Levels Of Branched-chain Amino Acids Research Articles

Serum branched-chain amino acid levels are associated with fracture risk in Japanese women.

Branched-chain amino acids (BCAAs) have been shown to exert beneficial effects on muscle and bone metabolism; however, no studies to date have investigated whether BCAAs have beneficial effects on bone fractures. Herein, we aim to prospectively investigate the relationship between serum BCAA concentrations and the occurrence of vertebral fractures (VFs) in Japanese women. During the observation period (7.5 ± 6.1 years), 188 of 983 participants experienced VF. Kaplan-Meier analyses were conducted to examine time-dependent variations in the vertebral compression fracture occurrence rate. Patients were stratified into quartiles based on serum BCAA concentration for this analysis. The analysis results indicated that the group with the lowest BCAA level developed VFs significantly earlier and with a higher frequency than the other groups (P < 0.001). A Cox proportional hazards model showed that BCAA concentration was a significant risk factor for incident fracture, even after adjusting for possible confounding factors. A series of multiple regression analyses were performed to identify factors related to serum BCAA concentration, with the results identifying levels of glycated hemoglobin (P < 0.001), adiponectin (P < 0.001), and NOx (P = 0.011) as significant factors associated with serum BCAA. Overall, the present study revealed that a lower serum BCAA level was an independent risk factor for incident VF in postmenopausal women. Geriatr Gerontol Int 2024; ••: ••-••.

СВЯЗЬ ЦИРКУЛИРУЮЩИХ УРОВНЕЙ АМИНОКИСЛОТ С РАЗВЕТВЛЕННОЙ ЦЕПЬЮ У ПАЦИЕНТОВ С ХРОНИЧЕСКОЙ СЕРДЕЧНОЙ НЕДОСТАТОЧНОСТЬЮ С НАЛИЧИЕМ НАРУШЕНИЙ УГЛЕВОДНОГО ОБМЕНА

The importance of the problem of chronic heart failure (CHF) is hard to overestimate: this syndrome is diagnosed in millions of patients around the world and its prevalence continues to grow. The proportion of patients suffering from carbohydrate metabolism disorders (CMD) is also steadily increasing. The close connection between carbohydrate metabolism disorders and the progression of CHF allowed such patients to be classified into a separate phenotype cluster - the “metabolic phenotype of CHF”. The pathophysiology of the “metabolic phenotype of CHF” is based on significant metabolic disorders, which determines the characteristic features of the metabolome of this cohort of patients. Therefore, the purpose of this work is to compare and evaluate the relationship between metabolites that occupy one of the most important places in the metabolic processes of the body - the levels of branched chain amino acids (BCAA) and the phenotypic characteristics of patients with CHF. The study included 218 patients: 133 patients of the main group suffering from CHF and having CMD; comparison group - 85 patients with CHF without CMD. The groups were comparable by gender (p=0,324) and age (p=0,936). The levels of BCAAs - leucine, isoleucine, valine - in the blood plasma of patients were assessed by high-performance liquid chromatography combined with mass spectrometry (HPLC-MS). Based on the results of the analysis, the following data were obtained: plasma levels of valine and leucine in patients with CHF and CMD were higher (p=0,022 and p&lt;0,001, respectively) than in patients with CHF and normal carbohydrate metabolism. A direct relationship between the level of leucine + isoleucine and the concentration of glucose (r=0,3, p&lt;0,001) and an inverse relationship between the plasma concentration of valine and the level of N-terminal propeptide of natriuretic hormone (NTproBNP) (r=-0,388, p&lt;0,001) were found. It has been established that a high level of tissue insulin resistance in patients is associated with increased concentrations of BCAA. The results indicate the important role of BCAA in the pathogenesis of the “metabolic phenotype of CHF,” which requires further research in this direction.

Partial suppression of BCAA catabolism as a potential therapy for BCKDK deficiency

Branched chain ketoacid dehydrogenase kinase (BCKDK) deficiency is a recently described inherited neurometabolic disorder of branched chain amino acid (BCAA) metabolism implying increased BCAA catabolism. It has been hypothesized that a severe reduction in systemic BCAA levels underlies the disease pathophysiology, and that BCAA supplementation may ameliorate disease phenotypes. To test this hypothesis, we characterized a recent mouse model of BCKDK deficiency and evaluated the efficacy of enteral BCAA supplementation in this model. Surprisingly, BCAA supplementation exacerbated neurodevelopmental deficits and did not correct biochemical abnormalities despite increasing systemic BCAA levels. These data suggest that aberrant flux through the BCAA catabolic pathway, not just BCAA insufficiency, may contribute to disease pathology. In support of this conclusion, genetic re-regulation of BCAA catabolism, through Dbt haploinsufficiency, partially rescued biochemical and behavioral phenotypes in BCKDK deficient mice. Collectively, these data raise into question assumptions widely made about the pathophysiology of BCKDK insufficiency and suggest a novel approach to develop potential therapies for this disease.

Molecular and physiological characterization of AIP1, encoding the acetolactate synthase regulatory subunit in rice

Flooding deprives plants of oxygen and thereby causes severe stress by interfering with energy production, leading to growth retardation. Enzymes and metabolites may help protect plants from waterlogging and hypoxic environmental conditions. Acetolactate synthase (ALS) is a key enzyme in the biosynthesis of branched-chain amino acids (BCAAs), providing the building blocks for proteins and various secondary metabolites. Additionally, under energy-poor conditions, free BCAAs can be used as an alternative energy source by mitochondria through a catabolic enzyme chain reaction. In this study, we characterized ALS-INTERACTING PROTEIN 1 (OsAIP1), which encodes the regulatory subunit of ALS in rice (Oryza sativa). This gene was expressed in all parts of the rice plant, and its expression level was significantly higher in submerged and low-oxygen environments. Rice transformants overexpressing OsAIP1 showed a higher survival rate under hypoxic stress than did non-transgenic control plants under the same conditions. The OsAIP1-overexpressing plants accumulated increased levels of BCAAs, demonstrating that OsAIP1 is an important factor in the hypoxia resistance mechanism. These results suggest that ALS proteins are part of a defense mechanism that improves the tolerance of plants to low-oxygen environments.

Transcriptomics and UHPLC-QQQ-MS analyses reveal the dysregulation of branched chain amino acids metabolism in renal fibrotic rats

The dysregulated levels of branched chain amino acids (BCAA) contribute to renal fibrosis in chronic kidney disease (CKD), yet specific analysis of BCAA contents and how they are regulated still remain unclear. It is therefore of great scientific interest to understand BCAA catabolism in CKD and develop a sensitive method for simultaneous determination of individual BCAA and their metabolites branched chain α-ketoacids (BCKA). In this work, the important role of BCAA metabolism that drives renal fibrosis in the process of CKD was first revealed by using transcriptomics. The key target genes controlling BCAA metabolism were then validated, that is, mRNA levels of BCKDHA and BCKDHB, the regulating rate-limiting enzymes during BCAA metabolism were abnormally reduced by quantitative PCR (qPCR), and a similar drop-off trend of protein expression of BCKDH, HIBCH and MCCC2 that are closely related to BCAA metabolism was also confirmed by western blotting. Furthermore, we established a novel strategy that simultaneously determines 6 individual BCAA and BCKA in serum and tissue. The method based on dansylhydrazine derivatization and ultra-high performance liquid chromatography-tandem triple quadrupole mass spectrometry (UHPLC-QQQ-MS) achieved to simultaneously determine the contents of BCAA and BCKA, which is efficient and stable. Compared with normal rats, levels of BCAA including leucine, isoleucine and valine in serum and kidney of CKD rats was decreased, while BCKA including α-ketoisocaproic acid, α-ketomethylvaleric acid and α-ketoisovaleric acid was increased. Together, these findings revealed the abnormality of BCAA metabolism in driving the course of kidney fibrosis and CKD. Our current study sheds new light on changes in BCAA metabolism during CKD, and may facilitate development of drugs to treat CKD and renal fibrosis.

17 Effect of branched-chain amino acids on lactating sow and piglet performance

Abstract Sows (n = 360 PIC 1050 and Genesus) were used to investigate the effect of various branched-chain amino acid (BCAA) levels on sow lactation and litter growth performance. Upon entering the farrowing room, sows were blocked by parity group (P0, P2, P3+) and randomly assigned to one of six dietary treatments containing various levels of BCAA. Experimental diets were formulated to various standardized ileal digestible (SID) leucine, isoleucine, and valine levels by replacing cornstarch with L-leucine, L-isoleucine, and L-valine. Levels of the BCAA were expressed as ratios to SID lysine and were formulated at 114 or 180 for Leu, 56 or 64 for Ile, and 64 or 120 for Val. Diets were formulated to be isocaloric (3.23 Mcal ME/kg) and met or exceeded all other NRC (2012) essential amino acid and vitamin and mineral recommendations. Sow body weight (BW), backfat, and body condition score were recorded at the time of entry into the farrowing room and at the time of weaning. Piglet litter weights were recorded after cross-fostering and at weaning to determine litter growth rate. Data were analyzed using generalized linear mixed models with fixed effects of dietary treatment and parity group and a random effect of lactation group. The models were fit using R version 4.3.1 (R Core Team, 2023). The sow and her litter were the experimental unit, and results were considered significant if P ≤ 0.05 and a tendency if 0.05 &amp;lt; P ≤ 0.10. Sows nursed piglets for 21.3 d (P = 0.998). The mean parity by treatment ranged from 3.8 to 3.9 (P = 0.999). After farrowing, the mean estimated sow BW was 219 kg, with a range between treatments of 216 to 221 kg (P = 0.651). On average, sows gained 2.82% of their BW (P = 0.696) with an average daily feed intake (ADFI) of 8.75 kg/d (P = 0.932). However, as expected, sow Leu, Ile, Val, and total BCAA intakes were different across treatments (P ≤ 0.001). Sows entered the farrowing house with an average of 11.50 mm of backfat (P = 0.919) and lost 6.04% backfat through lactation (P = 0.667). Sows started the trial with an average of 14.1 piglets/sow (P = 0.967) and weaned 12.6 piglets per sow (P = 0.981) with a piglet average daily gain of 0.22 kg/d (P = 0.193) and a daily litter growth rate of 2.89 kg/d (P = 0.291). In conclusion, there was no evidence of an effect of the various leucine, isoleucine, and valine levels evaluated in this study on lactating sow and piglet performance.

Nutritional and inflammation factors associated with current frailty level and effect of co-morbidities on the progression of frailty.

Frailty is defined as extreme vulnerability, a syndrome that exposes the individual to a higher risk of disability. While risk factors for frailty have been gradually uncovered, the full identification of biochemical factors and co-morbidities influencing frailty remains incomplete. Cross-sectional and longitudinal analyses were performed to elucidate the risk factors for the prevalence and progression of frailty. The study included 1035 Japanese female outpatients. At baseline, biochemical markers were measured. Co-morbidities included diabetes mellitus, dyslipidemia, hypertension, vertebral osteoarthritis, and osteoporosis. Frailty levels were assessed using frailty scores ranging from 0 to 5. Prevalence of frailty was judged by a score of 3 or above, and progression was judged by an increase in the frailty score during the observation period. Multiple regression analysis was used for the cross-sectional analysis, and the Cox hazard model was used for the longitudinal analysis. Of the 1035 selected participants, 212 were diagnosed with frailty. Advanced age and log IL-6 and branched-chain amino acids (BCAA) levels were significant independent risk factors for frailty. Subjects were followed for 7.7 ± 5.9 years and progression was observed in 130 subjects. Older age, the absence of hyperlipidemia, the presence of osteoporosis, and lower frailty scores were identified as significant risk factors for frailty progression. Inflammatory and nutritional markers exhibited significant associations with the current frailty status, whereas co-morbidities such as osteoporosis or hyperlipidemia emerged as independent risk or protective factors of future frailty progression. Geriatr Gerontol Int 2024; ••: ••-••.

Branched-chain amino acids and the risks of dementia, Alzheimer's disease, and Parkinson's disease.

We aimed to examine the association between blood levels of Branched-chain amino acids (BCAAs) - specifically isoleucine, leucine, and valine - and the susceptibility to three neurodegenerative disorders: dementia, Alzheimer's disease (AD), and Parkinson's disease (PD). Based on data from the UK Biobank, a Cox proportional hazard regression model and a dose-response relationship were used to analyze the association between BCAAs and the risks of dementia, AD, and PD. We also generated a healthy lifestyle score and a polygenic risk score. Besides, we conducted a sensitivity analysis to ensure the robustness of our findings. After adjusting for multiple covariates, blood concentrations of isoleucine, leucine, and valine were significantly associated with a reduced risk of dementia and AD. This association remained robust even in sensitivity analyses. Similarly, higher levels of isoleucine and leucine in the blood were found to be associated with an increased risk of PD, but this positive correlation could potentially be explained by the presence of covariates. Further analysis using a dose-response approach revealed that a blood leucine concentration of 2.14 mmol/L was associated with the lowest risk of dementia. BCAAs have the potential to serve as a biomarker for dementia and AD. However, the specific mechanism through which BCAAs are linked to the development of dementia, AD, and PD remains unclear and necessitates additional investigation.

Interplay Between Plasma Glycine and Branched-Chain Amino Acids Contributes to the Development of Hypertension and Coronary Heart Disease.

Higher levels of plasma glycine are linked to a reduced risk, while increased levels of total branched-chain amino acids (tBCAAs) are associated with a higher risk of essential hypertension (HTN) and coronary heart disease (CHD). As these metabolic components are interconnected, analyzing the tBCAAs/glycine ratio may help to understand their interplay in the pathogenesis of cardiovascular disease. The Cox regression approach was combined with the development of novel genetic tools for assessments of associations between plasma metabolomic data (glycine, tBCAAs, and tBCAAs/glycine ratio) from the UK Biobank and the development of hypertension and CHD. Genome-wide association study was performed on 186 523 White UK Biobank participants to identify new independent genetic instruments for the 2-sample Mendelian randomization analyses. P-gain statistic >10 identified instruments associated with tBCAAs/glycine ratio significantly stronger compared with individual amino acids. Outcomes of genome-wide association study on hypertension and CHD were derived from the UK Biobank (nonoverlapping sample), FinnGen, and CARDIoGRAMplusC4D. The tBCAAs/glycine ratio was prospectively associated with a higher risk of developing hypertension and CHD (hazard ratio quintile, Q5 versus Q1, 1.196 [95% CI, 1.109-1.289] and 1.1226 [95% CI, 1.160-1.1296], respectively). Mendelian randomization analysis demonstrated that tBCAAs/glycine ratio (P-gain >10) was a risk factor for hypertension (meta-analyzed inverse-variance weighted causal estimate 0.45 log odds ratio/SD (95% CI, 0.26-0.64) and CHD (0.48 [95% CI, 0.29-0.67]) with an absolute effect significantly larger compared with the effect of glycine (-0.06 [95% CI, -0.1 to -0.03] and -0.08 [95% CI, -0.11 to -0.05], respectively) or tBCAAs (0.22 95% CI, 0.09-0.34] and 0.12 [95% CI, 0.01-0.24], respectively). The total BCAAs/glycine ratio is a key element of the metabolic signature contributing to hypertension and CHD, which may reflect biological pathways shared by glycine and tBCAAs.

Excessive Tryptophan and Phenylalanine Induced Pancreatic Injury and Glycometabolism Disorder in Grower-finisher Pigs

BackgroundThe increase in circulating insulin levels is associated with the onset of type 2 diabetes (T2D), and the levels of branched-chain amino acids and aromatic amino acids (AAAs) are altered in T2D, but whether AAAs play a role in insulin secretion and signaling remains unclear. ObjectivesThis study aimed to investigate the effects of different AAAs on pancreatic function and on the use of insulin in finishing pigs. MethodsA total of 18 healthy finishing pigs (Large White) with average body weight of 100 ± 1.15 kg were randomly allocated to 3 dietary treatments: Con, a normal diet supplemented with 0.68% alanine; Phe, a normal diet supplemented with 1.26% phenylalanine; and Trp, a normal diet supplemented with 0.78% tryptophan. The 3 diets were isonitrogenous. There were 6 replicates in each group. ResultsHerein, we investigated the effects of tryptophan and phenylalanine on pancreatic function and the use of insulin in finishing pigs and found that the addition of tryptophan and phenylalanine aggravated pancreatic fat deposition, increased the relative content of saturated fatty acids, especially palmitate (C16:0) and stearate (C18:0), and the resulting lipid toxicity disrupted pancreatic secretory function. We also found that tryptophan and phenylalanine inhibited the growth and secretion of β-cells, downregulated the gene expression of the PI3K/Akt pathway in the pancreas and liver, and reduced glucose utilization in the liver. ConclusionsUsing fattening pigs as a model, multiorgan combined analysis of the insulin-secreting organ pancreas and the main insulin-acting organ liver, excessive intake of tryptophan and phenylalanine will aggravate pancreatic damage leading to glucose metabolism disorders, providing new evidence for the occurrence and development of T2D.

Plasma amino acids spectrum and Holter ECG monitoring indexes in coronary artery disease patients with atrial fibrillation

The research was conducted with the aim of establishing a connection between plasma amino acid peculiarities and Holter ECG monitoring indexes in Coronary Artery Disease (CAD) and Atrial Fibrillation (AF) patients. 300 patients were examined divided into 3 groups: I – 149 patients with CAD without arrhythmias, II – 124 patients with CAD and AF paroxysm, and the Control Group (CG) – 27 patients without CAD and arrhythmias. Holter ECG monitoring was performed for the patients with AF within 24 hours after sinus rhythm restoration, and for the patients without AF on the first day of observation. Plasma AA level was detected by the method of ion exchange liquid column chromatography. It was established that there is a significant increase glutamate and Branched-Chain Amino Acids (BCAA) levels in patients of the II group, and significant depletion in glycine levels comparison with the I group patients (p&lt;0.05). In the II group patients, an increase in SupraVentricular (SVE) and Ventricular Extrasystoles (VE) was checked in comparison with the I group patients (p&lt;0.05). Total SVE was significantly correlated with threonine (r=-0.316), serine (r=-0.336), glycine (r=-0.397), isoleucine (r=0.317), BCAA (r=0.356), and glycine+serine sum (r=-0.302), p&lt;0.05. AF paroxysm was significantly correlated with taurine (r=-0.302), serine (r=-0.328), glycine (r=-0.311), glutamine (r=-0.304), and glycine+serine sum (r=-0.379), p&lt;0.05. Total VE was significantly correlated with glycine (r=-0.370) and tyrosine (r=0.325), p&lt;0.05. Changes in ST-segment were significantly correlated with tyrosine (r=0.307), phenylalanine (r=0.318), and Aromatic Amino Acids (AAA) (r=0.379), p&lt;0.05. We concluded that glycine, serine, and BCAA are significantly correlated with cardiac arrhythmias. Changes in ST segment are significantly correlated with AAA levels. Keywords: heart rhythm violations, ischemia, arrhythmia, metabolomics.

Molecular mechanisms of metabolic dysregulation in diabetic cardiomyopathy.

Diabetic cardiomyopathy (DCM), one of the most serious complications of diabetes mellitus, has become recognized as a cardiometabolic disease. In normoxic conditions, the majority of the ATP production (>95%) required for heart beating comes from mitochondrial oxidative phosphorylation of fatty acids (FAs) and glucose, with the remaining portion coming from a variety of sources, including fructose, lactate, ketone bodies (KB) and branched chain amino acids (BCAA). Increased FA intake and decreased utilization of glucose and lactic acid were observed in the diabetic hearts of animal models and diabetic patients. Moreover, the polyol pathway is activated, and fructose metabolism is enhanced. The use of ketones as energy sources in human diabetic hearts also increases significantly. Furthermore, elevated BCAA levels and impaired BCAA metabolism were observed in the hearts of diabetic mice and patients. The shift in energy substrate preference in diabetic hearts results in increased oxygen consumption and impaired oxidative phosphorylation, leading to diabetic cardiomyopathy. However, the precise mechanisms by which impaired myocardial metabolic alterations result in diabetes mellitus cardiac disease are not fully understood. Therefore, this review focuses on the molecular mechanisms involved in alterations of myocardial energy metabolism. It not only adds more molecular targets for the diagnosis and treatment, but also provides an experimental foundation for screening novel therapeutic agents for diabetic cardiomyopathy.

Abstract 6627: Boosting macrophage-specific BCAA oxidation enhances immune activation within the tumor microenvironment and diminishes tumor growth in pancreatic cancer

Abstract Treating pancreatic ductal adenocarcinoma (PDAC) poses a significant challenge, mainly due to therapy resistance linked to the immunosuppressive tumor microenvironment (TME) within PDAC tumors. This TME is characterized by a fibrotic stroma and an abundance of immunosuppressive cells, notably tumor-associated macrophages (TAMs). TAMs crucially hinder effector T cell activity and contribute to T cell exhaustion. Redirecting TAMs toward an immunostimulatory state has emerged as a promising approach in PDAC treatment. Recent investigations, including our own studies, reveal a profound influence of metabolic pathways on the immune phenotype of TAMs. Specifically, dysregulation in branched-chain amino acid (BCAA) metabolism has been observed in PDAC patients, manifesting as elevated circulating BCAA levels correlating with a doubled risk of PDAC development. However, the extent to which BCAA metabolism influences TAM phenotype and anti-tumor immune responses remains a largely unexplored territory, presenting a challenge for PDAC treatment. Our focus revolves around understanding how heightened BCAA levels in PDAC affect TAM phenotype, the immunosuppressive tumor environment, and tumor progression. Employing an orthotopic PDAC model and genetically modified mice, specifically BCKDKfl/fl BCKDK LysMcre/+ (mimicking increased BCAA oxidation), alongside a BCKDK-targeting pharmacological inhibitor (BT-2), multicolor flow cytometry, and in vitro models, our research has revealed crucial insights. We found a diminished expression of BCAA oxidation genes in TAMs compared to normal pancreatic macrophages. Interestingly, M1 and M2 macrophages seemed to utilize BCAAs differently, reflected in varying levels of TCA cycle intermediates derived from BCAA oxidation. Notably, boosting BCAA oxidation specifically in TAMs through genetic modifications resulted in reduced PDAC growth associated with an enhanced immunostimulatory TAM phenotype and activation of CD8+ T cells in the TME. Conversely, administering BCAAs induced an immunosuppressive TAM phenotype, fostering PDAC growth, suggesting a direct influence of BCAAs on TAM phenotype. Pharmacologically enhancing BCAA oxidation via BT-2 bolstered immune activation within the tumor environment and reduced PDAC growth. Intriguingly, our analysis of publicly available data unveiled a significant correlation between high BCAA oxidation and favorable responses to anti-PD1 therapy in cancer patients. Our findings emphasize the pivotal role of BCAA metabolism in shaping the immune landscape of PDAC, offering potential avenues for therapeutic interventions targeting TAMs and mitigating TME immunosuppression. Citation Format: Gauri Mirji, Sajad Ahmad Bhat, Zachary Schug, Ben Z. Stanger, Zoltan Arany, Rahul S. Shinde. Boosting macrophage-specific BCAA oxidation enhances immune activation within the tumor microenvironment and diminishes tumor growth in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6627.

Alterations in the gut microbiota and its metabolites contribute to metabolic maladaptation in dairy cows during the development of hyperketonemia.

Metabolic maladaptation in dairy cows after calving can lead to long-term elevation of ketones, such as β-hydroxybutyrate (BHB), representing the condition known as hyperketonemia, which greatly influences the health and production performance of cows during the lactation period. Although the gut microbiota is known to alter in dairy cows with hyperketonemia, the association of microbial metabolites with development of hyperketonemia remains unknown. In this study, we performed a multi-omics analysis to investigate the associations between fecal microbial community, fecal/plasma metabolites, and serum markers in hyperketonemic dairy cows during the transition period. Dynamic changes in the abundance of the phyla Verrucomicrobiota and Proteobacteria were detected in the gut microbiota of dairy cows, representing an adaptation to enhanced lipolysis and abnormal glucose metabolism after calving. Random forest and univariate analyses indicated that Frisingicoccus is a key bacterial genus in the gut of cows during the development of hyperketonemia, and its abundance was positively correlated with circulating branched-chain amino acid levels and the ketogenesis pathway. Taurodeoxycholic acid, belonging to the microbial metabolite, was strongly correlated with an increase in blood BHB level, and the levels of other secondary bile acid in the feces and plasma were altered in dairy cows prior to the diagnosis of hyperketonemia, which link the gut microbiota and hyperketonemia. Our results suggest that alterations in the gut microbiota and its metabolites contribute to excessive lipolysis and insulin insensitivity during the development of hyperketonemia, providing fundamental knowledge about manipulation of gut microbiome to improve metabolic adaptability in transition dairy cows.IMPORTANCEAccumulating evidence is pointing to an important association between gut microbiota-derived metabolites and metabolic disorders in humans and animals; however, this association in dairy cows from late gestation to early lactation is poorly understood. To address this gap, we integrated longitudinal gut microbial (feces) and metabolic (feces and plasma) profiles to characterize the phenotypic differences between healthy and hyperketonemic dairy cows from late gestation to early lactation. Our results demonstrate that cows underwent excessive lipid mobilization and insulin insensitivity before hyperketonemia was evident. The bile acids are functional readouts that link gut microbiota and host phenotypes in the development of hyperketonemia. Thus, this work provides new insight into the mechanisms involved in metabolic adaptation during the transition period to adjust to the high energy and metabolic demands after calving and during lactation, which can offer new strategies for livestock management involving intervention of the gut microbiome to facilitate metabolic adaptation.

Association between branched-chain amino acids and renal function in the ELSA-Brasil study

Epidemiologic studies show high circulating Branched-chain amino acids (BCAA) are associated with excess body weight, impaired fasting glucose, insulin resistance, high blood pressure, and dyslipidemia. There is scarce data on the association between renal function and circulating levels of BCAA. Therefore, we aim to study this association in a sample of the Brazilian Longitudinal Study of Adults (ELSA-Brasil) METHODS: We analyzed participants who had at the baseline BCAA: valine, isoleucine, and leucine measured through nuclear magnetic resonance. The outcomes evaluated were estimated glomerular function (eGFR - CKD-EPI without race) and 12h-albumin-creatinine ratio (ACR). In addition, we built unadjusted and adjusted multivariable linear regression models to investigate the association between the BCAA (total and individual) and eGFR and ACR. We studied 4912 participants (age 51.7(±9.0) years, 53.4% women, 59.5% White (59.5%), 32.7% hypertension, and 18.2% diabetes). The mean BCAA level was 429.15±87.15. The mean eGFR was 84.95±15ml/min/1.73m2, and the median ACR was 6.5 (1.8-4920) mg/g. Descriptive analyses comparing eGFR stratified <60ml/min/1.73m2 and ACR≥30mg/g demonstrate that BCAA levels are higher in patients with eGFR<60 and ACR ≥30. Regarding eGFR, an inverse association was detected with BCAA levels when adjusted for demographic variables, and it is not maintained after adjustments for other confounders. Also, a positive association was found for ACR≥30mg/g, and BCAA levels, and this association is not confirmed after adjustments. BCAA levels were inversely associated with eGFR and positively associated with ACR. Further studies are necessary to allow the comprehension of those associations.

Maintenance of the branched-chain amino acid transporter LAT1 counteracts myotube atrophy following chemotherapy.

Prevention/management of cachexia remains a critical issue in muscle wasting conditions. The branched-chain amino acids (BCAA) have anabolic properties in skeletal muscle, but their use in treating cachexia has minimal benefits. This may be related to altered BCAA metabolism consequent to the use of chemotherapy, a main cancer treatment. Since this topic is minimally studied, we investigated the effect of chemotherapy on BCAA concentrations, transporter expression, and their metabolism. L6 myotubes were treated with vehicle (1.4 μL/mL DMSO) or a chemotherapy drug cocktail, FOLFIRI [CPT-11 (20 μg/mL), leucovorin (10 μg/mL), and 5-fluorouracil (50 μg/mL)] for 24-48 h. Chemotherapy reduced myotube diameter (-43%), myofibrillar protein content (-50%), and phosphorylation of the mechanistic target of rapamycin complex 1 (mTORC1) substrate S6K1thr389 (-80%). Drug-treated myotubes exhibited decreased BCAA concentrations (-52%) and expression of their transporter, L-type amino acid transporter 1 (LAT1; -67%). BCAA transaminase BCAT2 level was increased, but there was a reduction in PP2CM (-54%), along with increased inhibitory phosphorylation of BCKD-E1αser293 (+98%), corresponding with decreased BCKD enzyme activity (-23%) in chemotherapy-treated myotubes. Decreases in BCAA concentrations were a later response, preceded by decreases in LAT1 and BCKD activity. Although supplementation with the BCAA restored myotube BCAA levels, it had minimal effects on preventing the loss of myofibrillar proteins. However, RNAi-mediated depletion of neural precursor cell-expressed developmentally downregulated gene 4 (NEdd4), the protein ligase responsible for ubiquitin-dependent degradation of LAT1, attenuated the effects of chemotherapy on BCAA concentrations, anabolic signaling, protein synthesis, and myofibrillar protein abundance. Thus, if our findings are validated in preclinical models, interventions regulating muscle amino acid transporters might represent a promising strategy to treat cachexia.NEW & NOTEWORTHY This is the first study to attenuate chemotherapy-induced myotube atrophy by manipulating a BCAA transporter. Our findings suggest that positive regulation of amino acid transporters may be a promising strategy to treat cachexia.

Branched-chain amino acid supplementation drives dynamic changes in gut microbiota without impairing glucose and lipid homeostasis at the different stages of insulin resistance in mice on a high-fat diet

ObjectiveThe potential role of dietary branched-chain amino acids on circulating branched-chain amino acid levels and their relationship with metabolic health are complex, and the literature is inconsistent. We aimed to explore the dynamic effects of branched-chain amino acid supplementation on glucose and lipid homeostasis at different stages of insulin resistance in high-fat diet–fed mice. MethodsMale C57BL/6J mice were fed with a normal chow diet, high-fat diet, or high-fat diet supplemented with 100% branched-chain amino acids for 12 or 24 wk. Metabolic parameters and gut microbiota profiling were performed at these two time points. ResultsHigh-fat diet feeding caused varying degrees of branched-chain amino acid metabolic disorders in two different stages of insulin resistance. Supplementing with branched-chain amino acids further exacerbated branched-chain amino acid accumulation in the early stage of insulin resistance (12 wk), while adding branched-chain amino acids did not further elevate branched-chain amino acid levels in the hyperglycemia and hyperinsulinemia stage (24 wk). Compared with the high-fat diet group, branched-chain amino acid supplementation did not affect body weight; liver total cholesterol and triacylglycerol levels; and serum glucose, insulin, total cholesterol, triacylglycerol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol levels as well as glucose tolerance at these two time points but triggered dynamic changes in the gut bacterial diversity and gut microbiota composition and abundance, especially in the genus associated with obesity and related metabolic disorders. ConclusionDietary branched-chain amino acid supplementation drives dynamic changes in circulating branched-chain amino acid levels and gut microbiome without subsequent effects on glucose and lipid homeostasis in high-fat diet–induced obese mice within the parameters of our study.

Bergenin Alleviates Ulcerative Colitis By Decreasing Gut Commensal Bacteroides vulgatus-Mediated Elevated Branched-Chain Amino Acids.

Ulcerative colitis is closely associated with the dysregulation of gut microbiota. There is growing evidence that natural products may improve ulcerative colitis by regulating the gut microbiota. In this research, we demonstrated that bergenin, a naturally occurring isocoumarin, significantly ameliorates colitis symptoms in dextran sulfate sodium (DSS)-induced mice. Transcriptomic analysis and Caco-2 cell assays revealed that bergenin could ameliorate ulcerative colitis by inhibiting TLR4 and regulating NF-κB and mTOR phosphorylation. 16S rRNA sequencing and metabolomics analyses revealed that bergenin could improve gut microbiota dysbiosis by decreasing branched-chain amino acid (BCAA) levels. BCAA intervention mediated the mTOR/p70S6K signaling pathway to exacerbate the symptoms of ulcerative colitis in mice. Notably, bergenin greatly decreased the symbiotic bacteria Bacteroides vulgatus (B. vulgatus), and the gavage of B. vulgatus increased BCAA concentrations and aggravated the symptoms of ulcerative colitis in mice. Our findings suggest that gut microbiota-mediated BCAA metabolism plays a vital role in the protective effect of bergenin on ulcerative colitis, providing novel insights for ulcerative colitis prevention through manipulation of the gut microbiota.

Branched-chain amino acid levels are inversely associated with incident and prevalent chronic kidney disease in people with type 2 diabetes.

To investigate the association of plasma metabolites with incident and prevalent chronic kidney disease (CKD) in people with type 2 diabetes and establish whether this association is causal. The Hoorn Diabetes Care System cohort is a large prospective cohort consisting of individuals with type 2 diabetes from the northwest part of the Netherlands. In this cohort we assessed the association of baseline plasma levels of 172 metabolites with incident (Ntotal = 462/Ncase = 81) and prevalent (Ntotal = 1247/Ncase = 120) CKD using logistic regression. Additionally, replication in the UK Biobank, body mass index (BMI) mediation and causality of the association with Mendelian randomization was performed. Elevated levels of total and individual branched-chain amino acids (BCAAs)-valine, leucine and isoleucine-were associated with an increased risk of incident CKD, but with reduced odds of prevalent CKD, where BMI was identified as an effect modifier. The observed inverse effects were replicated in the UK Biobank. Mendelian randomization analysis did not provide evidence for a causal relationship between BCAAs and prevalent CKD. Our study shows the intricate relationship between plasma BCAA levels and CKD in individuals with type 2 diabetes. While an association exists, its manifestation varies based on disease status and BMI, with no definitive evidence supporting a causal link between BCAAs and prevalent CKD.

Abomasal infusion of branched-chain amino acids or branched-chain keto-acids alter lactation performance and liver triglycerides in fresh cows

BackgroundDairy cows are at high risk of fatty liver disease in early lactation, but current preventative measures are not always effective. Cows with fatty liver have lower circulating branched-chain amino acid (BCAA) concentrations whereas cows with high circulating BCAA levels have low liver triglyceride (TG). Our objective was to determine the impact of BCAA and their corresponding ketoacids (branched-chain ketoacids, BCKA) on production performance and liver TG accumulation in Holstein cows in the first 3 weeks postpartum.MethodsThirty-six multiparous Holstein cows were used in a randomized block design experiment. Cows were abomasally infused for the first 21 d postpartum with solutions of 1) saline (CON, n = 12); 2) BCA (67 g valine, 50 g leucine, and 34 g isoleucine, n = 12); and 3) BCK (77 g 2-ketovaline calcium salt, 57 g 2-ketoleucine calcium salt, and 39 g 2-ketoisoleucine calcium salt, n = 12). All cows received the same diet. Treatment effects were determined using PROC GLIMMIX in SAS.ResultsNo differences were detected for body weight, body condition score, or dry matter intake averaged over the first 21 d postpartum. Cows receiving BCK had significantly lower liver TG concentrations compared to CON (6.60% vs. 4.77%, standard error of the mean (SEM) 0.49) during the first 3 weeks of lactation. Infusion of BCA increased milk yield (39.5 vs. 35.3 kg/d, SEM 1.8), milk fat yield (2.10 vs. 1.69 kg/d, SEM 0.08), and lactose yield (2.11 vs. 1.67 kg/d, SEM 0.07) compared with CON. Compared to CON, cows receiving BCA had lower plasma glucose (55.0 vs. 59.2 mg/dL, SEM 0.86) but higher β-hydroxybutyrate (9.17 vs. 6.00 mg/dL, SEM 0.80).ConclusionsOverall, BCAA supplementation in this study improved milk production, whereas BCKA supplementation reduced TG accumulation in the liver of fresh cows.Graphical