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Adaptive thermogenesis is the heat production by muscle contractions (shivering thermogenesis) or brown adipose tissue (BAT) and beige fat (non-shivering thermogenesis) in response to external stimuli, including cold exposure. BAT and beige fat communicate with peripheral organs and the brain through a variegate secretory and absorption processes − controlling adipokines, microRNAs, extracellular vesicles, and metabolites − and have received much attention as potential therapeutic targets for managing obesity-related disorders. The sympathetic nervous system and norepinephrine-releasing adipose tissue macrophages (ATM) activate uncoupling protein 1 (UCP1), expressed explicitly in brown and beige adipocytes, dissolving the electrochemical gradient and uncoupling tricarboxylic acid cycle and the electron transport chain from ATP production. Mounting evidence has attracted attention to the multiple effects of dietary and endogenously synthesised amino acids in BAT thermogenesis and metabolic phenotype in animals and humans. However, the mechanisms implicated in these processes have yet to be conclusively characterized. In the present review article, we aim to define the principal investigation areas in this context, including intestinal microbiota constitution, adipose autophagy modulation, and secretome and metabolic fluxes control, which lead to increased brown/beige thermogenesis. Finally, also based on our recent epicardial adipose tissue results, we summarise the evidence supporting the notion that the new dual and triple agonists of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon (GCG) receptor − with never before seen weight loss and insulin-sensitizing efficacy − promote thermogenic-like amino acid profiles in BAT with robust heat production and likely trigger sympathetic activation and adaptive thermogenesis by controlling amino acid metabolism and ATM expansion in BAT and beige fat.

Branched-chain amino acids (BCAA) are essential for maintaining intestinal mucosal integrity. However, only a few studies have explored the role of BCAA in the modulation of intestinal inflammation. In this study, we investigated in vitro effects of BCAA on the inflammatory response induced by lipopolysaccharide (LPS) (1 µg/mL) in Caco-2 cells. Caco-2 cells were assigned to six groups: control without BCAA (CTL0), normal BCAA (CTL; 0.8 mM leucine, 0.8 mM isoleucine, and 0.8 mM valine); leucine (LEU; 2 mM leucine), isoleucine (ISO; 2 mM isoleucine), valine (VAL; 2 mM valine), and high BCAA (LIV; 2 mM leucine, 2 mM isoleucine, and 2 mM valine). BCAA was added to the culture medium 24 h before LPS stimulation. Our results indicated that BCAA supplementation did not impair cell viability. The amino acids leucine and isoleucine attenuated the synthesis of IL-8 and JNK and NF-kB phosphorylation induced by LPS. Furthermore, neither BCAA supplementation nor LPS treatment modulated the activity of glutathione peroxidase or the intracellular reduced glutathione/oxidized glutathione ratio. Therefore, leucine and isoleucine exert anti-inflammatory effects in Caco-2 cells exposed to LPS by modulating JNK and NF-kB phosphorylation and IL-8 production. Further in vivo studies are required to validate these findings and gather valuable information for potential therapeutic or dietary interventions.

Branched-chain amino acids (BCAAs; a mixture of leucine, valine and isoleucine) have important regulatory effects on glucose and lipid metabolism, protein synthesis and longevity. Many studies have reported that circulating BCAA levels or dietary intake of BCAAs is associated with longevity, sarcopenia, obesity, and diabetes. Among them, the influence of BCAAs on aging and insulin resistance often present different benefits or harmful effects in the elderly and in animals. Considering the nonobvious correlation between circulating BCAA levels and BCAA uptake, as well as the influence of diseases, diet and aging on the body, some of the contradictory conclusions have been drawn. The regulatory mechanism of the remaining contradictory role may be related to endogenous branched-chain amino acid levels, branched-chain amino acid metabolism and mTOR-related autophagy. Furthermore, the recent discovery that insulin resistance may be independent of longevity has expanded the research thinking related to the regulatory mechanism among the three. However, the negative effects of BCAAs on longevity and insulin resistance were mostly observed in high-fat diet-fed subjects or obese individuals, while the effects in other diseases still need to be studied further. In conclusion, there is still no definite conclusion on the specific conditions under which BCAAs and insulin resistance extend life, shorten life, or do not change lifespan, and there is still no credible and comprehensive explanation for the different effects of BCAAs and insulin resistance on lifespan.

Background The interplay between branched‐chain amino acid (BCAA) metabolism, an important pathway in adiposity and cardiometabolic disease, and visceral adipose depots such as hepatic steatosis (HS) and epicardial adipose tissue is unknown. We leveraged the PROMISE clinical trial with centrally adjudicated coronary computed tomography angiography imaging to determine relationships between adipose depots, BCAA dysregulation, and coronary artery disease (CAD). Methods and Results The PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain) trial randomized 10 003 outpatients with stable chest pain to computed tomography angiography versus standard‐of‐care diagnostics. For this study, we included 1798 participants with available computed tomography angiography data and biospecimens. Linear and logistic regression were used to determine associations between a molar sum of BCAAs measured by nuclear magnetic resonance spectroscopy with body mass index, adipose traits, and obstructive CAD. Mendelian randomization was then used to determine if BCAAs are in the causal pathway for adipose depots or CAD. The study sample had a mean age of 60 years (SD, 8.0), body mass index of 30.6 (SD, 5.9), and epicardial adipose tissue volume of 57.3 (SD, 21.3) cm3/m2; 27% had HS, and 14% had obstructive CAD. BCAAs were associated with body mass index (multivariable beta 0.12 per SD increase in BCAA [95% CI, 0.08–0.17]; P=4×10−8). BCAAs were also associated with HS (multivariable odds ratio [OR], 1.46 per SD increase in BCAAs [95% CI, 1.28–1.67]; P=2×10−8), but BCAAs were associated only with epicardial adipose tissue volume (odds ratio, 1.18 [95% CI, 1.07–1.32]; P=0.002) and obstructive CAD (OR, 1.18 [95% CI, 1.04–1.34]; P=0.009) in univariable models. Two‐sample Mendelian randomization did not support the role of BCAAs as within the causal pathways for HS or CAD. Conclusions BCAAs have been implicated in the pathogenesis of cardiometabolic diseases, and adipose depots have been associated with the risk of CAD. Leveraging a large clinical trial, we further establish the role of dysregulated BCAA catabolism in HS and CAD, although BCAAs did not appear to be in the causal pathway of either disease. This suggests that BCAAs may serve as an independent circulating biomarker of HS and CAD but that their association with these cardiometabolic diseases is mediated through other pathways.

Background: Perylenequinones from Shiraia fruiting bodies are excellent photosensitizers and widely used for anti-cancer photodynamic therapy (PDT). The lower yield of Shiraia perylenequinones becomes a significant bottleneck for their medical application. Branched-chain amino acids (BCAAs) not only serve as important precursors for protein synthesis, but also are involved in signaling pathway in cell growth and development. However, there are few reports concerning their regulation of fungal secondary metabolism. In present study, the eliciting effects of BCAAs including l-isoleucine (l-Ile), l-leucine (l-Leu) and l-valine (l-Val) on Shiraia perylenequinone production were investigated. Results: Based on the analysis of the transcriptome and amino acid contents of Shiraia in the production medium, we revealed the involvement of BCAAs in perylenequinone biosynthesis. The fungal conidiation was promoted by l-Val treatment at 1.5 g/L, but inhibited by l-Leu. The spore germination was promoted by both. The production of fungal perylenequinones including hypocrellins A (HA), HC and elsinochromes A-C (EA–EC) was stimulated significantly by l-Val at 1.5 g/L, but sharply suppressed by l-Leu. After l-Val treatment (1.5 g/L) in Shiraia mycelium cultures, HA, one of the main bioactive perylenequinones reached highest production 237.92 mg/L, about 2.12-fold than that of the control. Simultaneously, we found that the expression levels of key genes involved in the central carbon metabolism and in the late steps for perylenequinone biosynthesis were up-regulated significantly by l-Val, but most of them were down-regulated by l-Leu. Conclusions: Our transcriptome analysis demonstrated that BCAA metabolism was involved in Shiraia perylenequinone biosynthesis. Exogenous BCAAs exhibit contrasting effects on Shiraia growth and perylenequinones production. l-Val could promote perylenequinone biosynthesis via not only enhancing the central carbon metabolism for more precursors, but also eliciting perylenequinone biosynthetic gene expressions. This is the first report on the regulation of BCAAs on fungal perylenequinone production. These findings provided a basis for understanding physiological roles of BCAAs and a new avenue for increasing perylenequinone production in Shiraia mycelium cultures. [ABSTRACT FROM AUTHOR]

Background: Dietary supplementation with branched‐chain amino acids (BCAA) is often used in cirrhotic patients to improve nutritional status. We wanted to explore the evidence for BCAA supplementation in chronic liver disease. Methods: We searched MEDLINE and EMBASE for studies with BCAA supplementation with the presence of a disease‐control group (placebo or no intervention) using search terms 'liver cirrhosis', 'hepatocellular carcinoma', 'branched chain amino acids' and relevant synonyms. Risk of bias was assessed using ROBINS‐I and RoB 2.0 tools. Meta‐analyses were performed with a random‐effects model. Results were reported following EQUATOR guidelines. Results: Of 3378 studies screened by title and abstract, 54 were included (34 randomized controlled trials, 5 prospective case–control studies, 13 retrospective case–control studies: in total 2308 patients BCAA supplementation, 2876 disease‐controls). Risk of bias was high/serious for almost all studies. According to meta‐analyses, long‐term (at least 6 months) BCAA supplementation in cirrhotic patients significantly improved event‐free survival (p =.008; RR.61 95% CI.42–.88) and tended to improve overall survival (p =.05; RR.58 95% CI.34–1.00). Two retrospective studies suggested the beneficial effects during sorafenib for hepatocellular carcinoma. Available studies reported no beneficial effects or contradictory results of BCAA after other specific therapeutic interventions (resection or radiological interventions for hepatocellular carcinoma, liver transplantation, paracentesis or variceal ligation). No convincing beneficial effects of BCAA supplementation on liver function, nutritional status or quality of life were found. No study reported serious side effects of BCAA. Conclusions: Prophylactic BCAA supplementation appears safe and might improve survival in cirrhotic patients. [ABSTRACT FROM AUTHOR]

Background and aims: Apolipoprotein E (APOE) is known for its role in lipid metabolism and its association with age-related disease pathology. The aim of the present work was to identify previously unknown functions of APOE based on the detection of novel APOE protein–protein interaction candidates. Approach and results: APOE targeted replacement mice and transfected cultured hepatocytes expressing the human isoforms APOE3 and APOE4 were used. For 7 months, APOE3 and APOE4 mice were fed a high-fat and high-sugar diet to induce obesity, while a subgroup was subjected to 30% dietary restriction. Proteomic analysis of coimmunoprecipitation products from APOE mouse liver extracts revealed 28 APOE-interacting candidate proteins, including branched-chain alpha-keto acid dehydrogenase (BCKD) complex subunit alpha (BCKDHA) and voltage-dependent anion-selective channel 1 (VDAC1). The binding of APOE and BCKDHA was verified in situ by proximity ligation assay in cultured cells. The activity of the BCKD enzyme complex was significantly higher in obese APOE4 mice than in APOE3 mice, while the plasma levels of branched-chain amino acids and mTOR signalling proteins were not different. However, the protein–protein interaction with VDAC1 was strongly induced in APOE3 and APOE4 mice upon dietary restriction, suggesting a prominent role of APOE in mitochondrial function. Conclusions: The protein–protein interactions of APOE with BCKDHA and VDAC1 appear to be of physiological relevance and are modulated upon dietary restriction. Because these are mitochondrial proteins, it may be suggested that APOE is involved in mitochondria-related processes and adaptation to hepatic energy demands. [ABSTRACT FROM AUTHOR]

Systemic branched‐chain amino acid (BCAA) metabolism is dysregulated in cardiometabolic diseases. We previously demonstrated that upregulated AMP deaminase 3 (AMPD3) impairs cardiac energetics in a rat model of obese type 2 diabetes, Otsuka Long‐Evans‐Tokushima fatty (OLETF). Here, we hypothesized that the cardiac BCAA levels and the activity of branched‐chain α‐keto acid dehydrogenase (BCKDH), a rate‐limiting enzyme in BCAA metabolism, are altered by type 2 diabetes (T2DM), and that upregulated AMPD3 expression is involved in the alteration. Performing proteomic analysis combined with immunoblotting, we discovered that BCKDH localizes not only to mitochondria but also to the endoplasmic reticulum (ER), where it interacts with AMPD3. Knocking down AMPD3 in neonatal rat cardiomyocytes (NRCMs) increased BCKDH activity, suggesting that AMPD3 negatively regulates BCKDH. Compared with control rats (Long‐Evans Tokushima Otsuka [LETO] rats), OLETF rats exhibited 49% higher cardiac BCAA levels and 49% lower BCKDH activity. In the cardiac ER of the OLETF rats, BCKDH‐E1α subunit expression was downregulated, while AMPD3 expression was upregulated, resulting in an 80% lower AMPD3‐E1α interaction compared to LETO rats. Knocking down E1α expression in NRCMs upregulated AMPD3 expression and recapitulated the imbalanced AMPD3‐BCKDH expressions observed in OLETF rat hearts. E1α knockdown in NRCMs inhibited glucose oxidation in response to insulin, palmitate oxidation, and lipid droplet biogenesis under oleate loading. Collectively, these data revealed previously unrecognized extramitochondrial localization of BCKDH in the heart and its reciprocal regulation with AMPD3 and imbalanced AMPD3‐BCKDH interactions in OLETF. Downregulation of BCKDH in cardiomyocytes induced profound metabolic changes that are observed in OLETF hearts, providing insight into mechanisms contributing to the development of diabetic cardiomyopathy. [ABSTRACT FROM AUTHOR]

Background: The causality between plasma branched-chain amino acids (BCAAs) levels and stroke remains uncertain and the stratified research on the association between BCAAs levels and subtypes of stroke is not well studied. Therefore, the association of genetically proxied circulating BCAA levels with the risks of stroke and its subtypes was explored by Mendelian randomization (MR) in this study. Methods: Summary-level data derived from the published genome-wide association studies (GWAS) were employed for analyses. Data for plasma BCAA levels (n = 16,596) were obtained from a meta-analysis of GWAS. The MEGASTROKE consortium provided data for ischemic stroke (n = 440,328) and its subtypes and data for hemorrhagic stroke were available from 2 meta-analyses of GWAS of European-ancestry groups (intracerebral hemorrhage, n = 3,026; subarachnoid hemorrhage, n = 77,074). The inverse variance weighted (IVW) method was selected as the primary MR analysis. Supplementary analysis used included the weighted median, MR-Egger regression, Cochran’s Q statistic, MR Pleiotropy Residual Sum and Outlier global test, and leave-one-out analysis method. Results: According to IVW analysis, 1-SD increment in genetically determined circulating isoleucine was associated with increased risks of cardioembolic stroke (CES) (OR: 1.56, 95% CI: 1.21–2.20, P = 0.0007), but not with risks of other stroke subtypes. We could not discover any proof that leucine and valine levels could increase risk of any stroke subtype. All heterogeneity tests produced stable findings, and there was no concrete evidence to indicate the perturbation of horizontal multiplicity. Conclusion: Increasing plasma isoleucine level had a causal effect on the risk of CES but not on the risk of other stroke subtypes. Further research is needed to identify the mechanisms of the causal associations between BCAAs and stroke subtypes. [ABSTRACT FROM AUTHOR]

Although bariatric surgery is known to change the metabolome, it is unclear if this is specific for the intervention or a consequence of the induced bodyweight loss. As the weight loss after Roux-en-Y Gastric Bypass (RYGB) can hardly be mimicked with an evenly effective diet in humans, translational research efforts might be helpful. A group of 188 plasma metabolites of 46 patients from the randomized controlled Würzburg Adipositas Study (WAS) and from RYGB-treated rats (n = 6) as well as body-weight-matched controls (n = 7) were measured using liquid chromatography tandem mass spectrometry. WAS participants were randomized into intensive lifestyle modification (LS, n = 24) or RYGB (OP, n = 22). In patients in the WAS cohort, only bariatric surgery achieved a sustained weight loss (BMI −34.3% (OP) vs. −1.2% (LS), p ≤ 0.01). An explicit shift in the metabolomic profile was found in 57 metabolites in the human cohort and in 62 metabolites in the rodent model. Significantly higher levels of sphingolipids and lecithins were detected in both surgical groups but not in the conservatively treated human and animal groups. RYGB leads to a characteristic metabolomic profile, which differs distinctly from that following non-surgical intervention. Analysis of the human and rat data revealed that RYGB induces specific changes in the metabolome independent of weight loss. [ABSTRACT FROM AUTHOR]

Dietary strawberries have been shown to improve cardiometabolic risks in multiple clinical trials. However, no studies have reported effects on serum metabolomic profiles that may identify the target pathways affected by strawberries as underlying mechanisms. We conducted a 14-week randomized, controlled crossover study in which participants with features of metabolic syndrome were assigned to one of the three arms for four weeks separated by a one-week washout period: control powder, 1 serving (low dose: 13 g strawberry powder/day), or 2.5 servings (high dose: 32 g strawberry powder/day). Blood samples, anthropometric measures, blood pressure, and dietary and physical activity data were collected at baseline and at the end of each four-week phase of intervention. Serum samples were analyzed for primary metabolites and complex lipids using different mass spectrometry methods. Mixed-model ANOVA was used to examine differences in the targeted metabolites between treatment phases, and LASSO logistic regression was used to examine differences in the untargeted metabolites at end of the strawberry intervention vs. the baseline. The findings revealed significant differences in the serum branched-chain amino acids valine and leucine following strawberry intervention (high dose) compared with the low-dose and control phases. Untargeted metabolomic profiles revealed several metabolites, including serum phosphate, benzoic acid, and hydroxyphenyl propionic acid, that represented improved energy-metabolism pathways, compliance measures, and microbial metabolism of strawberry polyphenols, respectively. Thus, dietary supplementation of strawberries significantly improves the serum metabolic profiles of cardiometabolic risks in adults. [ABSTRACT FROM AUTHOR]

Background and Purpose: Although increasing evidence illustrated that the bidirectional communication between the brain and the gut is closely related to the occurrence of various complex diseases. Limited effort has been made to explore the influence of intestinal flora on the risk of ischaemic stroke. The present study aims to identify microbiota and specialized microbiota metabolites related to the occurrence and treatment of ischaemic stroke. Experimental Approach: The role of microbiota in the occurrence and the treatment of ischaemic stroke was evaluated on ischaemia/reperfusion (I/R), pseudo‐germ‐free and faecal transplantation animals. The target microbiota and specialized metabolites were identified by comparing their distribution in flora and metabolomic profiles in ischaemic stroke patients and animals with compared with healthy controls. The effects and mechanisms involved of the targeted metabolites in ischaemic stroke were explored in ischaemia/reperfusion rats, hypoxia/reoxygenation PC12 cells and LPS‐induced inflammatory BV2 cells. Key Results: Both ischaemic stroke patients and I/R rats had significant accumulation of branched‐chain amino acids, which were closely associated with gut microflora dysbiosis and the development of ischaemic stroke. Lactobacillus helveticus (L.hel) and Lactobacillus brevis (L.bre) are identified as the microbiota most affected by ischaemia/reperfusion modelling and treatment. L.hel and L.bre colonization exhibited significant neuroprotective activity and could greatly alleviate the accumulation of branched‐chain amino acids. In addition, branched‐chain amino acid (BCAA) accumulation was shown to exacerbate microglia‐induced neuroinflammation by activating AKT/STAT3/NF‐κB signalling. Conclusion and Implications: Our findings demonstrated the crucial role of intestinal flora and microbiota metabolites in the occurrence and treatment of ischaemic stroke. [ABSTRACT FROM AUTHOR]

The most frequent alterations in plasma amino acid concentrations in type 1 and type 2 diabetes are decreased L-serine and increased branched-chain amino acid (BCAA; valine, leucine, and isoleucine) levels. The likely cause of L-serine deficiency is decreased synthesis of 3-phosphoglycerate, the main endogenous precursor of L-serine, due to impaired glycolysis. The BCAA levels increase due to decreased supply of pyruvate and oxaloacetate from glycolysis, enhanced supply of NADH + H+ from beta-oxidation, and subsequent decrease in the flux through the citric acid cycle in muscles. These alterations decrease the supply of α-ketoglutarate for BCAA transamination and the activity of branched-chain keto acid dehydrogenase, the rate-limiting enzyme in BCAA catabolism. L-serine deficiency contributes to decreased synthesis of phospholipids and increased synthesis of deoxysphinganines, which play a role in diabetic neuropathy, impaired homocysteine disposal, and glycine deficiency. Enhanced BCAA levels contribute to increased levels of aromatic amino acids (phenylalanine, tyrosine, and tryptophan), insulin resistance, and accumulation of various metabolites, whose influence on diabetes progression is not clear. It is concluded that amino acid concentrations should be monitored in patients with diabetes, and systematic investigation is needed to examine the effects of L-serine and glycine supplementation on diabetes progression when these amino acids are decreased. [ABSTRACT FROM AUTHOR]

In age-related sarcopenia, the gradual loss of skeletal muscle mass, function and strength is underpinned by an imbalanced rate of protein synthesis/breakdown. Hence, an adequate protein intake is considered a valuable strategy to mitigate sarcopenia. Here, we investigated the effects of a 12-week oral supplementation with branched-chain amino acids (BCAAs: leucine, isoleucine, and valine) with recognized anabolic properties, in 17-month-old (AGED) C57BL/6J male mice. BCAAs (2:1:1) were formulated in drinking water, alone or plus two L-Alanine equivalents (2ALA) or dipeptide L-Alanyl-L-Alanine (Di-ALA) to boost BCAAs bioavailability. Outcomes were evaluated on in/ex vivo readouts vs. 6-month-old (ADULT) mice. In vivo hind limb plantar flexor torque was improved in AGED mice treated with BCAAs + Di-ALA or 2ALA (recovery score, R.S., towards ADULT: ≥20%), and all mixtures significantly increased hind limb volume. Ex vivo, myofiber cross-sectional areas were higher in gastrocnemius (GC) and soleus (SOL) muscles from treated mice (R.S. ≥ 69%). Contractile indices of isolated muscles were improved by the mixtures, especially in SOL muscle (R.S. ≥ 20%). The latter displayed higher mTOR protein levels in mice supplemented with 2ALA/Di-ALA-enriched mixtures (R.S. ≥ 65%). Overall, these findings support the usefulness of BCAAs-based supplements in sarcopenia, particularly as innovative formulations potentiating BCAAs bioavailability and effects. [ABSTRACT FROM AUTHOR]

The gut microbiota and microbial metabolites influence the enteric nervous system and the central nervous system via the microbial–gut–brain axis. Increasing body of evidence suggests that disturbances in the metabolism of peripheral branched-chain amino acids (BCAAs) can contribute to the development of neurodegenerative diseases through neuroinflammatory signaling. Preliminary research has shown that longitudinal changes in serum amino acid levels in mouse models of Parkinson’s disease (PD) are negatively correlated with disease progression. Therefore, the aim of the present study was to determine the changes in serum levels of short-chain fatty acids (SCFAs) in a mouse model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD after dietary BCAA supplementation. In our research, gas chromatography– mass spectrometry was used to detect serum SCFA concentrations. The data were then analyzed with principal component analysis and orthogonal partial least squares discriminant analysis. Finally, the correlations of serum SCFA levels with gut and motor function in MPTP-induced PD mice were explored. Propionic acid, acetic acid, butyric acid, and isobutyric acid concentrations were elevated in MPTP + H-BCAA mice compared with MPTP mice. Propionic acid concentration was increased the most, while the isovaleric acid concentration was decreased. Propionic acid concentration was positively correlated with fecal weight and water content and negatively correlated with the poleclimbing duration. In conclusion, these results not only suggest that propionic acid may be a potential biomarker for PD, but also indicate the possibility that PD may be treated by altering circulating levels of SCFA. [ABSTRACT FROM AUTHOR]

A total of 1,170 pigs (PIC 800 × PIC, initially 38.6 kg) were used in a 98-d grow-finish study to determine the performance response of pigs fed increasing levels standardized ileal digestible (SID) Trp:Lys ratio in diets containing 40% dried distillers grains with solubles (DDGS). Five dietary treatments were fed and consisted of a corn-soybean meal (SBM) diet or diets containing 40% DDGS with SID Trp:Lys ratios of 15%, 18%, 21%, or 24%. Each treatment was replicated 9 times and pens contained 26 pigs with the equal number of gilts and barrows. Data was analyzed as a randomized complete block design with previous nursery treatment as a random blocking factor. Pair-wise comparisons were used to evaluate the impact of diets on performance and carcass traits; specifically to compare the corn-SBM dietary treatment against other dietary treatments. Single degree of freedom orthogonal polynomials were used to evaluate the dose–response of increasing the SID Trp:Lys ratio in 40% DDGS diets. Increasing the SID Trp:Lys ratio in diets containing 40% DDGS increased (linear, P ≤ 0.02) average daily gain (ADG), average daily feed intake (ADFI), final body weight (BW), hot carcass weight (HCW), carcass gain, and daily carcass gain. Increasing the SID Trp:Lys ratio in 40% DDGS diets did not impact (P ≥ 0.65) gain to feed (G:F) for the cumulative period. Pigs fed the corn-SBM diet had greater (P ≤ 0.01) ADG and a heavier (P ≤ 0.01) final BW compared to pigs fed 40% DDGS diets, regardless of the SID Trp:Lys ratio. Diets that contained 40% DDGS with a SID Trp:Lys ratio of 24% had no difference (P|t| = 0.25) in ADFI compared to the corn-SBM dietary treatment. The cumulative G:F of pigs did not differ (P = 0.32) between pigs fed corn-SBM diets and diets containing 40% DDGS regardless of the SID Trp:Lys ratio. However, pigs receiving the corn-SBM diets had heavier HCW, greater carcass yields, total carcass gain, and daily carcass gain (P < 0.01) compared to pigs fed the 40% DDGS diets regardless of SID Trp:Lys ratio. In conclusion, increasing the SID Trp:Lys ratio in 40% DDGS diets improved ADG and ADFI for the overall grow-finish period. However, when compared to a corn-SBM diet, increasing the SID Trp:Lys ratio in 40% DDGS diets did not correct the growth performance or carcass characteristics of pigs. [ABSTRACT FROM AUTHOR]

Maple Syrup Urine Disease (MSUD) is an inborn error of metabolism (EIM) biochemically characterized by the tissue accumulation of branched-chain amino acids (BCAA) and their branched-chain alpha-keto acids. The mechanisms by which BCAA and their branched-chain alpha-keto acids lead to the neurological damage observed in MSUD are poorly understood. Mounting evidence has demonstrated that BCAA induce the overproduction of reactive oxygen species, which may modulate several important signaling pathways necessary for cellular homeostasis maintenance, such as autophagy. Taking this into account, we evaluated the effects of BCAA on the autophagic pathway in brain structures of rats submitted to the administration of these amino acids (animal model of MSUD). Our findings showed that BCAA significantly increased the levels of Beclin-1, ATG7, and ATG5 in the cerebral cortex of rats. In addition, BCAA augmented ATG12 levels in the striatum and ATG5 and LC3 I-II in the hippocampus. Therefore, our work demonstrates that the administration of BCAA increases autophagy and autophagic cell death, possibly mediated by the elevated levels of reactive species generated by BCAA. [ABSTRACT FROM AUTHOR]

A study was conducted to identify the effects of standardized ileal digestible (SID) branched-chain amino acids (BCAA):lysine (Lys) ratios on the growth performance, plasma nitrogen (N) profile, carcass traits, and economic analysis of growing–finishing pigs fed diets with high corn distillers dried grains with solubles (cDDGS) inclusions. A total of 1,140 pigs (initial body weight [BW] = 28.7 ± 2.0 kg) were housed in 45 pens of 25 or 26 pigs and fed one of five diets in a randomized complete block design. Experimental diets were fed in four phases based on BW. Dietary treatments were a corn–soybean meal (SBM) based diet (PC), a corn–SBM-cDDGS-based diet (NC) with SID BCAA:Lys ratio of PIC (2020) recommendation and NC diets with SID BCAA:Lys ratios targeted for the 73% SID Val:Lys, 60% SID Ile:Lys, and 144% SID Leu:Lys during the growing phases (25 to 80 kg, Grow), targeted for the 78% SID Val:Lys, 70% SID Ile:Lys, and 160% to 170% SID Leu:Lys during the finishing phases (80 to 120 kg, finish), and both during the growing and finishing phases (Grow–Finish). One pig from each pen was bled at the end of 7 and 13 wk. After the 11-wk-feeding trial, pigs were sent to a commercial abattoir to investigate carcass traits. Pigs fed the Finish diet had a greater overall average daily gain (P < 0.05) than pigs fed the other cDDGS diets. Dietary treatments did not affect the hot carcass weight. However, feeding the Finish diet increased (P < 0.05) the iodine value of pork belly samples and decreased (P < 0.05) carcass yield. The plasma urea nitrogen (PUN) concentration at the end of the growing phase and plasma concentrations of Leu and Val were greater (P < 0.05) in pigs fed the Finish diet compared to the other cDDGS diets. Feeding pigs the cDDGS diets with different BCAA:Lys ratios had no difference in income over feed cost and income over feed and facility costs compared to the corn–SBM diet. Therefore, feeding pigs cDDGS diets with SID BCAA:Lys ratios adjusted for the previously determined finishing phase (from 80 to 120 kg of BW) recommendations by SBM inclusion supported growth performance and economic benefits equal to the corn–SBM diet. [ABSTRACT FROM AUTHOR]

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Abstract Background Under current dietary regimens, milk production by lactating sows is insufficient to sustain the maximal growth of their piglets. As precursors of glutamate and glutamine as well as substrates and activators of protein synthesis, branched-chain amino acids (BCAAs) have great potential for enhancing milk production by sows. Methods Thirty multiparous sows were assigned randomly into one of three groups: control (a corn- and soybean meal-based diet), the basal diet + 1.535% BCAAs; and the basal diet + 3.07% BCAAs. The ratio (g/g) among the supplemental L-isoleucine, L-leucine and L-valine was 1.00:2.56:1.23. Diets were made isonitrogenous by the addition of appropriate amounts of L-alanine. Lactating sows had free access to drinking water and their respective diets. The number of live-born piglets was standardized to 9 per sow at d 0 of lactation (the day of parturition). On d 3, 15 and 29 of lactation, body weights and milk consumption of piglets were measured, and blood samples were obtained from sows and piglets 2 h and 1 h after feeding and nursing, respectively. Results Feed intake did not differ among the three groups of sows. Concentrations of asparagine, glutamate, glutamine, citrulline, arginine, proline, BCAAs, and many other amino acids were greater (P

Abstract Background The dietary environment promoting adiposity keeps evolving and of interest is the significance of dietary branched-chain amino acids (BCAA). This study assessed the association between dietary BCAA intakes and odds of obesity among immigrant Filipino women in Korea. Method We included 423 immigrant Filipino women enrolled in the Filipino Women’s diet and health study in the Republic of Korea. Dietary BCAA intakes were estimated from 24 hour recalls and adjusted for energy intake using the residual method. General obesity was derived from direct anthropometric measurements (height, weight and waist circumference – WC) and defined as body mass index (BMI) ≥25 kg/m2 and abdominal obesity as WC ≥80 cm. Odds ratios (OR) and 95% confidence intervals (CI) by tertile distribution of energy-adjusted BCAA intakes were estimated using multivariable logistic regression with a two-sided P

The branched-chain amino acids (BCAA) leucine, isoleucine, and valine are essential AA needed for energy production, protein synthesis, and anabolic signaling functions via the mammalian target of rapamycin (mTOR) pathway in turkeys. Imbalanced BCAA ratios can lead to antagonism and degradation of limiting BCAA, particularly in diets with excess leucine. Concentrated corn proteins contain high levels of leucine and can alter BCAA requirements; however, L-Ile and L-Val may be added to correct BCAA ratios. This study evaluated the effects of varying dietary BCAA ratio using corn gluten meal, L-Ile, and L-Val on performance, mTOR activation, and apparent ileal AA digestibility in commercial turkey hens from 0 to 21 d of age. A 38.4% corn and 49.8% soybean meal diet served as the Control. In uncorrected high leucine treatments, feed intake, bird weight, and live weight gain decreased (P < 0.05), and feed conversion ratio (FCR) increased relative to the Control at d 14 (P < 0.05). Performance equivalent to the Control was induced by adding both L-Ile and L-Val at d 14 (P > 0.05), and FCR decreased relative to the Control at d 21 (P < 0.05). Relative mTOR activation numerically increased with high leucine diets compared to the Control (P = 0.13). BCAA digestibility was maximized in high leucine diets with additional L-Ile and L-Val (P < 0.05). These results demonstrate that diets containing excess leucine from concentrated corn proteins can decrease poult hen performance, but concomitant additions of L-Ile and L-Val may restore performance. In production settings, nutritionists should assess the costs associated with BCAA supplementation at practical levels vs. corn and soybean meal-based diets. [ABSTRACT FROM AUTHOR]

Branched-chain amino acids (BCAAs) are essential amino acids that play a crucial role in regulating animal physiology and metabolism. The lack of sensitive, rapid, and portable methods for measuring BCAA concentrations in blood samples hinders precise and dynamic monitoring of nutritional status during swine production. In this work, a paper-based analytical device (PAD) was developed for quantifying BCAAs in blood samples. The device utilized a redox reaction between BCAAs and NAD+ catalyzed by leucine dehydrogenase, producing NADH that could be detected by NADH-responsive polymer dots with high selectivity, sensitivity, and accuracy. A separation membrane was incorporated in the PAD for spontaneous blood-plasma separation. The fluorescent images were captured by using a smartphone. It required only 20 μL of blood volume, and the entire assay could be completed in less than 5 minutes. The quantitation range spanned from 35 μM to 1000 μM, covering the normal BCAA concentration range in porcine bloods. The BCAA concentration measured with the PAD assay was in good agreement with those obtained with an ELISA kit. In sum, this PAD-based BCAA assay offers a point-of-care testing approach for monitoring BCAA levels in pig production, especially with a low-protein diet. • A portable paper-based analytical device was developed for BCAAs quantification. • The NADH-sensitive polymer dots were utilized as the ratiometric fluorescent probe. • A ratiometric fluorescent assay was achieved by using a smartphone. • Total BCAA level in pig blood was accurately determined. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the synthesis mechanism of 3-methylbutanal derived from leucine (Leu) by Lactococcus lactis 517 through changes in gene expression. The production of 3-methylbutanal was evaluated during 72 h of incubation using three models, including M17+ L. lactis 517, M17+Leu + L. lactis 517, and PBS + Leu + L. lactis 517. The PBS model exhibited the highest level of 3-methylbutanal (434.50 μM) and was employed to explore the pathway of 3-methylbutanal formation by transcriptomic analysis at different time points (0, 6, and 48 h). A total of 1973 genes were detected in L. lactis 517, among which 433 differential genes were identified. Gene ontology and Kyoto encyclopedia of genes and genomes enrichment analysis showed that differential genes mainly involved small molecule catabolism, organonitrogen compound catabolism, proteolysis, lysine biosynthesis, glycolysis, and pentose phosphate pathway. Several key differential genes related to the synthesis of 3-methylbutanal, including ilvE , kdcA , pdhA , pdhB , pdhC , pdhD , pta , ackA , and adh. The inhibition of α-keto acid dehydrogenase (KADH) activity by adding sodium arsenite resulted in a 15.30% decrease in the concentration of 3-methylbutanal. Our data suggest that the synthesis of 3-methylbutanal derived from Leu by L. lactis 517 primarily involves direct decarboxylation by α-keto acid decarboxylase, assisted by the KADH complex. • The synthesis of 3-methylbutanal is explored from a transcriptomics perspective. • 3-Methylbutanal is a secondary metabolite produced by L. lactis 517. • L. lactis 517 generates 3-methylbutanal via both direct and indirect pathways. • α-Keto acid decarboxylase pathway leads to more 3-methylbutanal formation. [ABSTRACT FROM AUTHOR]

Abstract Background Very low-protein (VLP) diets negatively impact calcium (Ca) metabolism and absorption. The objective of this study was to investigate the effect of supplemental branched-chain amino acids (BCAA) and limiting amino acids (LAA) on Ca digestibility, absorption and reabsorption in pigs fed with VLP diets. Forty-eight piglets were assigned to six treatments: positive control (PC), negative control (NC), and NC containing LAA 25%, LAA 50%, LAA + BCAA 25% (LB25) and LAA + BCAA 50% (LB50) more than recommendations. Results Relative to PC or NC, LB25 and LB50 had higher digestibility of Ca and plasma Ca and phosphorus (P), but lower plasma vitamin D3. LB50 tended to increase vitamin D receptor transcript and protein in the gut, but decreased mRNA or protein abundance of parathyroid hormone 1 receptor (PTH1R), calbindin 1 (CALB1), cytochrome P450 family 27 subfamily B member 1 and occludin in small intestine. LB50 increased the transcript of cytochrome P450 family 24 subfamily A member 1 and PTH1R but decreased the transcript of transient receptor potential cation channel subfamily V member 5, CALB1 and solute carrier family 17 member 4 in kidney. Conclusion Overall, BCAA increased Ca digestibility through regulating the transcellular and paracellular Ca absorption in the gut and reabsorption in kidney during protein restriction.

Abstract Background Hemodialysis (HD) is a protein catabolic event. However, the amino acid (AA) kinetics during HD sessions involved in protein breakdown have not been well investigated in patients with and without diabetes mellitus (DM). Case presentation Three patients (two patients with DM and one patient without DM) underwent fasting HD. Plasma levels of branched-chain AAs (BCAA; leucine, isoleucine, and valine), major non-essential AAs (alanine and glutamine, including glutamate), insulin, and ketone bodies were measured every hour during each HD session. After the start of the HD session, the plasma levels of insulin and all BCAAs dropped simultaneously. There was a significant subsequent increase in the plasma level of leucine and isoleucine levels, while valine levels remained constant. However, the recovery in levels of BCAAs during HD indicated a profound amount of BCAAs entering the blood from body tissues such as muscles. BCAAs may have surpassed their removal by HD. Ketone body levels increased continuously from the start of the sessions and reached high values in patients with DM. Synchronous changes in insulin depletion and an increase in the levels of ketone bodies may indicate disruption of energy metabolism. Conclusions This is the first report to demonstrate the time course of the changes in circulating levels of BCAAs and related metabolites in energy homeostasis during HD. An increase in BCAA levels during HD was found to be due to their transfer from the body tissue which suggested protein breakdown.

Background/Aims Patients with liver cirrhosis (LC) have low levels of branched-chain amino acids (BCAAs). There is accumulating evidence that BCAAs have anti-fibrotic effects in cirrhosis. This study is aimed to evaluate the effect of BCAAs on the function and phenotype of activated hepatic stellate cells (HSCs). Methods LX-2, an immortalized human stellate cell line, was used in in vitro experiments. LX-2 cells were exposed to transforming growth factor β1 (TGF-β1) and BCAAs or to valine, leucine, and isoleucine, which are components of BCAAs. Activation of the TGF-β signaling pathway in LX-2 cells was observed using real-time quantitative polymerase chain reaction and Western blotting. Results The increased expression of snail family transcriptional repressor 1 (SNAI1) was observed in LX-2 cells activated by TGF-β1. After BCAA treatment, its expression was significantly decreased at the mRNA level. The increased expression of Col1α1 and TIMP2 at the mRNA level and alpha smooth muscle actin at the protein level in activated LX-2 cells decreased after BCAA treatment. Among the BCAA components, leucine and valine significantly abrogated TGF-β-induced activation of LX-2 cells. BCAA treatment led to the decreased phosphorylation of Smad2 and p38 proteins, which are markers for Smad and Smad-independent p38 mitogen-activated protein kinase signaling pathways, respectively. Conclusions BCAA treatment can improve hepatic fibrosis by directly affecting the activated state of hepatic stellate cells through inhibition of the TGF-β signaling pathway. Among BCAA components, leucine and valine mainly abrogated TGF-β-induced activation of HSCs. Our results suggest that BCAA may be used to attenuate the progression of liver fibrosis.

BackgroundThere are many metabolic pathway abnormalities in Alzheimer's disease (AD). Several studies have linked branched-chain amino acid (BCAA) metabolism disorders with AD but have not obtained consistent results. The purpose of this study is to explore the causal association between BCAA concentration and the risk of AD.MethodsA bidirectional Mendelian randomized (MR) study was applied to explore the causal effect between BCAA level and the risk of AD. Genetic instrumental variables from the genome-wide association study (GWAS) of serum BCAA levels [total BCAAs (115,047 participants), valine (115,048 participants), leucine (115,074 participants), and isoleucine (115,075 participants)] from the UK Biobank and AD (21,982 AD cases and 41,944 controls) from the International Genomics of Alzheimer's Project were applied to explore the causal effect through the inverse variance-weighted (IVW) method, MR-Egger, and weighted median, accompanied by multiple pluripotency and heterogeneity tests.ResultsThe forward MR analysis showed that there was no causal effect of total BCAAs (OR: 1.067, 95% CI: 0.838–1.358; p = 0.838), valine (OR: 1.106, 95% CI: 0.917–1.333; p = 0.292), leucine (OR: 1.096, 95% CI: 0.861–1.396; p = 0.659), and isoleucine (OR: 1.457, 95% CI: 1.024–2.742; p = 0.037) levels on the risk of AD. The reverse analysis showed that AD was related to reduced levels of total BCAAs (OR: 0.979, 95% CI: 0.989–0.990; p < 0.001), valine (OR: 0.977, 95% CI: 0.963–0.991; p = 0.001), leucine (OR: 0.983, 95% CI: 0.973–0.994; p = 0.002), and isoleucine (OR: 0.982, 95% CI: 0.971–0.992; p = 0.001).ConclusionWe provide robust evidence that AD was associated with a decreased level of BCAAs, which can serve as a marker for early diagnosis of AD.

ABSTRACT Chicks are ideal to follow the development of the intestinal microbiota and to understand how a pathogen perturbs this developing population. Taxonomic/metagenomic analyses captured the development of the chick microbiota in unperturbed chicks and in chicks infected with Salmonella enterica serotype Typhimurium (STm) during development. Taxonomic analysis suggests that colonization by the chicken microbiota takes place in several waves. The cecal microbiota stabilizes at day 12 posthatch with prominent Gammaproteobacteria and Clostridiales. Introduction of S. Typhimurium at day 4 posthatch disrupted the expected waves of intestinal colonization. Taxonomic and metagenomic shotgun sequencing analyses allowed us to identify species present in uninfected chicks. Untargeted metabolomics suggested different metabolic activities in infected chick microbiota. This analysis and gas chromatography-mass spectrometry on ingesta confirmed that lactic acid in cecal content coincides with the stable presence of enterococci in STm-infected chicks. Unique metabolites, including 2-isopropylmalic acid, an intermediate in the biosynthesis of leucine, were present only in the cecal content of STm-infected chicks. The metagenomic data suggested that the microbiota in STm-infected chicks contained a higher abundance of genes, from STm itself, involved in branched-chain amino acid synthesis. We generated an ilvC deletion mutant (STM3909) encoding ketol-acid-reductoisomerase, a gene required for the production of l-isoleucine and l-valine. ΔilvC mutants are disadvantaged for growth during competitive infection with the wild type. Providing the ilvC gene in trans restored the growth of the ΔilvC mutant. Our integrative approach identified biochemical pathways used by STm to establish a colonization niche in the chick intestine during development. IMPORTANCE Chicks are an ideal model to follow the development of the intestinal microbiota and to understand how a pathogen perturbs this developing population. Using taxonomic and metagenomic analyses, we captured the development of chick microbiota to 19 days posthatch in unperturbed chicks and in chicks infected with Salmonella enterica serotype Typhimurium (STm). We show that normal development of the microbiota takes place in waves and is altered in the presence of a pathogen. Metagenomics and metabolomics suggested that branched-chain amino acid biosynthesis is especially important for Salmonella growth in the infected chick intestine. Salmonella mutants unable to make l-isoleucine and l-valine colonize the chick intestine poorly. Restoration of the pathway for biosynthesis of these amino acids restored the colonizing ability of Salmonella. Integration of multiple analyses allowed us to correctly identify biochemical pathways used by Salmonella to establish a niche for colonization in the chick intestine during development.

Abstract Systemic branched‐chain amino acid (BCAA) metabolism is dysregulated in cardiometabolic diseases. We previously demonstrated that upregulated AMP deaminase 3 (AMPD3) impairs cardiac energetics in a rat model of obese type 2 diabetes, Otsuka Long‐Evans‐Tokushima fatty (OLETF). Here, we hypothesized that the cardiac BCAA levels and the activity of branched‐chain α‐keto acid dehydrogenase (BCKDH), a rate‐limiting enzyme in BCAA metabolism, are altered by type 2 diabetes (T2DM), and that upregulated AMPD3 expression is involved in the alteration. Performing proteomic analysis combined with immunoblotting, we discovered that BCKDH localizes not only to mitochondria but also to the endoplasmic reticulum (ER), where it interacts with AMPD3. Knocking down AMPD3 in neonatal rat cardiomyocytes (NRCMs) increased BCKDH activity, suggesting that AMPD3 negatively regulates BCKDH. Compared with control rats (Long‐Evans Tokushima Otsuka [LETO] rats), OLETF rats exhibited 49% higher cardiac BCAA levels and 49% lower BCKDH activity. In the cardiac ER of the OLETF rats, BCKDH‐E1α subunit expression was downregulated, while AMPD3 expression was upregulated, resulting in an 80% lower AMPD3‐E1α interaction compared to LETO rats. Knocking down E1α expression in NRCMs upregulated AMPD3 expression and recapitulated the imbalanced AMPD3‐BCKDH expressions observed in OLETF rat hearts. E1α knockdown in NRCMs inhibited glucose oxidation in response to insulin, palmitate oxidation, and lipid droplet biogenesis under oleate loading. Collectively, these data revealed previously unrecognized extramitochondrial localization of BCKDH in the heart and its reciprocal regulation with AMPD3 and imbalanced AMPD3‐BCKDH interactions in OLETF. Downregulation of BCKDH in cardiomyocytes induced profound metabolic changes that are observed in OLETF hearts, providing insight into mechanisms contributing to the development of diabetic cardiomyopathy.

Background: Branched-chain amino acids (BCAAs; valine, leucine, and isoleucine) are essential amino acids that are associated with an increased risk of cardiometabolic diseases (CMD). However, there are still only limited insights into potential direct associations between BCAAs and a wide range of CMD parameters, especially those remaining after correcting for covariates and underlying causal relationships. Methods: To shed light on these relationships, we systematically characterized the associations between plasma BCAA concentrations and a large panel of 537 CMD parameters (including atherosclerosis-related parameters, fat distribution, plasma cytokine concentrations and cell counts, circulating concentrations of cardiovascular-related proteins and plasma metabolites) in 1400 individuals from the Dutch population cohort LifeLines DEEP and 294 overweight individuals from the 300OB cohort. After correcting for age, sex, and BMI, we assessed associations between individual BCAAs and CMD parameters. We further assessed the underlying causality using Mendelian randomization. Results: A total of 838 significant associations were detected for 409 CMD parameters. BCAAs showed both common and specific associations, with the most specific associations being detected for isoleucine. Further, we found that obesity status substantially affected the strength and direction of associations for valine, which cannot be corrected for using BMI as a covariate. Subsequent univariable Mendelian randomization (UVMR), after removing BMI-associated SNPs, identified seven significant causal relationships from four CMD traits to BCAA levels, mostly for diabetes-related parameters. However, no causal effects of BCAAs on CMD parameters were supported. Conclusions: Our cross-sectional association study reports a large number of associations between BCAAs and CMD parameters. Our results highlight some specific associations for isoleucine, as well as obesity-specific effects for valine. MR-based causality analysis suggests that altered BCAA levels can be a consequence of diabetes and alteration in lipid metabolism. We found no MR evidence to support a causal role for BCAAs in CMD. These findings provide evidence to (re)evaluate the clinical importance of individual BCAAs in CMD diagnosis, prevention, and treatment. [ABSTRACT FROM AUTHOR]

The repair of exercise-induced muscle damage (EIMD) is closely related with inflammation. Branched-chain amino acids (BCAAs), as a nutritional supplement, promote EIMD repair; however, the underlying mechanism remains unclear. In vivo, Sprague–Dawley rats were subjected to Armstrong’s eccentric exercise (a 120-min downhill run with a slope of −16° and a speed of 16 m min−1 ) to induce EIMD and BCAA supplement was administered by oral gavage. Protein expression of macrophages (CD68 and CD163) and myogenic regulatory factors (MYOD and MYOG) in gastrocnemius was analyzed. Inflammatory cytokines and creatine kinase (CK) levels in serum was also measured. In vitro, peritoneal macrophages from mice were incubated with lipopolysaccharide (LPS) or IL-4 with or without BCAAs in culture medium. For co-culture experiment, C2C12 cells were cultured with the conditioned medium from macrophages prestimulated with LPS or IL-4 in the presence or absence of BCAAs. The current study indicated BCAA supplementation enhanced the M1/M2 polarization of macrophages in skeletal muscle during EIMD repair, and BCAAs promoted M1 polarization through enhancing mTORC1-HIF1α-glycolysis pathway, and promoted M2 polarization independently of mTORC1. In addition, BCAA-promoted M1 macrophages further stimulated the proliferation of muscle satellite cells, whereas BCAA- promoted M2 macrophages stimulated their differentiation. Together, these results show macrophages mediate the BCAAs’ beneficial impacts on EIMD repair via stimulating the proliferation and differentiation of muscle satellite cells, shedding light on the critical role of inflammation in EIMD repair and the potential nutritional strategies to ameliorate muscle damage. [ABSTRACT FROM AUTHOR]

Objectives: We aimed to investigate the associations between dietary branched-chain amino acids (BCAA) intake and long-term risks of CVD, cancer and all-cause mortality in nationwide survey participants aged ≥ 18. Design: This was a prospective cohort study. Dietary intakes of BCAA (leucine, isoleucine and valine) were determined from the total nutrient intake document. The main outcomes were CVD, cancer and all-cause mortality. Setting: A nationally representative sample of US adults were recruited by the National Center for Health Statistics (NCHS) from 1988 to 1994. Participants: A total of 14 397 adults aged ≥ 18 who participated in the United States National Health and Nutrition Examination Survey III (NHANES III) were included. Results: During 289 406 person-years of follow-up, we identified 4219 deaths, including 1133 from CVD and 926 from cancer. After multivariate adjustment, the hazard ratios (95 % confidence intervals) of all-cause mortality in the highest dietary BCAA and isoleucine intake quintile (reference: lowest quintiles) were 0·68 (0·48, 0·97) and 0·68 (0·48, 0·97), respectively. Each one-standard-deviation increase in total dietary BCAA or isoleucine intake was associated with an 18 % or 21 % decrease in the risk of all-cause mortality, respectively. The serum triglyceride (TAG) concentration was found to modify the association between the dietary BCAA intake and all-cause mortality (P for interaction = 0·008). Conclusions: In a nationally representative cohort, higher dietary intakes of BCAA and isoleucine were independently associated with a lower risk of all-cause mortality, and these associations were stronger in participants with higher serum TAG concentrations. [ABSTRACT FROM AUTHOR]

α-unsaturated esters are fruity-aromatic compounds which are largely spread in the volatilome of many different fruits, but they are rarely found in the volatilome of yeasts. The yeast S. suaveolens has been recently shown to produce relatively high amounts of α-unsaturated esters and it appears to be an interesting model for the production of these compounds. This study aimed to isolate new α-unsaturated ester-producing yeasts by focusing on strains displaying a similar metabolism to S. suaveolens. While the production of α-unsaturated esters by S. suaveolens is believed to be closely related to its ability to grow on media containing branched-chain amino acids (isoleucine, leucine and valine) as the sole carbon source (ILV+ phenotype), in this study, an original screening method was developed that selects for yeast strains displaying ILV+ phenotypes and is able to produce α-unsaturated esters. Among the 119 yeast strains isolated from the feces of 42 different South African wild animal species, 43 isolates showed the ILV+ phenotype, among which 12 strains were able to produce α-unsaturated esters. Two interesting α-unsaturated esters were detected in two freshly isolated strains, both identified as Galactomyces candidus. These new esters were detected neither in the volatilome of the reference strain S. suaveolens, nor in any other yeast species previously studied for their aroma production. This work demonstrated the efficiency of an original method to rapidly screen for α-unsaturated ester-producing yeasts. In addition, it demonstrated that wild animal feces are interesting resources to isolate novel strains producing compounds with original aromas. [ABSTRACT FROM AUTHOR]

[Objective] The purpose of this study is to understand the distribution, properties and expression patterns of members of the BCAT (Branched-chain Aminotransferase) gene family, so as to lay a foundation for further research on the function of Capsicum chinense Jacq BCAT genes. C. chinense is one of the five main cultivars of pepper. Its fruit usually has a strong fruity aroma formed by branched chain esters. BCAT is responsible for catalyzing the synthesis of corresponding 2-oxo acids from branched-chain amino acids, and is the first reaction enzyme to catalyze the synthesis of branched-chain esters. [Method] The BCAT gene family members of C. chinense were identified, expressed and cloned using bioinformatics analysis and real-time quantitative PCR. [Result] Five members of the BCAT gene family were obtained and named as CcBCAT1~CcBCAT5, and then bioinformatics analysis and CcBCAT1-CcBCAT4 cloning were performed on them. Bioinformatics analysis showed that these genes were distributed on the four chromosomes of pepper, and the proteins were all hydrophilic proteins with amino acid lengths ranging from 184 aa to 557 aa, molecular weights ranging from 20.29 ku to 89.60 ku, and isoelectric points ranging from 5.57~8.34. Subcellular localization prediction results showed that CcBCAT1 was located in chloroplast and mitochondria, and other gene family members were located in chloroplast. The spatiotemporal expression analysis of CcBCATs genes showed that CcBCAT1-4 genes had tissue expression specificity. The regular expression of CcBCAT4 gradually increased with the maturity of pepper, and the accumulation trend of branched-chain amino acid derivatives related to pepper fruit was similar. CcBCAT5 was not detected. [Conclusion] In conclusion, this study clarified the expression pattern of the BCAT gene family in Chinese pepper, speculated that CcBCAT4 was involved in the synthesis of secondary metabolites related to pepper fruit. [ABSTRACT FROM AUTHOR]

Background: Abdominal obesity (AO) is linked to reduced health status and mortality. While it is known that AO is prevalent in chronic obstructive pulmonary disease (AO-COPD), the specific metabolic and functional consequences associated with AO-COPD remain understudied. Methods: We studied 199 older adults with COPD and 168 control subjects with and without AO and assessed visceral adipose tissue (VAT) by dual-energy X-ray absorptiometry. VAT > 70th percentile of the control group qualified a subject as AO in a sex specific manner. We measured plasma concentrations and whole body production (WBP) rates of multiple amino acids to assess the metabolic profile. We assessed medical history, body composition by Dual-Energy X-ray Absorptiometry, muscle strength, and cognitive function. We performed statistics by analysis of covariance (p) and FDR (q) for multiple comparisons. Results: AO-COPD subjects had 27% more VAT (q < 0.01) than AO-Control subjects despite correction for BMI. Branched-chain amino acid concentrations and WBP rates were generally elevated in AO-COPD but whole body clearance rate was only elevated in COPD. Metabolic syndrome comorbidities (p < 0.01) and systemic inflammation (P < 0.05) were most prevalent in the AO-COPD group. Muscle strength was reduced in COPD subjects (p < 0.001), but partially preserved when combined with AO. Cognitive dysfunction and mood disturbances were present in COPD subjects (p < 0.001) with worst performers in AO-COPD (q < 0.05). Conclusion: The presence of AO is associated with specific metabolic and functional phenotypes in COPD. Clinical trial registry Trial registration ClinicalTrials.gov. In the present paper, we report an analysis of the baseline measurements of COPD subjects and healthy controls from the study numbers: NCT01787682, NCT01787682, NCT02157844, NCT02082418, NCT02065141, NCT02770092, NCT02908425, NCT03159390, NCT02780219, NCT03327181, NCT03796455, NCT04928872, NCT04461236, NCT01173354, NCT01154400. [ABSTRACT FROM AUTHOR]

Atherosclerosis (AS) is a chronic inflammatory disease that serves as a common pathogenic underpinning for various cardiovascular diseases. Although high circulating branched-chain amino acid (BCAA) levels may represent a risk factor for AS, it is unclear whether dietary BCAA supplementation causes elevated levels of circulating BCAAs and hence influences AS, and the related mechanisms are not well understood. Here, ApoE-deficient mice (ApoE−/−) were fed a diet supplemented with or without BCAAs to investigate the effects of BCAAs on AS and determine potential related mechanisms. In this study, compared with the high-fat diet (HFD), high-fat diet supplemented with BCAAs (HFB) reduced the atherosclerotic lesion area and caused a significant decrease in serum cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels. BCAA supplementation suppressed the systemic inflammatory response by reducing macrophage infiltration; lowering serum levels of inflammatory factors, including monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6); and suppressing inflammatory related signaling pathways. Furthermore, BCAA supplementation altered the gut bacterial beta diversity and composition, especially reducing harmful bacteria and increasing probiotic bacteria, along with increasing bile acid (BA) excretion. In addition, the levels of total BAs, primary BAs, 12α-hydroxylated bile acids (12α-OH BAs) and non-12α-hydroxylated bile acids (non-12α-OH BAs) in cecal and colonic contents were increased in the HFB group of mice compared with the HFD group. Overall, these data indicate that dietary BCAA supplementation can attenuate atherosclerosis induced by HFD in ApoE−/− mice through improved dyslipidemia and inflammation, mechanisms involving the intestinal microbiota, and promotion of BA excretion. [ABSTRACT FROM AUTHOR]

Gestational diabetes mellitus (GDM) results in an increased risk of pre- and postpartum health complications for both mother and child. Metabolomics analysis can potentially identify predictive biomarkers and provide insight into metabolic alterations associated with GDM pathogenesis and progression, but few metabolomics studies investigate alterations observed across the first and third trimester. We hypothesize that metabolites altered in first-trimester GDM that remain altered in late pregnancy may best inform interventions. Metabolomic studies comparing plasma and serum metabolite alterations in GDM vs non-GDM pregnancies were retrieved by searching PubMed, Medline, and CINAHL Plus databases. The present scoping review summarizes the metabolites found to be consistently altered throughout the course of GDM and proposes mechanisms that explain how these metabolic perturbations relate to GDM development and progression. Metabolites involved in fatty acid metabolism, reductive carboxylation, branched-chain amino acid metabolism, cell membrane lipid metabolism, purine degradation, and the gut microbiome were found to be altered throughout GDM pregnancies, with many of these pathways showing mechanistic links to insulin resistance, inflammation, and impaired cell signaling. Future studies are required to investigate if normalization of these perturbed pathways can be the targets of interventions. [ABSTRACT FROM AUTHOR]

Acute liver failure (ALF) presents with an acute abnormality of liver blood tests in an individual without underlying chronic liver disease. The clinical course leads to the development of coagulopathy and hepatic encephalopathy. The role of nutrition in its prevention and treatment remains uncertain. We aimed to review literature data on the concept of ALF and the role of nutrition in its treatment and prevention, considering the impact of gut microbiota dysbiosis and eubiosis. We conducted a review of the literature on the main medical databases using the following keywords and acronyms and their associations: liver failure, nutrition, branched-chain amino acids, gut microbiota, dysbiosis, and probiotics. Upon their arrival at the emergency department, an early, accurate nutritional assessment is crucial for individuals with ALF. Branched-chain amino acids (BCAAs), stable euglycemia maintenance, and moderate caloric support are crucial for this subset of patients. An excessive protein load must be avoided because it worsens hepatic encephalopathy. Preclinical evidence supports future probiotics use for ALF treatment/prevention. Nutritional support and treatment for ALF are crucial steps against patient morbidity and mortality. BCAAs and euglycemia remain the mainstay of nutritional treatment of ALF. Gut dysbiosis re-modulation has an emerging and natural-history changing impact on ALF. [ABSTRACT FROM AUTHOR]

Background: Postoperative insulin resistance (PIR) represents an important characteristic of metabolic response following surgical injury. Clinical outcomes are negatively correlated to postoperative insulin resistance and hyperglycemia, indicating a novel treatment for reducing postoperative insulin resistance is urgently needed. The current work aimed to assess the protective effects of branched-chain amino acids (BCAA) on glucose metabolism disorders induced surgically in a rat model, and to explore the underpinning mechanism. Methods and results: Rats were randomly assigned to 2 groups, including the control and BCAA groups. Rats were given a compulsory oral 3 mL load by gavage two hours before surgery. The results showed that BCAA remarkably reduced glycemia by suppressing liver gluconeogenesis via reduction of cAMP-response element-binding protein-regulated transcription coactivator 2 (CRTC2) and glucose-6-phosphatase (G6PC) gene and protein expression levels (all Ps < 0.05). Conclusions: This study revealed that BCAA lower blood glucose levels by reducing liver gluconeogenesis without significant elevation of plasma insulin levels. We anticipate that preoperative BCAA supplementation may be a means for preventing postoperative insulin resistance. [ABSTRACT FROM AUTHOR]

• The longitudinal shifts of gut microbial community after rotenone treatment for 3 and 4 weeks are associated with the pathological α-synuclein-mediated motor and non-motor deficits. • Gut microbiota alter dynamically in rotenone-induced PD models, which is accompanied by the gradual decrease in serum BCAA levels. • High BCAA diet alleviate the inflammations of the gut and brain and improve the loss of the dopaminergic neurons. Neuroinflammation caused by the disorder of gut microbiota and its metabolites is associated with the pathogenesis of Parkinson's disease (PD). Thus, it is necessary to identify certain molecules derived from gut microbiota to verify whether they could become intervention targets for the treatment of PD. The branched-chain amino acids (BCAAs), as a common dietary supplement, could modulate brain function. Herein, we investigated the longitudinal shifts of microbial community in mice treated with rotenone for 0, 3 and 4 weeks by 16S rRNA gene sequencing to identify the microbial markers at different PD stages. Serum BCAAs were determined by gas chromatography-mass spectrometry. Then, rotenone-induced mice were given a high BCAA diet to evaluate the motor and non-motor functions, dopaminergic neuron loss, and inflammation levels. Using a PD mouse model, we discovered that during PD progression, the alterations of gut microbiota compositions led to the peripheral decrease of BCAAs. Based on the serum lipopolysaccharide binding protein concentrations and the levels of pro-inflammatory factors (including tumor necrosis factor-α, interleukin [IL]-1β, and IL-6) in the colon and substantia nigra, we found that the high BCAA diet could attenuate the inflammatory levels in PD mice, and reverse motor and non-motor dysfunctions and dopaminergic neuron impairment. Together, our results emphasize the dynamic changes of gut microbiota and BCAA metabolism and propose a novel strategy for PD therapy: a high BCAA diet intervention could improve PD progression by regulating the levels of inflammation. [ABSTRACT FROM AUTHOR]

Background: Given that, studies on the association of dietary intake of branched-chain amino acids (BCAAs) with risk of cancers, especially breast cancer, are limited, we aimed to examine the association between dietary intake of BCAAs and risk of breast cancer. Methods: This case–control study was performed on Iranian women aged ≥ 30 years from July 2013 to July 2015. Overall 1050 women including 350 patients and 700 controls were included. Breast cancer was diagnosed by physical examination, mammography and pathological confirmation. We assessed dietary intakes using the validated 106-item Willett-format semi-quantitative dish-based food frequency questionnaire. The total intake of valine, leucine, and isoleucine from all food items in the questionnaire was used to calculate BCAAs intake. To estimate odds ratios (ORs) and 95% confidence intervals (95% CI), we used logistic regression analysis. Results: After controlling for potential confounders, we found that women in the highest quartile of BCAAs had lower odds of breast cancer compared with the first quartile (OR: 0.50; 95% CI 0.34–0.72). When we stratified the analysis based on menopausal status, a significant inverse association between BCAAs intake and odds of postmenopausal breast cancer was observed (OR: 0.22; 95% CI 0.13–0.39), although this significant relationship was not found in premenopausal breast cancer (OR: 2.57; 95% CI 0.51–12.73). Also, this significant association was also observed for valine, leucine, and isoleucine separately. Conclusion: We found that higher dietary intake of BCAAs was significantly associated with a reduced risk of postmenopausal breast cancer. [ABSTRACT FROM AUTHOR]

Coffee protein is reported to have high levels of branched-chain amino acids of value in sports nutrition and malnutrition recovery. However, data demonstrating this unusual amino acid composition are limited. We investigated the extraction and isolation of protein concentrates from coffee bean fractions, viz. green coffee, roasted coffee, spent coffee and silver skin, and determined their amino acid profile, caffeine content and protein nutritional quality, polyphenol content and antioxidant activity. Alkaline extraction/isoelectric precipitation gave lower concentrate yields and protein content than alkaline extraction/ultrafiltration. The protein concentrate from green coffee beans had a higher protein content than those from roasted coffee, spent coffee and silver skin, regardless of extraction method. The isoelectric precipitated green coffee protein concentrate had the highest in vitro protein digestibility and in vitro protein digestibility corrected amino acid score (PDCAAS). Silver skin protein concentrate had a very low digestibility and in vitro PDCAAS. In contrast to a previous finding, the amino acid levels in all coffee concentrates did not demonstrate high levels of branched-chain amino acids. All protein concentrates had very high levels of polyphenols and high antioxidant activity. The study suggested investigating coffee protein's techno-functional and sensory attributes to demonstrate their potential applications in different food matrices. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the potential associations of dietary BCAAs (isoleucine, leucine, and valine) with physical function in the elderly Chinese population. A validated semiquantitative food frequency questionnaire and anthropometric and physical function measurements were used to collect data. We modeled trends in physical function indicators for BCAA quartiles using multivariate linear regression models. Among 4336 (43.97% men) participants aged 72.73 ± 5.48 years, a higher dietary intake of BCAAs was positively associated with increased handgrip strength (all p trends < 0.001), shorter times for 4-m fast walking (all p trends < 0.001) and repeated chair rises (all p trends < 0.001). No linear association was found between subtypes of amino acids and any physical functions (all p trends > 0.05). Individuals in the highest quartiles of BCAA intake had a reduced risk of developing low muscle strength, and the multiadjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) for women and men were 0.50 (0.38–0.65) and 0.67 (0.50–0.91), respectively. Similarly, higher BCAA consumption was associated with a lower risk of developing low physical performance (4-m walking speed: OR = 0.68 [0.50–0.93]; repeated chair rises: OR = 0.66 [0.54–0.81]). Higher dietary BCAA intake might be beneficial for physical function in the elderly population. [ABSTRACT FROM AUTHOR]

Objective: Branched-chain amino acids (BCAAs) are closely associated with type 2 diabetes mellitus, but their roles in gestational diabetes mellitus (GDM) are still controversial. This study aims to explore the dynamic changes of BCAAs during pregnancy and identify potential early biomarkers for GDM. Methods: This study is a nested case-control study involved 49 women with GDM and 50 age- and body mass index (BMI)-matched healthy pregnant women. The dynamic changes of valine (Val), isoleucine (Ile), and leucine (Leu) were detected in the first (8-12 weeks) and second trimesters (24-28 weeks) by liquid chromatography-mass spectrometry. Results: Serum Val, Ile, and Leu were higher in GDM patients than in controls in the first trimester. Compared with the first trimester, the serum Val, Ile, and Leu in GDM patients were decreased in the second trimester. In addition, Val, Ile, and Leu in the first trimester were the risk factors for GDM, and Ile presented a high predictive value for GDM. Ile + age (≥ 35) + BMI (≥ 24) exhibited the highest predictive value for GDM (AUC = 0.902, sensitivity = 93.9%, specificity = 80%). Conclusion: Maternal serum Ile in the first trimester was a valuable biomarker for GDM. Ile combined with advanced maternal age and overweight may be used for the early prediction of GDM. [ABSTRACT FROM AUTHOR]

Although branched-chain amino acids (BCAA) are known to stimulate myofibrillar protein synthesis and affect insulin signaling and kynurenine metabolism (the latter being a metabolite of tryptophan associated with depression and dementia), the effects of BCAA supplementation on type 2 diabetes (T2D) are not clear. Therefore, a 24-week, prospective randomized open blinded-endpoint trial was conducted to evaluate the effects of supplementation of 8 g of BCAA or 7.5 g of soy protein on skeletal muscle and glycemic control as well as adverse events in elderly individuals with T2D. Thirty-six participants were randomly assigned to the BCAA group (n = 21) and the soy protein group (n = 15). Skeletal muscle mass and HbA1c, which were primary endpoints, did not change over time or differ between groups. However, knee extension muscle strength was significantly increased in the soy protein group and showed a tendency to increase in the BCAA group. Homeostasis model assessment for insulin resistance did not significantly change during the trial. Depressive symptoms were significantly improved in the BCAA group but the difference between groups was not significant. Results suggested that BCAA supplementation may not affect skeletal muscle mass and glycemic control and may improve depressive symptoms in elderly individuals with T2D. [ABSTRACT FROM AUTHOR]

Studies from the last decades indicate that increased levels of ammonia contribute to muscle wasting in critically ill patients. The aim of the article is to examine the effects of two different causes of hyperammonemia—increased ATP degradation in muscles during strenuous exercise and impaired ammonia detoxification to urea due to liver cirrhosis. During exercise, glycolysis, citric acid cycle (CAC) activity, and ATP synthesis in muscles increase. In cirrhosis, due to insulin resistance and mitochondrial dysfunction, glycolysis, CAC activity, and ATP synthesis in muscles are impaired. Both during exercise and in liver cirrhosis, there is increased ammonia detoxification to glutamine (Glu + NH3 + ATP → Gln + ADP + Pi), increased drain of ketoglutarate (α-KG) from CAC for glutamate synthesis by α-KG-linked aminotransferases, glutamate, aspartate, and α-KG deficiency, increased oxidation of branched-chain amino acids (BCAA; valine, leucine, and isoleucine), and protein-energy wasting in muscles. It is concluded that ammonia can contribute to muscle wasting regardless of the cause of its increased levels and that similar strategies can be designed to increase muscle performance in athletes and reduce muscle loss in patients with hyperammonemia. The pros and cons of glutamate, α-KG, aspartate, BCAA, and branched-chain keto acid supplementation are discussed. [ABSTRACT FROM AUTHOR]

The metabolism of branched-chain amino acids by gut microbiota can improve overall health and may reverse aging. In this study, we investigated Parabacteroides merdae, a gut microbe that is known to catabolise branched-chain amino acids (BCAAs). Three metabolites of BCAAs isovalerate, 2-methylbutyrate, and isobutyrate were used to treat D-gal induced aging mice. The results showed that these treatments could delay aging in mice by providing health benefits in reducing oxidative stress and inflammation, improving muscle capacity, reversing brain acetylcholine levels, and regulating blood glucose. The mechanism was preliminarily explored by combining the gut microbiota metagenome and faecal serum metabolome. Parabacteroides merdae altered the species composition and structure of the gut microbiota in mice. Increasing the abundance of beneficial bacteria, such as Bifidobacterium pseudolongum. Three metabolites affects the gut microbiota and the body's pathways of protein and improves the overall health through a variety of signaling pathways. Overall, regulating the gut microbiota involved in branched-chain amino acid metabolism to bring health benefits may be a new way of reversing aging., (© 2024 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)