced in mice deficient of Ppm1k, a positive regulator of BCAA catabolism, which protects against obesity-induced glucose intolerance. Accumulation of branched-chain keto acids (BCKAs) inhibits glucose production in hepatocytes. BCKAs suppress liver mitochondrial pyruvate carrier (MPC) activity and pyruvate-supported respiration. Pyruvate-supported gluconeogenesis is selectively suppressed in Ppm1k-deficient mice and can be restored with pharmacological activation of BCKA catabolism by BT2. Finally, hepatocytes lack branched-chain aminotransferase that alleviates BCKA accumulation via reversible conversion between BCAAs and BCKAs. This renders liver MPC most susceptible to circulating BCKA levels hence a sensor of BCAA catabolism.

The increasing number of people diagnosed with diabetes (type 2) is a global issue. Reduced sensitivity to insulin is the most significant risk factor for developing diabetes, and it always precedes the onset of the disease. There is evidence that a disruption in the metabolism of branched-chain amino acids, also known as BCAAs, plays an increasingly important role in the development of diabetes. It has been shown that BCAA levels are elevated in the blood of individuals with insulin resistance and diabetes, possibly due to a lower BCAA breakdown. This thesis focuses on the role of BCAA breakdown as a cause of diabetes and promoting BCAA breakdown as a new treatment for diabetes. The studies outlined in this thesis demonstrate that the increased BCAA levels in the blood are associated with the degree of insulin sensitivity and other metabolic disruptions. The results indicate that diabetic patients have impaired BCAA breakdown, which could potentially explain the elevated BCAA levels in these patients. This thesis also demonstrates that stimulating BCAA breakdown improves blood glucose regulation and could, therefore, be a new treatment strategy.

Liver cirrhosis is commonly associated with nutritional alterations, reported in 20% of patients with compensated disease and over 60% of patients with decompensated cirrhosis. Nutritional disturbances are associated with a worse prognosis and increased risk of complication. Serum levels of branched-chain amino acids (BCAAs) are decreased in patients with liver cirrhosis. The imbalance of amino acids levels has been suggested to be associated with the development of complications, such as hepatic encephalopathy and sarcopenia, and to affect the clinical presentation and prognosis of these patients. Several studies investigated the efficacy of BCAAs supplementation as a therapeutic option in liver cirrhosis, but uncertainties remain about the real efficacy, the best route of administration, and dosage.

Obesity is a global pandemic, but there is yet no effective measure to control it. Recent metabolomics studies have identified a signature of altered amino acid profiles to be associated with obesity, but it is unclear whether these findings have actionable clinical potential. The aims of this study were to reveal the metabolic alterations of obesity and to explore potential strategies to mitigate obesity. We performed targeted metabolomic profiling of the plasma/serum samples collected from six independent cohorts and conducted an individual data meta-analysis of metabolomics for body mass index (BMI) and obesity. Based on the findings, we hypothesized that restriction of branched-chain amino acids (BCAAs), phenylalanine, or tryptophan may prevent obesity and tested our hypothesis in a dietary restriction trial with eight groups of 4-week-old male C57BL/6J mice (n = 5/group) on eight different types of diets, respectively, for 16 weeks. A total of 3397 individuals were included in the meta-analysis. The mean BMI was 30.7 ± 6.1 kg/m2, and 49% of participants were obese. Fifty-eight metabolites were associated with BMI and obesity (all p ≤ 2.58 × 10-4), linked to alterations of the BCAA, phenylalanine, tryptophan, and phospholipid metabolic pathways. The restriction of BCAAs within a high-fat diet (HFD) maintained the mice's weight, fat and lean volume, subcutaneous and visceral adipose tissue weight, and serum glucose and insulin at levels similar to those in the standard chow group, and prevented obesity, adipocyte hypertrophy, adipose inflammation, and insulin resistance induced by HFD. Our data suggest that four metabolic pathways, BCAA, phenylalanine, tryptophan, and phospholipid metabolic pathways, are altered in obesity and restriction of BCAAs within a HFD can prevent the development of obesity and insulin resistance in mice, providing a promising strategy to potentially mitigate diet-induced obesity.

Background & aims: Circulating levels of acylcarnitines (ACs) have been associated with the risk of various diseases such as cancer and type 2 diabetes. Diet and lifestyle factors have been shown to influence AC concentrations but a better understanding of their biological, lifestyle and metabolic determinants is needed. Methods: Circulating ACs were measured in blood by targeted (15 ACs) and untargeted metabolomics (50 ACs) in 7770 and 395 healthy participants of the European Prospective Investigation into Cancer and Nutrition (EPIC), respectively. Associations with biological and lifestyle characteristics, dietary patterns, self-reported intake of individual foods, estimated intake of carnitine and fatty acids, and fatty acids in plasma phospholipid fraction and amino acids in blood were assessed. Results: Age, sex and fasting status were associated with the largest proportion of AC variability (partial-r up to 0.19, 0.18 and 0.16, respectively). Some AC species of medium or long-chain fatty acid moiety were associated with the corresponding fatty acids in plasma (partial-r = 0.24) or with intake of specific foods such as dairy foods containing the same fatty acid. ACs of short-chain fatty acid moiety (propionylcarnitine and valerylcarnitine) were moderately associated with concentrations of branched-chain amino acids (partial-r = 0.5). Intake of most other foods and of carnitine showed little association with AC levels. Conclusions: Our results show that determinants of ACs in blood vary according to their fatty acid moiety, and that their concentrations are related to age, sex, diet, and fasting status. Knowledge on their potential determinants may help interpret associations of ACs with disease risk and inform on potential dietary and lifestyle factors that might be modified for disease prevention.

Background & aims: Circulating levels of acylcarnitines (ACs) have been associated with the risk of various diseases such as cancer and type 2 diabetes. Diet and lifestyle factors have been shown to influence AC concentrations but a better understanding of their biological, lifestyle and metabolic determinants is needed. Methods: Circulating ACs were measured in blood by targeted (15 ACs) and untargeted metabolomics (50 ACs) in 7770 and 395 healthy participants of the European Prospective Investigation into Cancer and Nutrition (EPIC), respectively. Associations with biological and lifestyle characteristics, dietary patterns, self-reported intake of individual foods, estimated intake of carnitine and fatty acids, and fatty acids in plasma phospholipid fraction and amino acids in blood were assessed. Results: Age, sex and fasting status were associated with the largest proportion of AC variability (partial-r up to 0.19, 0.18 and 0.16, respectively). Some AC species of medium or long-chain fatty acid moiety were associated with the corresponding fatty acids in plasma (partial-r = 0.24) or with intake of specific foods such as dairy foods containing the same fatty acid. ACs of short-chain fatty acid moiety (propionylcarnitine and valerylcarnitine) were moderately associated with concentrations of branched-chain amino acids (partial-r = 0.5). Intake of most other foods and of carnitine showed little association with AC levels. Conclusions: Our results show that determinants of ACs in blood vary according to their fatty acid moiety, and that their concentrations are related to age, sex, diet, and fasting status. Knowledge on their potential determinants may help interpret associations of ACs with disease risk and inform on potential dietary and lifestyle factors that might be modified for disease prevention.

Background & aims: Circulating levels of acylcarnitines (ACs) have been associated with the risk of various diseases such as cancer and type 2 diabetes. Diet and lifestyle factors have been shown to influence AC concentrations but a better understanding of their biological, lifestyle and metabolic determinants is needed. Methods: Circulating ACs were measured in blood by targeted (15 ACs) and untargeted metabolomics (50 ACs) in 7770 and 395 healthy participants of the European Prospective Investigation into Cancer and Nutrition (EPIC), respectively. Associations with biological and lifestyle characteristics, dietary patterns, self-reported intake of individual foods, estimated intake of carnitine and fatty acids, and fatty acids in plasma phospholipid fraction and amino acids in blood were assessed. Results: Age, sex and fasting status were associated with the largest proportion of AC variability (partial-r up to 0.19, 0.18 and 0.16, respectively). Some AC species of medium or long-chain fatty acid moiety were associated with the corresponding fatty acids in plasma (partial-r = 0.24) or with intake of specific foods such as dairy foods containing the same fatty acid. ACs of short-chain fatty acid moiety (propionylcarnitine and valerylcarnitine) were moderately associated with concentrations of branched-chain amino acids (partial-r = 0.5). Intake of most other foods and of carnitine showed little association with AC levels. Conclusions: Our results show that determinants of ACs in blood vary according to their fatty acid moiety, and that their concentrations are related to age, sex, diet, and fasting status. Knowledge on their potential determinants may help interpret associations of ACs with disease risk and inform on potential dietary and lifestyle factors that might be modified for disease prevention.

Background & aims: Circulating levels of acylcarnitines (ACs) have been associated with the risk of various diseases such as cancer and type 2 diabetes. Diet and lifestyle factors have been shown to influence AC concentrations but a better understanding of their biological, lifestyle and metabolic determinants is needed. Methods: Circulating ACs were measured in blood by targeted (15 ACs) and untargeted metabolomics (50 ACs) in 7770 and 395 healthy participants of the European Prospective Investigation into Cancer and Nutrition (EPIC), respectively. Associations with biological and lifestyle characteristics, dietary patterns, self-reported intake of individual foods, estimated intake of carnitine and fatty acids, and fatty acids in plasma phospholipid fraction and amino acids in blood were assessed. Results: Age, sex and fasting status were associated with the largest proportion of AC variability (partial-r up to 0.19, 0.18 and 0.16, respectively). Some AC species of medium or long-chain fatty acid moiety were associated with the corresponding fatty acids in plasma (partial-r = 0.24) or with intake of specific foods such as dairy foods containing the same fatty acid. ACs of short-chain fatty acid moiety (propionylcarnitine and valerylcarnitine) were moderately associated with concentrations of branched-chain amino acids (partial-r = 0.5). Intake of most other foods and of carnitine showed little association with AC levels. Conclusions: Our results show that determinants of ACs in blood vary according to their fatty acid moiety, and that their concentrations are related to age, sex, diet, and fasting status. Knowledge on their potential determinants may help interpret associations of ACs with disease risk and inform on potential dietary and lifestyle factors that might be modified for disease prevention.

Obesity is a global pandemic, but there is yet no effective measure to control it. Recent metabolomics studies have identified a signature of altered amino acid profiles to be associated with obesity, but it is unclear whether these findings have actionable clinical potential. The aims of this study were to reveal the metabolic alterations of obesity and to explore potential strategies to mitigate obesity. We performed targeted metabolomic profiling of the plasma/serum samples collected from six independent cohorts and conducted an individual data meta-analysis of metabolomics for body mass index (BMI) and obesity. Based on the findings, we hypothesized that restriction of branched-chain amino acids (BCAAs), phenylalanine, or tryptophan may prevent obesity and tested our hypothesis in a dietary restriction trial with eight groups of 4-week-old male C57BL/6J mice (n = 5/group) on eight different types of diets, respectively, for 16 weeks. A total of 3397 individuals were included in the meta-analysis. The mean BMI was 30.7 ± 6.1 kg/m2, and 49% of participants were obese. Fifty-eight metabolites were associated with BMI and obesity (all p ≤ 2.58 × 10-4), linked to alterations of the BCAA, phenylalanine, tryptophan, and phospholipid metabolic pathways. The restriction of BCAAs within a high-fat diet (HFD) maintained the mice's weight, fat and lean volume, subcutaneous and visceral adipose tissue weight, and serum glucose and insulin at levels similar to those in the standard chow group, and prevented obesity, adipocyte hypertrophy, adipose inflammation, and insulin resistance induced by HFD. Our data suggest that four metabolic pathways, BCAA, phenylalanine, tryptophan, and phospholipid metabolic pathways, are altered in obesity and restriction of BCAAs within a HFD can prevent the development of obesity and insulin resistance in mice, providing a promising strategy to potentially mitigate diet-induced obesity.

Plasma levels of branched-chain amino acids (BCAA) and aromatic amino acids (AAA) are considered early metabolic markers of obesity and insulin resistance (IR). This study aimed to assess changes in plasma concentrations of BCAA/AAA and HOMA-IR2 (homeostasis model assessment of IR) after intervention-induced modifications in fat mass (FM) and fat-free mass (FFM) among French Polynesian adolescents. FM, FFM, plasma levels of BCAA and AAA, HOMA-IR2 were recorded at baseline and post intervention among 226 adolescents during a 5-month school-based intervention on diet and physical activity. Participants were divided into two subgroups according to their college attendance status which determined their intervention adherence: externs/half-residents (n = 157) and residents (n = 69). Four ordinal categories of body composition changes post-intervention were created for the analysis (FMgain/FFMlost < FMgain/FFMgain < FMlost/FFMlost < FMlost/FFMgain). After 5 months, changes in BCAA (p−trend < 0.001) and AAA (p−trend = 0.007) concentrations were positively associated with ordinal categories of body composition. HOMA-IR2 significantly decreased with FMlost (−0.40; 95% CI, −0.60 to −0.20) and increased with FMgain (0.23; 95% CI, 0.11 to 0.36). Our results suggest that FM loss is associated with a decrease in concentrations of obesity and IR metabolic markers which is more substantial when FM loss is accompanied with FFM gain.

Plasma levels of branched-chain amino acids (BCAA) and aromatic amino acids (AAA) are considered early metabolic markers of obesity and insulin resistance (IR). This study aimed to assess changes in plasma concentrations of BCAA/AAA and HOMA-IR2 (homeostasis model assessment of IR) after intervention-induced modifications in fat mass (FM) and fat-free mass (FFM) among French Polynesian adolescents. FM, FFM, plasma levels of BCAA and AAA, HOMA-IR2 were recorded at baseline and post intervention among 226 adolescents during a 5-month school-based intervention on diet and physical activity. Participants were divided into two subgroups according to their college attendance status which determined their intervention adherence: externs/half-residents (n = 157) and residents (n = 69). Four ordinal categories of body composition changes post-intervention were created for the analysis (FMgain/FFMlost < FMgain/FFMgain < FMlost/FFMlost < FMlost/FFMgain). After 5 months, changes in BCAA (p−trend < 0.001) and AAA (p−trend = 0.007) concentrations were positively associated with ordinal categories of body composition. HOMA-IR2 significantly decreased with FMlost (−0.40; 95% CI, −0.60 to −0.20) and increased with FMgain (0.23; 95% CI, 0.11 to 0.36). Our results suggest that FM loss is associated with a decrease in concentrations of obesity and IR metabolic markers which is more substantial when FM loss is accompanied with FFM gain.

Background & aims: Circulating levels of acylcarnitines (ACs) have been associated with the risk of various diseases such as cancer and type 2 diabetes. Diet and lifestyle factors have been shown to influence AC concentrations but a better understanding of their biological, lifestyle and metabolic determinants is needed. Methods: Circulating ACs were measured in blood by targeted (15 ACs) and untargeted metabolomics (50 ACs) in 7770 and 395 healthy participants of the European Prospective Investigation into Cancer and Nutrition (EPIC), respectively. Associations with biological and lifestyle characteristics, dietary patterns, self-reported intake of individual foods, estimated intake of carnitine and fatty acids, and fatty acids in plasma phospholipid fraction and amino acids in blood were assessed. Results: Age, sex and fasting status were associated with the largest proportion of AC variability (partial-r up to 0.19, 0.18 and 0.16, respectively). Some AC species of medium or long-chain fatty acid moiety were associated with the corresponding fatty acids in plasma (partial-r = 0.24) or with intake of specific foods such as dairy foods containing the same fatty acid. ACs of short-chain fatty acid moiety (propionylcarnitine and valerylcarnitine) were moderately associated with concentrations of branched-chain amino acids (partial-r = 0.5). Intake of most other foods and of carnitine showed little association with AC levels. Conclusions: Our results show that determinants of ACs in blood vary according to their fatty acid moiety, and that their concentrations are related to age, sex, diet, and fasting status. Knowledge on their potential determinants may help interpret associations of ACs with disease risk and inform on potential dietary and lifestyle factors that might be modified for disease prevention.

Background & aims: Circulating levels of acylcarnitines (ACs) have been associated with the risk of various diseases such as cancer and type 2 diabetes. Diet and lifestyle factors have been shown to influence AC concentrations but a better understanding of their biological, lifestyle and metabolic determinants is needed. Methods: Circulating ACs were measured in blood by targeted (15 ACs) and untargeted metabolomics (50 ACs) in 7770 and 395 healthy participants of the European Prospective Investigation into Cancer and Nutrition (EPIC), respectively. Associations with biological and lifestyle characteristics, dietary patterns, self-reported intake of individual foods, estimated intake of carnitine and fatty acids, and fatty acids in plasma phospholipid fraction and amino acids in blood were assessed. Results: Age, sex and fasting status were associated with the largest proportion of AC variability (partial-r up to 0.19, 0.18 and 0.16, respectively). Some AC species of medium or long-chain fatty acid moiety were associated with the corresponding fatty acids in plasma (partial-r = 0.24) or with intake of specific foods such as dairy foods containing the same fatty acid. ACs of short-chain fatty acid moiety (propionylcarnitine and valerylcarnitine) were moderately associated with concentrations of branched-chain amino acids (partial-r = 0.5). Intake of most other foods and of carnitine showed little association with AC levels. Conclusions: Our results show that determinants of ACs in blood vary according to their fatty acid moiety, and that their concentrations are related to age, sex, diet, and fasting status. Knowledge on their potential determinants may help interpret associations of ACs with disease risk and inform on potential dietary and lifestyle factors that might be modified for disease prevention.

Non-alcoholic steatohepatitis (NASH) is associated with a disturbed metabolism in liver, insulin resistance, and excessive accumulation of ectopic fat. Branched-chain amino acids (BCAAs) may beneficially modulate hepatic lipids, however, it remains unclear whether individual BCAAs can attenuate already established NASH and associated oxidative-inflammatory stress. After a 26 weeks run-in on fast food diet (FFD), obese Ldlr−/−.Leiden mice were treated for another 12 weeks with either valine or isoleucine (3% of FFD) and then compared to FFD controls. Valine and isoleucine did not affect obesity, dyslipidemia, gut permeability, or fecal fatty acid excretion, but significantly reduced hyperinsulinemia. Valine and isoleucine reduced ALT, CK18-M30, and liver steatosis with a particularly pronounced suppression of the microvesicular component (−61% by valine and −71% by isoleucine). Both BCAAs decreased intrahepatic diacylglycerols and 4-hydroxynonenal immunoreactivity, a marker for oxidative stress-induced lipid peroxidation. Functional genomics analysis demonstrated that valine and isoleucine affected BCAA metabolism genes, deactivated master regulators of anabolic pathways related to steatosis (e.g., SREBPF1), and activated master regulators of mitochondrial biogenesis (e.g., PPARGC1A) and lipid catabolism (e.g., ACOX1, AMPK). This correction of critical metabolic pathways on gene expression level was accompanied by a significant decrease in histological liver inflammation, and suppression of FFD-stimulated cytokine and chemokine proteins KC/CXCL1, MCP-1/CCL2, and MIP-2/CXCL2 and their pathways. In conclusion, dietary intervention with either valine or isoleucine corrected liver diacylglycerols, gene expression of multiple metabolic processes, and reduced NASH histology with profound hepatoprotective effects on oxidative stress and inflammatory proteins.

Background & aims: Circulating levels of acylcarnitines (ACs) have been associated with the risk of various diseases such as cancer and type 2 diabetes. Diet and lifestyle factors have been shown to influence AC concentrations but a better understanding of their biological, lifestyle and metabolic determinants is needed. Methods: Circulating ACs were measured in blood by targeted (15 ACs) and untargeted metabolomics (50 ACs) in 7770 and 395 healthy participants of the European Prospective Investigation into Cancer and Nutrition (EPIC), respectively. Associations with biological and lifestyle characteristics, dietary patterns, self-reported intake of individual foods, estimated intake of carnitine and fatty acids, and fatty acids in plasma phospholipid fraction and amino acids in blood were assessed. Results: Age, sex and fasting status were associated with the largest proportion of AC variability (partial-r up to 0.19, 0.18 and 0.16, respectively). Some AC species of medium or long-chain fatty acid moiety were associated with the corresponding fatty acids in plasma (partial-r = 0.24) or with intake of specific foods such as dairy foods containing the same fatty acid. ACs of short-chain fatty acid moiety (propionylcarnitine and valerylcarnitine) were moderately associated with concentrations of branched-chain amino acids (partial-r = 0.5). Intake of most other foods and of carnitine showed little association with AC levels. Conclusions: Our results show that determinants of ACs in blood vary according to their fatty acid moiety, and that their concentrations are related to age, sex, diet, and fasting status. Knowledge on their potential determinants may help interpret associations of ACs with disease risk and inform on potential dietary and lifestyle factors that might be modified for disease prevention.

Background & aims: Circulating levels of acylcarnitines (ACs) have been associated with the risk of various diseases such as cancer and type 2 diabetes. Diet and lifestyle factors have been shown to influence AC concentrations but a better understanding of their biological, lifestyle and metabolic determinants is needed. Methods: Circulating ACs were measured in blood by targeted (15 ACs) and untargeted metabolomics (50 ACs) in 7770 and 395 healthy participants of the European Prospective Investigation into Cancer and Nutrition (EPIC), respectively. Associations with biological and lifestyle characteristics, dietary patterns, self-reported intake of individual foods, estimated intake of carnitine and fatty acids, and fatty acids in plasma phospholipid fraction and amino acids in blood were assessed. Results: Age, sex and fasting status were associated with the largest proportion of AC variability (partial-r up to 0.19, 0.18 and 0.16, respectively). Some AC species of medium or long-chain fatty acid moiety were associated with the corresponding fatty acids in plasma (partial-r = 0.24) or with intake of specific foods such as dairy foods containing the same fatty acid. ACs of short-chain fatty acid moiety (propionylcarnitine and valerylcarnitine) were moderately associated with concentrations of branched-chain amino acids (partial-r = 0.5). Intake of most other foods and of carnitine showed little association with AC levels. Conclusions: Our results show that determinants of ACs in blood vary according to their fatty acid moiety, and that their concentrations are related to age, sex, diet, and fasting status. Knowledge on their potential determinants may help interpret associations of ACs with disease risk and inform on potential dietary and lifestyle factors that might be modified for disease prevention.

Background & aims: Circulating levels of acylcarnitines (ACs) have been associated with the risk of various diseases such as cancer and type 2 diabetes. Diet and lifestyle factors have been shown to influence AC concentrations but a better understanding of their biological, lifestyle and metabolic determinants is needed. Methods: Circulating ACs were measured in blood by targeted (15 ACs) and untargeted metabolomics (50 ACs) in 7770 and 395 healthy participants of the European Prospective Investigation into Cancer and Nutrition (EPIC), respectively. Associations with biological and lifestyle characteristics, dietary patterns, self-reported intake of individual foods, estimated intake of carnitine and fatty acids, and fatty acids in plasma phospholipid fraction and amino acids in blood were assessed. Results: Age, sex and fasting status were associated with the largest proportion of AC variability (partial-r up to 0.19, 0.18 and 0.16, respectively). Some AC species of medium or long-chain fatty acid moiety were associated with the corresponding fatty acids in plasma (partial-r = 0.24) or with intake of specific foods such as dairy foods containing the same fatty acid. ACs of short-chain fatty acid moiety (propionylcarnitine and valerylcarnitine) were moderately associated with concentrations of branched-chain amino acids (partial-r = 0.5). Intake of most other foods and of carnitine showed little association with AC levels. Conclusions: Our results show that determinants of ACs in blood vary according to their fatty acid moiety, and that their concentrations are related to age, sex, diet, and fasting status. Knowledge on their potential determinants may help interpret associations of ACs with disease risk and inform on potential dietary and lifestyle factors that might be modified for disease prevention.

Recent evidence shows that obesity correlates negatively with bone mass. However, traditional anthropometric measures such as body mass index could not discriminate visceral adipose tissue from subcutaneous adipose tissue. The visceral adiposity index (VAI) is a reliable sex-specified indicator of visceral adipose distribution and function. Thus, we aimed to identify metabolomic profiles associated with VAI and low bone mineral density (BMD). A total of 602 individuals from the Health Workers Cohort Study were included. Forty serum metabolites were measured using the targeted metabolomics approach, and multivariate regression models were used to test associations of metabolomic profiles with anthropometric, clinical, and biochemical parameters. The analysis showed a serum amino acid signature composed of glycine, leucine, arginine, valine, and acylcarnitines associated with high VAI and low BMD. In addition, we found a sex-dependent VAI in pathways related to primary bile acid biosynthesis, branched-chain amino acids, and the biosynthesis of pantothenate and coenzyme A (CoA). In conclusion, a metabolic profile differs by VAI and BMD status, and these changes are gender-dependent.

Background: Liver cirrhosis is the irreversible fibrosis of the liver and causes refractory ascites and hepatic encephalopathy, which might not respond to treatment. Living donor liver transplantation (LDLT) is an effective treatment for patients with cirrhosis. However, post-LDLT patients are prone to muscle atrophy and sarcopenia. Therefore, physiotherapy of post-LDLT patients is essential for preventing the progression of sarcopenia. Recently, rehabilitation using neuromuscular electrical stimulation (NMES) has been reported to be useful for preventing the progression of sarcopenia. Similarly, nutrition therapy is essential for post-LDLT patients because these patients frequently experience malnutrition. However, the effects of combined NMES and nutrition therapy on post-LDLT patients remain unknown. Methods/design: This open-label, randomized, parallel-group study will compare the effects of combined therapy with NMES and branched-chain amino acids (BCAA) with those of NMES alone in patients with decompensated cirrhosis after LDLT. After LDLT, 50 patients with decompensated cirrhosis will be randomly assigned to receive NMES with BCAA or NMES without BCAA. The duration of the intervention will be 3 months. To analyze the change in skeletal muscle mass, InBody 770 body composition and body water analysis and ultrasonography will be performed before LDLT and 4 weeks and 12 weeks post-LDLT. The primary endpoint is changes in the skeletal muscle mass from baseline to 3 months. Important secondary endpoints are the changes in the skeletal muscle mass from baseline to 1 month and changes in the quadriceps strength from baseline to 1 month. Discussion: The results of this study are expected to provide evidence regarding the effect of NMES combined with BCAA therapy on the skeletal muscle of post-LDLT patients. Trial registration: Japan Registry of Clinical Research jRCTs071190051. Registered on February 26, 2020., Trials, 22(1), art.no.137; 2021

Low-protein diets promote metabolic health in rodents and humans, and the benefits of low-protein diets are recapitulated by specifically reducing dietary levels of the three branched-chain amino acids (BCAAs), leucine, isoleucine, and valine. Here, we demonstrate that each BCAA has distinct metabolic effects. A low isoleucine diet reprograms liver and adipose metabolism, increasing hepatic insulin sensitivity and ketogenesis and increasing energy expenditure, activating the FGF21-UCP1 axis. Reducing valine induces similar but more modest metabolic effects, whereas these effects are absent with low leucine. Reducing isoleucine or valine rapidly restores metabolic health to diet-induced obese mice. Finally, we demonstrate that variation in dietary isoleucine levels helps explain body mass index differences in humans. Our results reveal isoleucine as a key regulator of metabolic health and the adverse metabolic response to dietary BCAAs and suggest reducing dietary isoleucine as a new approach to treating and preventing obesity and diabetes.

A collection of 33 Saccharomyces yeasts were used for wine fermentation with a sole nitrogen source: ammonium and four individual aroma-inducing amino acids. The fermentation performance and chemical wine composition were evaluated. The most valuable nitrogen sources were valine as a fermentation promoter on non-cerevisiae strains, phenylalanine as fruity aromas enhancer whereas the ethanol yield was lessened by leucine and isoleucine. S. cerevisiae SC03 and S. kudriavzevii SK02 strains showed to be the greatest producers of fruity ethyl esters while S. kudriavzevii strains SK06 and SK07 by shortening the fermentation duration. S. uvarum strains produced the greatest succinic acid amounts and, together with S. eubayanus, they reached the highest production of 2-phenylethanol and its acetate ester; whereas S. kudriavzevii strains were found to be positively related to high glycerol production.

Water deficit has a global impact on plant growth and crop yield. Climate changes are going to increase the intensity, duration and frequency of severe droughts, particularly in southern and south-eastern Europe, elevating the water scarcity issues. We aimed to assess the contribution of endogenous abscisic acid (ABA) in the protective mechanisms against water deficit, including stomatal conductance, relative water potential and the accumulation of osmoprotectants, as well as on growth parameters. To achieve that, we used a suitable model system, ABA-deficient tomato mutant, flacca and its parental line. Flacca mutant exhibited constitutively higher levels of soluble sugars (e.g., galactose, arabinose, sorbitol) and free amino acids (AAs) compared with the wild type (WT). Water deficit provoked the strong accumulation of proline in both genotypes, and total soluble sugars only in flacca. Upon re-watering, these osmolytes returned to the initial levels in both genotypes. Our results indicate that flacca compensated higher stomatal conductance with a higher constitutive level of free sugars and AAs. Additionally, we suggest that the accumulation of AAs, particularly proline and its precursors and specific branched-chain AAs in both, glucose and sucrose in flacca, and sorbitol in WT, could contribute to maintaining growth rate during water deficit and recovery in both tomato genotypes.

Background: Subjects with morbid obesity have low levels of serum branched-chain fatty acids (BCFAs), which correlate inversely with insulin resistance, hypertriglyceridemia, and inflammation. Recent evidence suggests BCFAs are produced during branched-chain amino acid (BCAA) catabolism in human adipose tissue. Elevated concentrations of BCAAs are associated with insulin resistance.Objectives: In this single-center study, we evaluated the effect of one anastomosis gastric bypass (OAGB) on circulating BCFA and BCAA. Moreover, we determined the expression of genes involved in BCAA catabolism in adipose tissue of patients with obesity and lean controls.Methods: Fasting levels of BCFAs and BCAAs were determined by gas and liquid chromatography, respectively, coupled with mass spectrometry, in 50 patients with morbid obesity before and 6-9 months after surgery, and in 32 lean controls. Visceral and subcutaneous adipose tissue (VAT and SAT, respectively) biopsies were collected at baseline to determine mRNA levels for enzymes involved in BCAA catabolism.Results: Before surgery, patients with obesity had lower BCFAs and greater BCAAs than control subjects. OAGB increased BCFA and decreased BCAA levels. Insulin resistance (assessed by HOMA) correlated inversely with BCFAs and positively with BCAAs. Expression of genes involved in BCAA catabolism in VAT (but not SAT) was lower in patients with obesity than in lean controls.Conclusions: OAGB-induced weight loss increases circulating BCFAs and decreases circulating BCAAs in patients with morbid obesity, perhaps by altering BCAA catabolism in VAT. We speculate that this shift may be related to the improvement in insulin sensitivity after surgery.

Cardiovascular disease is the leading global health concern and responsible for more deaths worldwide than any other type of disorder. Atherosclerosis is a chronic inflammatory disease in the arterial wall, which underpins several types of cardiovascular disease. It has emerged that a strong relationship exists between alterations in amino acid (AA) metabolism and the development of atherosclerosis. Recent studies have reported positive correlations between levels of branched-chain amino acids (BCAAs) such as leucine, valine, and isoleucine in plasma and the occurrence of metabolic disturbances. Elevated serum levels of BCAAs indicate a high cardiometabolic risk. Thus, BCAAs may also impact atherosclerosis prevention and offer a novel therapeutic strategy for specific individuals at risk of coronary events. The metabolism of AAs, such as L-arginine, homoarginine, and L-tryptophan, is recognized as a critical regulator of vascular homeostasis. Dietary intake of homoarginine, taurine, and glycine can improve atherosclerosis by endothelium remodeling. Available data also suggest that the regulation of AA metabolism by indoleamine 2,3-dioxygenase (IDO) and arginases 1 and 2 are mediated through various immunological signals and that immunosuppressive AA metabolizing enzymes are promising therapeutic targets against atherosclerosis. Further clinical studies and basic studies that make use of animal models are required. Here we review recent data examining links between AA metabolism and the development of atherosclerosis.

Water deficit has a global impact on plant growth and crop yield. Climate changes are going to increase the intensity, duration and frequency of severe droughts, particularly in southern and south-eastern Europe, elevating the water scarcity issues. We aimed to assess the contribution of endogenous abscisic acid (ABA) in the protective mechanisms against water deficit, including stomatal conductance, relative water potential and the accumulation of osmoprotectants, as well as on growth parameters. To achieve that, we used a suitable model system, ABA-deficient tomato mutant, flacca and its parental line. Flacca mutant exhibited constitutively higher levels of soluble sugars (e.g., galactose, arabinose, sorbitol) and free amino acids (AAs) compared with the wild type (WT). Water deficit provoked the strong accumulation of proline in both genotypes, and total soluble sugars only in flacca. Upon re-watering, these osmolytes returned to the initial levels in both genotypes. Our results indicate that flacca compensated higher stomatal conductance with a higher constitutive level of free sugars and AAs. Additionally, we suggest that the accumulation of AAs, particularly proline and its precursors and specific branched-chain AAs in both, glucose and sucrose in flacca, and sorbitol in WT, could contribute to maintaining growth rate during water deficit and recovery in both tomato genotypes.

Background: Metabolic profiles have been shown to be associated to obesity status and insulin sensitivity. Dietary intakes influence metabolic pathways and therefore, different dietary patterns may relate to modifications in metabolic signatures. The objective was to verify associations between dietary patterns and metabolic profiles composed of amino acids (AAs) and acylcarnitines (ACs). Methods: 210 participants were recruited in the greater Quebec City area between September 2009 and December 2011. Dietary patterns had been previously derived using principal component analysis (PCA). The Prudent dietary pattern was characterised by higher intakes of vegetables, fruits, whole grain products, non-hydrogenated fat and lower intakes of refined grain products, whereas the Western dietary pattern was associated with higher intakes of refined grain products, desserts, sweets and processed meats. Targeted metabolites were quantified in 37 participants with the Biocrates Absolute IDQ p150 (Biocrates Life Sciences AG, Austria) mass spectrometry method (including 14 amino acids and 41 acylcarnitines). Results: PCA analysis with metabolites including AAs and ACs revealed two main components explaining the most variance in overall data (13.8%). PC1 was composed mostly of medium- to long-chain ACs (C16:2, C14:2, C14:2-OH, C16, C14:1-OH, C14:1, C10:2, C5-DC/C6-OH, C12, C18:2, C10, C4:1-DC/C6, C8:1 and C2) whereas PC2 included certain AAs and short-chain ACs (xLeu, Met, Arg, Phe, Pro, Orn, His, C0, C3, C4 and C5). The Western dietary pattern correlated negatively with PC1 and positively with PC2 (r = −0.34, p = 0.05 and r = 0.38, p = 0.03, respectively), independently of age, sex and BMI. Conclusion: These findings suggest that the Western dietary pattern is associated with a specific metabolite signature characterized by increased levels of AAs including branched-chain AAs (BCAAs) and short-chain ACs.

Elevated plasma branched-chain amino acids (BCAA) and C3 and C5 acylcarnitines (AC) levels observed in individuals with insulin resistance (IR) might be influenced by dietary protein intakes. This study explores the associations between dietary protein sources, plasma BCAA levels and C3 and C5 ACs in normal weight (NW) or overweight (OW) individuals with or without metabolic syndrome (MS). Data from 199 men and women aged 18–55 years with complete metabolite profile were analyzed. Associations between metabolic parameters, protein sources, plasma BCAA and AC levels were tested. OW/MS+ consumed significantly more animal protein (p = 0.0388) and had higher plasma BCAA levels (p < 0.0001) than OW/MS− or NW/MS− individuals. Plasma BCAA levels were not associated with BCAA intakes in the whole cohort, while there was a trend for an association between plasma BCAA levels and red meat or with animal protein in OW/MS+. These associations were of weak magnitude. In NW/MS− individuals, the protein sources associated with BCAA levels varied greatly with adjustment for confounders. Plasma C3 and C5 ACs were associated with plasma BCAA levels in the whole cohort (p < 0.0001) and in subgroups based on OW and MS status. These results suggest a modest association of meat or animal protein intakes and an association of C3 and C5 ACs with plasma BCAA levels, obesity and MS.

Purpose of reviewAn increasing body of evidence suggests that the gut microbiome influences the pathogenesis of insulin resistance and type 2 diabetes (T2D). In this review, we will discuss the latest findings regarding the mechanisms linking the gut microbiome and microbial metabolites with T2D and therapeutic approaches based on the gut microbiota for the prevention and treatment of T2D.Recent findingsAlterations in the gut microbial composition are associated with the risk of T2D. The gut microbiota can metabolize dietary- and host-derived factors to produce numerous microbial metabolites, which are involved in metabolic processes modulating nutrition and energy harvest, gut barrier function, systemic inflammation, and glucose metabolism. Microbial metabolites are important mediators of microbial-host crosstalk impacting host glucose metabolism. Furthermore, microbiome-based interventions may have beneficial effects on glycemic control. Future research is required to develop personalized T2D therapy based on microbial composition and/or metabolites.

Water deficit has a global impact on plant growth and crop yield. Climate changes are going to increase the intensity, duration and frequency of severe droughts, particularly in southern and south-eastern Europe, elevating the water scarcity issues. We aimed to assess the contribution of endogenous abscisic acid (ABA) in the protective mechanisms against water deficit, including stomatal conductance, relative water potential and the accumulation of osmoprotectants, as well as on growth parameters. To achieve that, we used a suitable model system, ABA-deficient tomato mutant, flacca and its parental line. Flacca mutant exhibited constitutively higher levels of soluble sugars (e.g., galactose, arabinose, sorbitol) and free amino acids (AAs) compared with the wild type (WT). Water deficit provoked the strong accumulation of proline in both genotypes, and total soluble sugars only in flacca. Upon re-watering, these osmolytes returned to the initial levels in both genotypes. Our results indicate that flacca compensated higher stomatal conductance with a higher constitutive level of free sugars and AAs. Additionally, we suggest that the accumulation of AAs, particularly proline and its precursors and specific branched-chain AAs in both, glucose and sucrose in flacca, and sorbitol in WT, could contribute to maintaining growth rate during water deficit and recovery in both tomato genotypes.

Water deficit has a global impact on plant growth and crop yield. Climate changes are going to increase the intensity, duration and frequency of severe droughts, particularly in southern and south-eastern Europe, elevating the water scarcity issues. We aimed to assess the contribution of endogenous abscisic acid (ABA) in the protective mechanisms against water deficit, including stomatal conductance, relative water potential and the accumulation of osmoprotectants, as well as on growth parameters. To achieve that, we used a suitable model system, ABA-deficient tomato mutant, flacca and its parental line. Flacca mutant exhibited constitutively higher levels of soluble sugars (e.g., galactose, arabinose, sorbitol) and free amino acids (AAs) compared with the wild type (WT). Water deficit provoked the strong accumulation of proline in both genotypes, and total soluble sugars only in flacca. Upon re-watering, these osmolytes returned to the initial levels in both genotypes. Our results indicate that flacca compensated higher stomatal conductance with a higher constitutive level of free sugars and AAs. Additionally, we suggest that the accumulation of AAs, particularly proline and its precursors and specific branched-chain AAs in both, glucose and sucrose in flacca, and sorbitol in WT, could contribute to maintaining growth rate during water deficit and recovery in both tomato genotypes.

Cardiovascular disease is the leading global health concern and responsible for more deaths worldwide than any other type of disorder. Atherosclerosis is a chronic inflammatory disease in the arterial wall, which underpins several types of cardiovascular disease. It has emerged that a strong relationship exists between alterations in amino acid (AA) metabolism and the development of atherosclerosis. Recent studies have reported positive correlations between levels of branched-chain amino acids (BCAAs) such as leucine, valine, and isoleucine in plasma and the occurrence of metabolic disturbances. Elevated serum levels of BCAAs indicate a high cardiometabolic risk. Thus, BCAAs may also impact atherosclerosis prevention and offer a novel therapeutic strategy for specific individuals at risk of coronary events. The metabolism of AAs, such as L-arginine, homoarginine, and L-tryptophan, is recognized as a critical regulator of vascular homeostasis. Dietary intake of homoarginine, taurine, and glycine can improve atherosclerosis by endothelium remodeling. Available data also suggest that the regulation of AA metabolism by indoleamine 2,3-dioxygenase (IDO) and arginases 1 and 2 are mediated through various immunological signals and that immunosuppressive AA metabolizing enzymes are promising therapeutic targets against atherosclerosis. Further clinical studies and basic studies that make use of animal models are required. Here we review recent data examining links between AA metabolism and the development of atherosclerosis.

Background: Subjects with morbid obesity have low levels of serum branched-chain fatty acids (BCFAs), which correlate inversely with insulin resistance, hypertriglyceridemia, and inflammation. Recent evidence suggests BCFAs are produced during branched-chain amino acid (BCAA) catabolism in human adipose tissue. Elevated concentrations of BCAAs are associated with insulin resistance.Objectives: In this single-center study, we evaluated the effect of one anastomosis gastric bypass (OAGB) on circulating BCFA and BCAA. Moreover, we determined the expression of genes involved in BCAA catabolism in adipose tissue of patients with obesity and lean controls.Methods: Fasting levels of BCFAs and BCAAs were determined by gas and liquid chromatography, respectively, coupled with mass spectrometry, in 50 patients with morbid obesity before and 6-9 months after surgery, and in 32 lean controls. Visceral and subcutaneous adipose tissue (VAT and SAT, respectively) biopsies were collected at baseline to determine mRNA levels for enzymes involved in BCAA catabolism.Results: Before surgery, patients with obesity had lower BCFAs and greater BCAAs than control subjects. OAGB increased BCFA and decreased BCAA levels. Insulin resistance (assessed by HOMA) correlated inversely with BCFAs and positively with BCAAs. Expression of genes involved in BCAA catabolism in VAT (but not SAT) was lower in patients with obesity than in lean controls.Conclusions: OAGB-induced weight loss increases circulating BCFAs and decreases circulating BCAAs in patients with morbid obesity, perhaps by altering BCAA catabolism in VAT. We speculate that this shift may be related to the improvement in insulin sensitivity after surgery.

Water deficit has a global impact on plant growth and crop yield. Climate changes are going to increase the intensity, duration and frequency of severe droughts, particularly in southern and south-eastern Europe, elevating the water scarcity issues. We aimed to assess the contribution of endogenous abscisic acid (ABA) in the protective mechanisms against water deficit, including stomatal conductance, relative water potential and the accumulation of osmoprotectants, as well as on growth parameters. To achieve that, we used a suitable model system, ABA-deficient tomato mutant, flacca and its parental line. Flacca mutant exhibited constitutively higher levels of soluble sugars (e.g., galactose, arabinose, sorbitol) and free amino acids (AAs) compared with the wild type (WT). Water deficit provoked the strong accumulation of proline in both genotypes, and total soluble sugars only in flacca. Upon re-watering, these osmolytes returned to the initial levels in both genotypes. Our results indicate that flacca compensated higher stomatal conductance with a higher constitutive level of free sugars and AAs. Additionally, we suggest that the accumulation of AAs, particularly proline and its precursors and specific branched-chain AAs in both, glucose and sucrose in flacca, and sorbitol in WT, could contribute to maintaining growth rate during water deficit and recovery in both tomato genotypes.

Background: Subjects with morbid obesity have low levels of serum branched-chain fatty acids (BCFAs), which correlate inversely with insulin resistance, hypertriglyceridemia, and inflammation. Recent evidence suggests BCFAs are produced during branched-chain amino acid (BCAA) catabolism in human adipose tissue. Elevated concentrations of BCAAs are associated with insulin resistance.Objectives: In this single-center study, we evaluated the effect of one anastomosis gastric bypass (OAGB) on circulating BCFA and BCAA. Moreover, we determined the expression of genes involved in BCAA catabolism in adipose tissue of patients with obesity and lean controls.Methods: Fasting levels of BCFAs and BCAAs were determined by gas and liquid chromatography, respectively, coupled with mass spectrometry, in 50 patients with morbid obesity before and 6-9 months after surgery, and in 32 lean controls. Visceral and subcutaneous adipose tissue (VAT and SAT, respectively) biopsies were collected at baseline to determine mRNA levels for enzymes involved in BCAA catabolism.Results: Before surgery, patients with obesity had lower BCFAs and greater BCAAs than control subjects. OAGB increased BCFA and decreased BCAA levels. Insulin resistance (assessed by HOMA) correlated inversely with BCFAs and positively with BCAAs. Expression of genes involved in BCAA catabolism in VAT (but not SAT) was lower in patients with obesity than in lean controls.Conclusions: OAGB-induced weight loss increases circulating BCFAs and decreases circulating BCAAs in patients with morbid obesity, perhaps by altering BCAA catabolism in VAT. We speculate that this shift may be related to the improvement in insulin sensitivity after surgery.

Water deficit has a global impact on plant growth and crop yield. Climate changes are going to increase the intensity, duration and frequency of severe droughts, particularly in southern and south-eastern Europe, elevating the water scarcity issues. We aimed to assess the contribution of endogenous abscisic acid (ABA) in the protective mechanisms against water deficit, including stomatal conductance, relative water potential and the accumulation of osmoprotectants, as well as on growth parameters. To achieve that, we used a suitable model system, ABA-deficient tomato mutant, flacca and its parental line. Flacca mutant exhibited constitutively higher levels of soluble sugars (e.g., galactose, arabinose, sorbitol) and free amino acids (AAs) compared with the wild type (WT). Water deficit provoked the strong accumulation of proline in both genotypes, and total soluble sugars only in flacca. Upon re-watering, these osmolytes returned to the initial levels in both genotypes. Our results indicate that flacca compensated higher stomatal conductance with a higher constitutive level of free sugars and AAs. Additionally, we suggest that the accumulation of AAs, particularly proline and its precursors and specific branched-chain AAs in both, glucose and sucrose in flacca, and sorbitol in WT, could contribute to maintaining growth rate during water deficit and recovery in both tomato genotypes.

Background: South Africa (SA) has the highest global projected increase in diabetes risk. Factors typically associated with insulin resistance and type 2 diabetes risk in Caucasians are not significant correlates in black African populations. Therefore, we aimed to identify circulating metabolite patterns that predict type 2 diabetes development in this high-risk, yet understudied SA population. Methods: We conducted a prospective cohort study in black SA women with normal glucose tolerance (NGT). Participants were followed for 13 years and developed (i) type 2 diabetes (n = 20, NGT-T2D), (ii) impaired glucose tolerance (IGT) (n = 27, NGT-IGT), or (iii) remained NGT (n = 28, NGT-NGT). Mass-spectrometry based metabolomics and multivariate analyses were used to elucidate metabolite patterns at baseline and at follow-up that were associated with type 2 diabetes development. Results: Metabolites of phospholipid, bile acid and branched-chain amino acid (BCAA) metabolism, differed significantly between the NGT-T2D and NGT-NGT groups. At baseline: the NGT-T2D group had i) a higher lysophosphatidylcholine:lysophosphatidylethanolamine ratio containing linoleic acid (LPC(C18:2):LPE(C18:2)), ii) lower proliferation-related bile acids (ursodeoxycholic- and chenodeoxycholic acid), iii) higher levels of leucine and its catabolic intermediates (ketoleucine and C5-carnitine), compared to the NGT-NGT group. At follow-up: the NGT-T2D group had i) lower LPC(C18:2) levels, ii) higher apoptosis-related bile acids (deoxycholic- and glycodeoxycholic acid), and iii) higher levels of all BCAAs and their catabolic intermediates. Conclusions: Changes in lysophospholipid metabolism and the bile acid pool occur during the development of type 2 diabetes in black South African women. Further, impaired leucine catabolism precedes valine and isoleucine catabolism in the development of type 2 diabetes. These metabolite patterns can be useful to identify and monitor type 2 diabetes risk >10 years

Elevated plasma branched-chain amino acids (BCAA) and C3 and C5 acylcarnitines (AC) levels observed in individuals with insulin resistance (IR) might be influenced by dietary protein intakes. This study explores the associations between dietary protein sources, plasma BCAA levels and C3 and C5 ACs in normal weight (NW) or overweight (OW) individuals with or without metabolic syndrome (MS). Data from 199 men and women aged 18–55 years with complete metabolite profile were analyzed. Associations between metabolic parameters, protein sources, plasma BCAA and AC levels were tested. OW/MS+ consumed significantly more animal protein (p = 0.0388) and had higher plasma BCAA levels (p < 0.0001) than OW/MS− or NW/MS− individuals. Plasma BCAA levels were not associated with BCAA intakes in the whole cohort, while there was a trend for an association between plasma BCAA levels and red meat or with animal protein in OW/MS+. These associations were of weak magnitude. In NW/MS− individuals, the protein sources associated with BCAA levels varied greatly with adjustment for confounders. Plasma C3 and C5 ACs were associated with plasma BCAA levels in the whole cohort (p < 0.0001) and in subgroups based on OW and MS status. These results suggest a modest association of meat or animal protein intakes and an association of C3 and C5 ACs with plasma BCAA levels, obesity and MS.

Valine belongs to the group of branched-chain amino acids, has an important structural role and is primarily deposited as body protein. The present study evaluated the effects of valine in diets of juvenile Nile tilapia. A total of 216 juveniles with weight of 21.40 ± 0.42 g and length of 10.07 ± 1.00 cm were distributed into 18 aquarium in a completely randomized design with six treatments and three replicates. Six diets containing 24.30% digestible protein, 3,100 kcal/kg digestible energy, and increasing valine levels (0.54; 0.63; 0.72; 0.81; 0.90; 0.99%) were prepared. The following factors were evaluated: performance, chemical composition, blood hematological and biochemical, and skeletal muscle development. Differences were observed in productive performance between treatments for weight gain, daily weight gain and apparent feed conversion, where inclusion levels from 0.81% to 0.99% provide better performances. According to the equation of quadratic regression, the inclusion of 0.86% of valine provided greater weight gain. Regarding the hematological and biochemical parameters, there were differences among the treatments for hemoglobin, triglycerides, and cholesterol. Not difference was observed for the chemical composition and muscle fiber growth. It is recommended the inclusion of 0.86% of valine in the diet of juveniles of Nile tilapia because it provides greater weight gain.

Valine belongs to the group of branched-chain amino acids, has an important structural role and is primarily deposited as body protein. The present study evaluated the effects of valine in diets of juvenile Nile tilapia. A total of 216 juveniles with weight of 21.40 ± 0.42 g and length of 10.07 ± 1.00 cm were distributed into 18 aquarium in a completely randomized design with six treatments and three replicates. Six diets containing 24.30% digestible protein, 3,100 kcal/kg digestible energy, and increasing valine levels (0.54; 0.63; 0.72; 0.81; 0.90; 0.99%) were prepared. The following factors were evaluated: performance, chemical composition, blood hematological and biochemical, and skeletal muscle development. Differences were observed in productive performance between treatments for weight gain, daily weight gain and apparent feed conversion, where inclusion levels from 0.81% to 0.99% provide better performances. According to the equation of quadratic regression, the inclusion of 0.86% of valine provided greater weight gain. Regarding the hematological and biochemical parameters, there were differences among the treatments for hemoglobin, triglycerides, and cholesterol. Not difference was observed for the chemical composition and muscle fiber growth. It is recommended the inclusion of 0.86% of valine in the diet of juveniles of Nile tilapia because it provides greater weight gain.

The first step in branched-chain amino acid (BCAA) catabolism is catalyzed by the two BCAA transferase isoenzymes, cytoplasmic branched-chain amino acid transferase (BCAT) 1, and mitochondrial BCAT2. Defects in the second step of BCAA catabolism cause maple syrup urine disease (MSUD), a condition which has been far more extensively investigated. Here, we studied the consequences of BCAT2 deficiency, an ultra-rare condition in humans. We present genetic, clinical, and functional data in five individuals from four different families with homozygous or compound heterozygous BCAT2 mutations which were all detected following abnormal biochemical profile results or familial mutation segregation studies. We demonstrate that BCAT2 deficiency has a recognizable biochemical profile with raised plasma BCAAs and, in contrast with MSUD, low-normal branched-chain keto acids (BCKAs) with undetectable l-allo-isoleucine. Interestingly, unlike in MSUD, none of the individuals with BCAT2 deficiency developed acute encephalopathy even with exceptionally high BCAA levels. We observed wide-ranging clinical phenotypes in individuals with BCAT2 deficiency. While one adult was apparently asymptomatic, three individuals had presented with developmental delay and autistic features. We show that the biochemical characteristics of BCAT2 deficiency may be amenable to protein-restricted diet and that early treatment may improve outcome in affected individuals. BCAT2 deficiency is an inborn error of BCAA catabolism. At present, it is unclear whether developmental delay and autism are parts of the variable phenotypic spectrum of this condition or coincidental. Further studies will be required to explore this.

Tato bakalářská práce je psána formou literární rešerše se zaměřením na stanovení aminokyselin s rozvětveným řetězcem. Nejprve je popsána struktura, vlastnosti a dělení aminokyselin. Poté jsou diskutovány fyziologické účinky rozvětvených aminokyselin nejen ve sportu a je popsán jejich metabolismus. Dále se bakalářská práce věnuje analytickému stanovení aminokyselin pomocí HPLC v systémech s obrácenými fázemi a derivatizačním činidlům, které si při jejich stanovení používají. V rámci práce jsou diskutovány jejich výhody i nevýhody., This bachelor thesis is written as a literature research with focusing on the determination of branched-chain amino acids. First, the structure, properties and division of amino acids are described. Then, the physiological effects of branched-chain amino acids are discussed not only in sport and their metabolism is described. Further, the bachelor thesis is devoted to the analytical determination of amino acids by reversed-phase HPLC and to different derivatizing agents which are frequently used during their determination. Their advantages and disadvantages are discussed., Fakulta chemicko-technologická, Studentka seznámila členy zkušební komise s obsahem své bakalářské práce, poté byla seznámena s posudkem vedoucího bakalářské práce. Studentka odpověděla na otázky členů zkušební komise., Dokončená práce s úspěšnou obhajobou

Lowering protein level in diets for piglets urge to have knowledge on the piglet's requirements for essential amino acids (AA) and their interactions. The present studies aimed to determine the interaction between the dietary level of valine (Val) and tryptophan (Trp) and the effect of AA imbalance at two levels of dietary Val on the growth performance of post-weaning piglets. In Experiment 1 (duration 4 weeks), the effects of supplementation of free l-Val (1.0 g/kg) and/or l-Trp (0.5 g/kg) in a low-CP diet (CP 17.7%), marginal in Trp and Val, was studied in a 2×2 factorial design and using an additional reference treatment (CP 19.5%). In Experiment 2 (duration 5 weeks), the influence of a stepwise increase in excess supply of isoleucine (Ile), histidine (His) and leucine (Leu), up to 10, 10% and 30% relative to their requirement values respectively, was evaluated at 60% or 70% standardized ileal digestible (SID) Val relative to SID lysine, using a 3×2 factorial design. In Experiment 1, over the whole experimental period, feed intake (FI) was affected by dietary Trp level (P<0.05) and feed conversion ratio (FCR) by both the level of Trp and Val in the diet (both P<0.05). Increasing Trp level increased FI and decreased FCR while increasing dietary Val level reduced FI and increased FCR. For BW gain (BWG), there was an interaction between dietary level of Trp and Val (P<0.05). Valine supplementation decreased BWG using a diet marginal in Trp, whereas it increased BWG when using a Trp sufficient diet. Piglets fed the low-CP diet with adequate levels of Val and Trp showed at least same performance compared to piglets fed the high CP reference diet. In Experiment 2, increasing dietary Val improved FI and BWG (P<0.001) and tended to improve FCR. Dietary AA excess for Ile, His and Leu reduced FI and BWG (P<0.05) and only affected FCR (P<0.01) in the 1st week of the study. Dietary level of Val and AA excess did not show interactive effects, except for FCR over the final 2 w

Background Visceral adipose tissue (VAT) area is a strong predictor of obesity-related cardiometabolic alterations, but its measurement is costly, time consuming and, in some cases, involves radiation exposure. Glutamate, a by-product of branched-chain-amino-acid (BCAA) catabolism, has been shown to be increased in visceral obese individuals. In this follow-up data analysis, we aimed to investigate the ability of plasma glutamate to identify individuals with visceral obesity and concomitant metabolic alterations. Methods Measurements of adiposity, targeted blood metabolomics and cardiometabolic risk factors were performed in 59 healthy middle-aged women. Visceral and subcutaneous adipose tissue areas were measured by computed tomography (CT) whereas body fat and lean mass were assessed by dual-energy x-ray absorptiometry (DEXA). Results The univariate Pearson correlation coefficient between glutamate and VAT area was r = 0.46 (p < 0.001) and it was r = 0.36 (p = 0.006) when adjusted for total body fat mass. Glutamate allowed to identify individuals with VAT areas ≥100 cm2 (ROC_AUC: 0.78, 95% CI: 0.66–0.91) and VAT ≥130 cm2 (ROC_AUC: 0.71, 95% CI: 0.56–0.87). The optimal glutamate concentration threshold determined from the ROC curve (glutamate ≥34.6 μmol/L) had a greater sensitivity than the metabolic syndrome (MetS) and the hypertriglyceridemic waist (HTW) phenotype to identify individuals with VAT ≥100 cm2 (83% for glutamate vs 52% for the MetS and 35% for the HTW). Variance analysis showed that women with a high circulating glutamate level (≥34.6 μmol/L) had an altered metabolic profile, particularly regarding total triglyceride levels and the amount of triglycerides and cholesterol in very-low-density lipoproteins (all p < 0.01). Conclusion Circulating glutamate is strongly associated with VAT area and may represent a potential screening tool for visceral obesity and alterations of the metabolic profile.

Bakgrund: BCAA eller grenade aminosyror är ett vanligt förekommande kosttillskott. Tillskott av BCAA antas öka fysisk prestation baserat på forskningsresultat erhållna från djurexperiment och även en del forskning på människor. Resultaten är dock delvis motsägelsefulla. Fysisk prestation går att dela upp i olika former, utefter mätmetoder och tester som skiljer dessa åt. Exempel på olika former av fysisk prestation är aerob prestation, anaerob prestation samt muskelprestation. Syfte: Syftet med studien var att undersöka eventuell koppling mellan tillskott av BCAA och ökad fysisk prestation, inom områdena aerob prestation, anaerob prestation samt muskelprestation. Utöver detta undersöks även huruvida effekt av BCAA påverkas av hur lång tid som supplementering pågår. Metod: Sex studier inkluderades i denna litteraturstudie, vilka undersökt påverkan av tillskott av BCAA på fysisk prestation, i form av antingen aerob prestation, anaerob prestation eller muskelprestation. Resultat: Två studier påvisade positiv effekt på muskelprestation efter långsiktig supplementering, den ena med signifikant koppling till tillskottet. En studie misslyckades med att påvisa positiv effekt på muskelprestation efter kortsiktig supplementering. En studie visade positiv effekt på muskelprestation efter långsiktig supplementering med signifikant koppling till tillskottet. Två studier misslyckades att påvisa positiv effekt på aerob prestation, oavsett längd på supplementeringsperiod. Den ena av de två sistnämnda studierna påvisade positiv effekt på anaerob prestation, utan signifikant koppling till tillskottet. Slutsats: Flera studier påvisade positiv effekt på prestation efter supplementering av BCAA, men olikheter och bristande signifikant koppling mellan BCAA-tillskottet och studerad effekt hos flera av studierna gör det svårt att säkerställa att tillskott av BCAA har effekt. Mer forskning på området behövs., Background: BCAA or branched amino acids are a commonly used dietary supplement. Supplements of BCAA are assumed to increase physical performance based on research results obtained from animal experiments and some research on humans. The results are, however, partly contradictory. Physical performance can be divided into different types, depending on measurement methods and tests that differentiate them. Examples of different forms of physical performance are aerobic performance, anaerobic performance and muscle performance. Aim: The purpose of the study was to investigate possible correlation between supplements of BCAA and increased physical performance in the areas of aerobic performance, anaerobic performance and muscle performance. In addition, it is also investigated whether the effect of BCAA is affected by the duration of supplementation. Method: Six studies were included in this literature study, which investigated the impact of supplementation of BCAA on physical performance, in terms of either aerobic performance, anaerobic performance or muscle performance. Results: Two studies demonstrated positive effect on muscle performance after long-term supplementation, one with significant correlation with the supplement. One study failed to demonstrate positive effect on muscle performance after short-term supplementation. One study showed a positive effect on muscle performance after long-term supplementation, with significant association with the supplement. Two studies failed to show positive effect on aerobic performance, regardless of the length of the supplementation period. One of the two latter studies demonstrated positive effects on anaerobic performance, without significant correlation with the supplement. Conclusion: Several studies demonstrated a positive effect on performance after supplementation of BCAA, but differences and lack of significant association between BCAA supplementation and the studied effect in several of the studies make it diffic

Bakgrund: BCAA eller grenade aminosyror är ett vanligt förekommande kosttillskott. Tillskott av BCAA antas öka fysisk prestation baserat på forskningsresultat erhållna från djurexperiment och även en del forskning på människor. Resultaten är dock delvis motsägelsefulla. Fysisk prestation går att dela upp i olika former, utefter mätmetoder och tester som skiljer dessa åt. Exempel på olika former av fysisk prestation är aerob prestation, anaerob prestation samt muskelprestation. Syfte: Syftet med studien var att undersöka eventuell koppling mellan tillskott av BCAA och ökad fysisk prestation, inom områdena aerob prestation, anaerob prestation samt muskelprestation. Utöver detta undersöks även huruvida effekt av BCAA påverkas av hur lång tid som supplementering pågår. Metod: Sex studier inkluderades i denna litteraturstudie, vilka undersökt påverkan av tillskott av BCAA på fysisk prestation, i form av antingen aerob prestation, anaerob prestation eller muskelprestation. Resultat: Två studier påvisade positiv effekt på muskelprestation efter långsiktig supplementering, den ena med signifikant koppling till tillskottet. En studie misslyckades med att påvisa positiv effekt på muskelprestation efter kortsiktig supplementering. En studie visade positiv effekt på muskelprestation efter långsiktig supplementering med signifikant koppling till tillskottet. Två studier misslyckades att påvisa positiv effekt på aerob prestation, oavsett längd på supplementeringsperiod. Den ena av de två sistnämnda studierna påvisade positiv effekt på anaerob prestation, utan signifikant koppling till tillskottet. Slutsats: Flera studier påvisade positiv effekt på prestation efter supplementering av BCAA, men olikheter och bristande signifikant koppling mellan BCAA-tillskottet och studerad effekt hos flera av studierna gör det svårt att säkerställa att tillskott av BCAA har effekt. Mer forskning på området behövs., Background: BCAA or branched amino acids are a commonly used dietary supplement. Supplements of BCAA are assumed to increase physical performance based on research results obtained from animal experiments and some research on humans. The results are, however, partly contradictory. Physical performance can be divided into different types, depending on measurement methods and tests that differentiate them. Examples of different forms of physical performance are aerobic performance, anaerobic performance and muscle performance. Aim: The purpose of the study was to investigate possible correlation between supplements of BCAA and increased physical performance in the areas of aerobic performance, anaerobic performance and muscle performance. In addition, it is also investigated whether the effect of BCAA is affected by the duration of supplementation. Method: Six studies were included in this literature study, which investigated the impact of supplementation of BCAA on physical performance, in terms of either aerobic performance, anaerobic performance or muscle performance. Results: Two studies demonstrated positive effect on muscle performance after long-term supplementation, one with significant correlation with the supplement. One study failed to demonstrate positive effect on muscle performance after short-term supplementation. One study showed a positive effect on muscle performance after long-term supplementation, with significant association with the supplement. Two studies failed to show positive effect on aerobic performance, regardless of the length of the supplementation period. One of the two latter studies demonstrated positive effects on anaerobic performance, without significant correlation with the supplement. Conclusion: Several studies demonstrated a positive effect on performance after supplementation of BCAA, but differences and lack of significant association between BCAA supplementation and the studied effect in several of the studies make it diffic

Branched-chain amino acids (BCAAs) and aromatic amino acids (AAAs) are associated with type 2 diabetes. However, repeated measurements of BCAA/AAA and their interactions with dietary interventions have not been evaluated. We investigated the associations between baseline and changes at 1 year in BCAA/AAA with type 2 diabetes in the context of a Mediterranean diet (MedDiet) trial.We included 251 participants with incident type 2 diabetes and a random sample of 694 participants (641 participants without type 2 diabetes and 53 overlapping cases) in a case-cohort study nested within the PREvención con DIeta MEDiterránea (PREDIMED) trial. Participants were randomised to a MedDiet+extra-virgin olive oil (n?=?273), a MedDiet+nuts (n?=?324) or a control diet (n?=?295). We used LC-MS/MS to measure plasma levels of amino acids. Type 2 diabetes was a pre-specified secondary outcome of the PREDIMED trial.Elevated plasma levels of individual BCAAs/AAAs were associated with higher type 2 diabetes risk after a median follow-up of 3.8 years: multivariable HR for the highest vs lowest quartile ranged from 1.32 for phenylalanine ([95% CI 0.90, 1.92], p for trend?=?0.015) to 3.29 for leucine ([95% CI 2.03, 5.34], p for trend<0.001). Increases in BCAA score at 1 year were associated with higher type 2 diabetes risk in the control group with HR per SD?=?1.61 (95% CI 1.02, 2.54), but not in the MedDiet groups (p for interaction <0.001). The MedDiet+extra-virgin olive oil significantly reduced BCAA levels after 1 year of intervention (p?= 0.005 vs the control group).Our results support that higher baseline BCAAs and their increases at 1 year were associated with higher type 2 diabetes risk. A Mediterranean diet rich in extra-virgin olive oil significantly reduced the levels of BCAA and attenu

Protein-energy malnourishment is commonly encountered in patients with end-stage liver disease who undergo liver transplantation. Malnutrition may further increase morbidity, mortality and costs in the post-transplantation setting. The importance of carefully assessing the nutritional status during the work-up of patients who are candidates for liver replacement is widely recognized. The metabolic abnormalities induced by liver failure render the conventional assessment of nutritional status to be challenging. Preoperative loss of skeletal muscle mass, namely, sarcopenia, has a significant detrimental impact on post-transplant outcomes. It is essential to provide sufficient nutritional support during all phases of liver transplantation. Oral nutrition is preferred, but tube enteral nutrition may be required to provide the needed energy intake. Herein, the latest currently employed perioperative nutritional interventions in liver transplant recipients are thoroughly illustrated including synbiotics, micronutrients, branched-chain amino acid supplementation, immunonutrition formulas, fluid and electrolyte balance, the offering of nocturnal meals, dietary counselling, exercise and rehabilitation.