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PURPOSE: To investigate the associations between dietary/serum branched-chain amino acids (BCAAs) and cardiometabolic risk markers. METHODS: In a cohort of 2791 participants, diet and cardiometabolic risk markers were measured twice at baseline in overall participants and after 1-year in a subset of 423 participants. We assessed serum BCAAs at baseline and arterial stiffness after 1-year. The cross-sectional associations between dietary/serum BCAAs and cardiometabolic risk markers were analyzed using baseline measurements by linear regression, while the 1-year longitudinal association were analyzed using repeated measurements by linear mixed-effects regression. RESULTS: Higher BCAA intake from poultry was associated with lower triglycerides (ß=-0.028, P = 0.027) and higher high-density lipoprotein cholesterol (HDL-C, ß = 0.013, P = 0.006), while BCAAs in red and processed meat or fish were inversely associated with low-density lipoprotein cholesterol (ß = 0.025, P = 0.001) and total cholesterol (ß = 0.012, P = 0.033), respectively. BCAAs in whole grains and nuts were associated with higher HDL-C (ß = 0.011, P = 0.016), and lower TG (ß=-0.021, P = 0.041) and diastolic blood pressure (ß=-0.003, P = 0.027). Also, BCAAs from soy or vegetables and fruits were inversely associated with arterial stiffness (ß=-0.018, P = 0.047) and systolic blood pressure (ß=-0.011, P = 0.003), respectively. However, BCAAs in refined grains were positively associated with triglycerides (ß = 0.037, P = 0.014). Total serum BCAAs were unfavorably associated with multiple cardiometabolic risk markers (all P < 0.05). CONCLUSION: Dietary BCAAs in poultry, whole grains and nuts, soy, and vegetables and fruits may be favorably, while BCAAs in red and processed meat, fish, and refined grains were unfavorably associated with cardiometabolic health. Serum BCAAs showed a detrimental association with cardiometabolic risk markers.
Assuntos
Aminoácidos de Cadeia Ramificada , Biomarcadores , Fatores de Risco Cardiometabólico , Dieta , Humanos , Masculino , Aminoácidos de Cadeia Ramificada/sangue , Feminino , Pessoa de Meia-Idade , Estudos Transversais , Biomarcadores/sangue , Dieta/métodos , Dieta/estatística & dados numéricos , Vida Independente , Adulto , Triglicerídeos/sangue , Estudos de Coortes , HDL-Colesterol/sangue , Estudos Longitudinais , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/epidemiologia , Idoso , Animais , Rigidez Vascular/fisiologia , Grãos Integrais , Nozes , Aves Domésticas , CarneRESUMO
BACKGROUND: Emerging evidence suggests that alterations in BCAA metabolism may contribute to the pathogenesis of sarcopenia. However, the relationship between branched-chain amino acids (BCAAs) and sarcopenia is incompletely understood, and existing literature presents conflicting results. In this study, we conducted a community-based study involving > 100,000 United Kingdom adults to comprehensively explore the association between BCAAs and sarcopenia, and assess the potential role of muscle mass in mediating the relationship between BCAAs and muscle strength. METHODS: Multivariable linear regression analysis examined the relationship between circulating BCAAs and muscle mass/strength. Logistic regression analysis assessed the impact of circulating BCAAs and quartiles of BCAAs on sarcopenia risk. Subgroup analyses explored the variations in associations across age, and gender. Mediation analysis investigated the potential mediating effect of muscle mass on the BCAA-muscle strength relationship. RESULTS: Among 108,017 participants (mean age: 56.40 ± 8.09 years; 46.23% men), positive associations were observed between total BCAA, isoleucine, leucine, valine, and muscle mass (beta, 0.56-2.53; p < 0.05) and between total BCAA, leucine, valine, and muscle strength (beta, 0.91-3.44; p < 0.05). Logistic regression analysis revealed that increased circulating valine was associated with a 47% reduced sarcopenia risk (odds ratio = 0.53; 95% confidence interval = 0.3-0.94; p = 0.029). Subgroup analyses demonstrated strong associations between circulating BCAAs and muscle mass/strength in men and individuals aged ≥ 60 years. Mediation analysis suggested that muscle mass completely mediated the relationship between total BCAA, and valine levels and muscle strength, partially mediated the relationship between leucine levels and muscle strength, obscuring the true effect of isoleucine on muscle strength. CONCLUSION: This study suggested the potential benefits of BCAAs in preserving muscle mass/strength and highlighted muscle mass might be mediator of BCAA-muscle strength association. Our findings contribute new evidence for the clinical prevention and treatment of sarcopenia and related conditions involving muscle mass/strength loss.
Assuntos
Aminoácidos de Cadeia Ramificada , Força Muscular , Sarcopenia , Humanos , Sarcopenia/sangue , Sarcopenia/epidemiologia , Masculino , Feminino , Estudos Transversais , Aminoácidos de Cadeia Ramificada/sangue , Pessoa de Meia-Idade , Força Muscular/fisiologia , Idoso , Reino Unido/epidemiologia , Músculo Esquelético/metabolismo , AdultoRESUMO
Male hypogonadism is a disorder characterized by low levels of testosterone, but patients can either show normal insulin (insulin-sensitive (IS)) or over time they can become insulin-resistant (IR). Since the two groups showed different altered metabolisms, testosterone replacement therapy (TRT) could achieve different results. In this paper, we analyzed plasma from 20 IS patients with low testosterone (<8 nmol/L) and HOMAi < 2.5. The samples, pre- and post-treatment with testosterone for 60 days, were analyzed by UHPLC and mass spectrometry. Glycolysis was significantly upregulated, suggesting an improved glucose utilization. Conversely, the pentose phosphate pathway was reduced, while the Krebs cycle was not used. Branched amino acids and carnosine metabolism were positively influenced, while ß-oxidation of fatty acids (FFA) was not activated. Cholesterol, HDL, and lipid metabolism did not show any improvements at 60 days but did so later in the experimental period. Finally, both malate and glycerol shuttle were reduced. As a result, both NADH and ATP were significantly lower. Interestingly, a significant production of lactate was observed, which induced the activation of the Cori cycle between the liver and muscles, which became the main source of energy for these patients without involving alanine. Thus, the treatment must be integrated with chemicals which are not restored in order to reactivate energy production.
Assuntos
Aminoácidos de Cadeia Ramificada/sangue , Carnosina/sangue , Glicerol/sangue , Terapia de Reposição Hormonal/métodos , Hipogonadismo/tratamento farmacológico , Malatos/sangue , Metabolômica/métodos , Adulto , Estudos de Casos e Controles , Cromatografia Líquida de Alta Pressão , Glicólise , Humanos , Hipogonadismo/sangue , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Via de Pentose FosfatoRESUMO
BACKGROUND: Ageing and insulin resistant states such as diabetes mellitus frequently coexist and increase the risk of cardiovascular disease development among older adults. Here we investigate metabolic differences in amino acid profiles between ageing and diabetes mellitus, and their associations with cardiovascular function. METHODS: In a group of community older adults we performed echocardiography, cardiac magnetic resonance imaging as well as cross sectional and longitudinal metabolomics profiling based on current and archived sera obtained fifteen years prior to examination. RESULTS: We studied a total of 515 participants (women 50%, n = 255) with a mean age 73 (SD = 4.3) years. Diabetics had higher alanine (562 vs 448, p < 0.0001), higher glutamate (107 vs 95, p = 0.016), higher proline (264 vs 231, p = 0.008) and lower arginine (107 vs 117, p = 0.043), lower citrulline (30 vs 38, p = 0.006) levels (µM) compared to non-diabetics. Over time, changes in amino acid profiles differentiated diabetic older adults from non-diabetic older adults, with greater accumulation of alanine (p = 0.002), proline (p = 0.008) and (non-significant) trend towards greater accumulation of glycine (p = 0.057) among the older diabetics compared to the older non-diabetics. However, independent of diabetes status, amino acids were associated with cardiovascular functions in ageing, [archived valine (p = 0.011), leucine (p = 0.011), archived isoleucine (p = 0.0006), archived serine (p = 0.008), archived glycine (p = 0.006) methionine (p = 0.003)] which were associated with impairments in E/A ratio. CONCLUSION: Markers of branched chain amino acids and one carbon metabolism pathways were associated with changes in cardiovascular function in older adults regardless of diabetes status. However, nitrogen handling pathways were specifically altered among older adults with diabetes. These findings broaden our understanding into specific amino acid pathways that may be altered between diabetic and non-diabetic older adults, and their relevance to cardiovascular function in ageing. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02791139.
Assuntos
Envelhecimento/sangue , Aminoácidos de Cadeia Ramificada/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/epidemiologia , Diabetes Mellitus/sangue , Diabetes Mellitus/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Doenças Cardiovasculares/diagnóstico por imagem , China/epidemiologia , Comorbidade , Estudos Transversais , Ecocardiografia/métodos , Feminino , Humanos , Estudos Longitudinais , Espectroscopia de Ressonância Magnética/métodos , Masculino , Metaboloma , Metabolômica/métodos , Estudos Prospectivos , Fatores de RiscoRESUMO
Branched-chain α-keto acids (BCKAs) are catabolites of branched-chain amino acids (BCAAs). Intracellular BCKAs are cleared by branched-chain ketoacid dehydrogenase (BCKDH), which is sensitive to inhibitory phosphorylation by BCKD kinase (BCKDK). Accumulation of BCKAs is an indicator of defective BCAA catabolism and has been correlated with glucose intolerance and cardiac dysfunction. However, it is unclear whether BCKAs directly alter insulin signaling and function in the skeletal and cardiac muscle cell. Furthermore, the role of excess fatty acids (FAs) in perturbing BCAA catabolism and BCKA availability merits investigation. By using immunoblotting and ultra-performance liquid chromatography MS/MS to analyze the hearts of fasted mice, we observed decreased BCAA-catabolizing enzyme expression and increased circulating BCKAs, but not BCAAs. In mice subjected to diet-induced obesity (DIO), we observed similar increases in circulating BCKAs with concomitant changes in BCAA-catabolizing enzyme expression only in the skeletal muscle. Effects of DIO were recapitulated by simulating lipotoxicity in skeletal muscle cells treated with saturated FA, palmitate. Exposure of muscle cells to high concentrations of BCKAs resulted in inhibition of insulin-induced AKT phosphorylation, decreased glucose uptake, and mitochondrial oxygen consumption. Altering intracellular clearance of BCKAs by genetic modulation of BCKDK and BCKDHA expression showed similar effects on AKT phosphorylation. BCKAs increased protein translation and mTORC1 activation. Pretreating cells with mTORC1 inhibitor rapamycin restored BCKA's effect on insulin-induced AKT phosphorylation. This study provides evidence for FA-mediated regulation of BCAA-catabolizing enzymes and BCKA content and highlights the biological role of BCKAs in regulating muscle insulin signaling and function.
Assuntos
Aminoácidos de Cadeia Ramificada/metabolismo , Insulina/metabolismo , Músculo Esquelético/metabolismo , 3-Metil-2-Oxobutanoato Desidrogenase (Lipoamida)/antagonistas & inibidores , 3-Metil-2-Oxobutanoato Desidrogenase (Lipoamida)/genética , 3-Metil-2-Oxobutanoato Desidrogenase (Lipoamida)/metabolismo , Aminoácidos de Cadeia Ramificada/sangue , Animais , Linhagem Celular , Dieta Hiperlipídica , Regulação para Baixo/efeitos dos fármacos , Insulina/farmacologia , Cetoácidos/sangue , Cetoácidos/metabolismo , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/citologia , Miocárdio/metabolismo , Palmitatos/farmacologia , Proteína Fosfatase 2/antagonistas & inibidores , Proteína Fosfatase 2/genética , Proteína Fosfatase 2/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND: Elevations of circulating branched-chain amino acids (BCAA) are observed in humans with obesity and metabolic comorbidities, such as insulin resistance. Although it has been described that microbial metabolism contributes to the circulating pool of these amino acids, studies are still scarce, particularly in pediatric populations. Thus, we aimed to explore whether in early adolescents, gut microbiome was associated to circulating BCAA and in this way to insulin resistance. METHODS: Shotgun sequencing was performed in DNA from fecal samples of 23 early adolescents (10-12 years old) and amino acid targeted metabolomics analysis was performed by LC-MS/MS in serum samples. By using the HUMAnN2 algorithm we explored microbiome functional profiles to identify whether bacterial metabolism contributed to serum BCAA levels and insulin resistance markers. RESULTS: We identified that abundance of genes encoding bacterial BCAA inward transporters were negatively correlated with circulating BCAA and HOMA-IR (P < 0.01). Interestingly, Faecalibacterium prausnitzii contributed to approximately ~ 70% of bacterial BCAA transporters gene count. Moreover, Faecalibacterium prausnitzii abundance was also negatively correlated with circulating BCAA (P = 0.001) and with HOMA-IR (P = 0.018), after adjusting for age, sex and body adiposity. Finally, the association between Faecalibacterium genus and BCAA levels was replicated over an extended data set (N = 124). CONCLUSIONS: We provide evidence that gut bacterial BCAA transport genes, mainly encoded by Faecalibacterium prausnitzii, are associated with lower circulating BCAA and lower insulin resistance. Based on the later, we propose that the relationship between Faecalibacterium prausnitzii and insulin resistance, could be through modulation of BCAA.
Assuntos
Aminoácidos de Cadeia Ramificada/sangue , Faecalibacterium prausnitzii/fisiologia , Microbioma Gastrointestinal , Adolescente , Fatores Etários , Aminoácidos de Cadeia Ramificada/metabolismo , Biomarcadores , Pesos e Medidas Corporais , Criança , Feminino , Humanos , Resistência à Insulina , Masculino , Metabolômica/métodos , Metagenoma , Metagenômica/métodos , Obesidade/metabolismo , Vigilância em Saúde PúblicaRESUMO
BACKGROUND AND AIMS: The progression of nonalcoholic fatty liver disease (NAFLD) into severe histological forms (steatohepatitis - NASH) is paralleled by the occurrence of complex molecular processes. Mitochondrial dysfunction is a hallmark feature of advanced disease. Mitochondrially encoded cytochrome B (cytochrome b, MT-CYB), a member of the oxidative phosphorylation system, is a key component of the respirasome supercomplex. Here, we hypothesized that NAFLD severity is associated with liver tissue cytochrome b mutations and damaged mitochondrial DNA (mtDNA). METHODS: We included 252 liver specimens of NAFLD patients - in whom histological disease ranged from mild to severe - which were linked to clinical and biochemical information. Tissue molecular explorations included MT-CYB sequencing and analysis of differential mtDNA damage. Profiling of circulating Krebs cycle metabolites and global liver transcriptome was performed in a subsample of patients. Tissue levels of 4-hydroxynonenal - a product of lipid peroxidation and 8-hydroxy-2'-deoxyguanosine, a marker of oxidative damage - were measured. RESULTS: Compared to simple steatosis, NASH is associated with a higher level of MT-CYB variance, 12.1 vs. 15.6 substitutions per 103 bp (P = 5.5e-10). The burden of variants was associated with increased levels of 2-hydroxyglutarate, branched-chain amino acids, and glutamate, and changes in the global liver transcriptome. Liver mtDNA damage was associated with advanced disease and inflammation. NAFLD severity was associated with increased tissue levels of DNA oxidative adducts and lipid peroxyl radicals. CONCLUSION: NASH is associated with genetic alterations of the liver cellular respirasome, including high cytochrome b variation and mtDNA damage, which may result in broad cellular effects.
Assuntos
Citocromos b/genética , Dano ao DNA , DNA Mitocondrial , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , 8-Hidroxi-2'-Desoxiguanosina/sangue , Adulto , Idoso , Aldeídos/sangue , Aminoácidos de Cadeia Ramificada/sangue , Progressão da Doença , Ácido Glutâmico/sangue , Glutaratos/sangue , Humanos , Peroxidação de Lipídeos , Pessoa de Meia-Idade , Mutação , Hepatopatia Gordurosa não Alcoólica/complicações , Obesidade/complicações , Obesidade/genética , Obesidade/metabolismo , Fosforilação Oxidativa , Estresse Oxidativo , Índice de Gravidade de Doença , TranscriptomaRESUMO
AIMS: To evaluate whether the association between plasma branched-chain amino acids (BCAA) and intrahepatic lipid (IHL) was affected by physical activity level. Furthermore, to investigate if a conventional exercise training program, a subcategory of physical activity, could lower plasma BCAA along with alterations in IHL content in patients with type 2 diabetes (T2DM) and people with nonalcoholic fatty liver (NAFL). METHODS: To investigate the effect of physical activity on the association between plasma BCAA and IHL content, linear regression analyses were performed in 1983 individuals from the Netherlands Epidemiology of Obesity (NEO) stratified by physical activity frequency. Furthermore, the effect of a 12-week supervised combined aerobic resistance-exercise program on plasma BCAA, insulin sensitivity (hyperinsulinemic-euglycemic clamp), and IHL (proton-magnetic resonance spectroscopy (1H-MRS)) was investigated in seven patients with T2DM, seven individuals with NAFL and seven BMI-matched control participants (CON). RESULTS: We observed positive associations between plasma valine, isoleucine and leucine level, and IHL content (1.29 (95% CI: 1.21, 1.38), 1.52 (95% CI: 1.43, 1.61), and 1.54 (95% CI: 1.44, 1.64) times IHL, respectively, per standard deviation of plasma amino acid level). Similar associations were observed in less active versus more active individuals. Exercise training did not change plasma BCAA levels among groups, but reduced IHL content in NAFL (from 11.6 ± 3.0% pre-exercise to 8.1 ± 2.0% post exercise, p < 0.05) and CON (from 2.4 ± 0.6% pre-exercise to 1.6 ± 1.4% post exercise, p < 0.05), and improved peripheral insulin sensitivity in NAFL as well by ~23% (p < 0.05). CONCLUSIONS: The association between plasma BCAA levels and IHL is not affected by physical activity level. Exercise training reduced IHL without affecting plasma BCAA levels in individuals with NAFL and CON. We conclude that exercise training-induced reduction in IHL content is not related to changes in plasma BCAA levels. TRIAL REGISTRATION: Trial registry number: NCT01317576.
Assuntos
Aminoácidos de Cadeia Ramificada/sangue , Exercício Físico , Lipídeos/análise , Fígado , Obesidade , Idoso , Estudos Transversais , Diabetes Mellitus Tipo 2/metabolismo , Exercício Físico/fisiologia , Exercício Físico/estatística & dados numéricos , Humanos , Metabolismo dos Lipídeos/fisiologia , Fígado/diagnóstico por imagem , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/sangue , Obesidade/epidemiologia , Obesidade/metabolismoRESUMO
Alisol B 23-acetate (AB23A) is a natural triterpenoid isolated from Rhizoma alisamatis that has been widely used as a traditional Chinese medicine (TCM). Previous studies have documented the beneficial effect of AB23A on non-alcoholic fatty liver disease (NAFLD), but the functional interactions between gut microbiota and the anti-NAFLD effect of AB23A remain unclear. In this study, we investigated the benefits of experimental treatment with AB23A on gut microbiota dysbiosis in NAFLD with an obesity model. C57BL/6J mice were administrated a high-fat diet (HFD) with or without AB23A for 12 weeks. AB23A significantly improved metabolic phenotype in the HFD-fed mice. Moreover, results of 16S rRNA gene-based amplicon sequencing in each group reveled that AB23A not only reduced the abundance of the Firmicutes/Bacteroidaeota ratio and Actinobacteriota/Bacteroidaeota ratio, but regulated the abundance of the top 10 genera, including norank_f__Muribaculaceae, Lactobacillus, Ileibacterium, Turicibacter, Faecalibaculum, the Lachnospiraceae_NK4A136_group, unclassified_f__Lachnospiraceae, and norank_f__Lachnospiraceae. AB23A significantly reduced the serum levels of lipopolysaccharide and branched-chain amino acids, which are positively correlated with the abundances of Ileibacterium and Turicibacter. Moreover, AB23A led to remarkable reductions in the activation of TLR4, NF-κB, and mTOR, and upregulated the expression of tight junction proteins, including ZO-1 and occludin. These results revealed that AB23A displayed a prebiotic capacity in HFD-fed NAFLD mice.
Assuntos
Aminoácidos de Cadeia Ramificada/sangue , Colestenonas/farmacologia , Dieta Hiperlipídica , Lipopolissacarídeos/sangue , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Probióticos , Animais , Peso Corporal/efeitos dos fármacos , Microbioma Gastrointestinal , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/metabolismo , RNA Ribossômico 16S/genética , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Receptor 4 Toll-Like/antagonistas & inibidores , Receptor 4 Toll-Like/metabolismo , Aumento de Peso/efeitos dos fármacosRESUMO
Heart failure (HF) causes a hypercatabolic state that enhances the catabolic activity of branched-chain amino acids (BCAA; leucine, isoleucine, and valine) in the heart and skeletal muscles and reduces protein synthesis in the liver. Consequently, free plasma aromatic amino acids (AAA, tyrosine and phenylalanine) are increased. To date, we have reported the prognostic value of the BCAA/AAA ratio (Fischer's ratio) in patients with HF. However, the leucine/phenylalanine ratio, which is a simpler index than the Fischer's ratio, has not been examined. Therefore, the prognostic value of the leucine/phenylalanine ratio in patients with HF was investigated. Overall 157 consecutive patients hospitalized for worsening HF (81 men, median age 78 years) were enrolled in the study. Plasma amino acid levels were measured when the patients were stabilized at discharge. Cardiac events were defined as a composite of cardiac death and hospitalization for worsening HF. A total of 46 cardiac events occurred during the median follow-up period of 238 (interquartile range 93-365) days. The median leucine/phenylalanine ratio was significantly lower in patients with cardiac events than in those without cardiac events (1.4 vs. 1.8, P < 0.001). The best cutoff value of the leucine/phenylalanine ratio was determined as 1.7 in the receiver operating characteristic (ROC) curve for cardiac events. Following a Kaplan-Meier survival analysis, the low group (leucine/phenylalanine ratio < 1.7, n = 72) had more cardiac events than the high group (leucine/phenylalanine ratio ≥ 1.7, n = 85) (log-rank, P < 0.001). Multivariate Cox proportional hazards regression analysis showed that the leucine/phenylalanine ratio was an independent predictor of cardiac events. Furthermore, on comparing the prognostic values for cardiac events based on ROC curves of leucine levels, BCAA levels, Fischer's ratio, and leucine/phenylalanine ratio, the leucine/phenylalanine ratio was the most accurate in predicting future cardiac events (area under the curve 0.763,; sensitivity 0.783,; specificity 0.676,; P < 0.001). The leucine/phenylalanine ratio could be a useful predictor of future cardiac events in patients with HF, reflecting an imbalance in amino acid metabolism.
Assuntos
Aminoácidos de Cadeia Ramificada/sangue , Insuficiência Cardíaca/sangue , Leucina/sangue , Fenilalanina/sangue , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Curva ROC , Estudos RetrospectivosRESUMO
BACKGROUND: Depression is one of the most common and untreated comorbidities in chronic obstructive pulmonary disease (COPD), and is associated with poor health outcomes (e.g. increased hospitalization/exacerbation rates). Although metabolic disturbances have been suggested in depressed non-diseased conditions, comprehensive metabolic phenotyping has never been conducted in those with COPD. We examined whether depressed COPD patients have certain clinical/functional features and exhibit a specific amino acid phenotype which may guide the development of targeted (nutritional) therapies. METHODS: Seventy-eight outpatients with moderate to severe COPD (GOLD II-IV) were stratified based on presence of depression using a validated questionnaire. Lung function, disease history, habitual physical activity and protein intake, body composition, cognitive and physical performance, and quality of life were measured. Comprehensive metabolic flux analysis was conducted by pulse stable amino acid isotope administration. We obtained blood samples to measure postabsorptive kinetics (production and clearance rates) and plasma concentrations of amino acids by LC-MS/MS. Data are expressed as mean [95% CI]. Stats were done by graphpad Prism 9.1.0. É < 0.05. RESULTS: The COPD depressed (CD, n = 27) patients on average had mild depression, were obese (BMI: 31.7 [28.4, 34.9] kg/m2), and were characterized by shorter 6-min walk distance (P = 0.055), physical inactivity (P = 0.03), and poor quality of life (P = 0.01) compared to the non-depressed COPD (CN, n = 51) group. Lung function, disease history, body composition, cognitive performance, and daily protein intake were not different between the groups. In the CD group, plasma branched chain amino acid concentration (BCAA) was lower (P = 0.02), whereas leucine (P = 0.01) and phenylalanine (P = 0.003) clearance rates were higher. Reduced values were found for tyrosine plasma concentration (P = 0.005) even after adjustment for the large neutral amino acid concentration (= sum BCAA, tyrosine, phenylalanine and tryptophan) as a marker of dopamine synthesis (P = 0.048). CONCLUSION: Mild depression in COPD is associated with poor daily performance and quality of life, and a set of metabolic changes in depressed COPD that include perturbation of large neutral amino acids, specifically the BCAAs. Trial registration clinicaltrials.gov: NCT01787682, 11 February 2013-Retrospectively registered; NCT02770092, 12 May 2016-Retrospectively registered; NCT02780219, 23 May 2016-Retrospectively registered; NCT03796455, 8 January 2019-Retrospectively registered.
Assuntos
Aminoácidos de Cadeia Ramificada/sangue , Depressão/metabolismo , Depressão/psicologia , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/psicologia , Idoso , Índice de Massa Corporal , Depressão/sangue , Depressão/epidemiologia , Exercício Físico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/sangue , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Inquéritos e Questionários , Texas/epidemiologiaRESUMO
Maple syrup urine disease (MSUD) is a genetic disorder that leads the accumulation of branched-chain amino acids (BCAA) leucine (Leu), isoleucine, valine and metabolites. The symptomatology includes psychomotor delay and mental retardation. MSUD therapy comprises a lifelong protein strict diet with low BCAA levels and is well established that high concentrations of Leu and/or its ketoacid are associated with neurological symptoms. Recently, it was demonstrated that the phenylbutyrate (PBA) have the ability to decrease BCAA concentrations. This work aimed the development of lipid-based nanoparticles loaded with PBA, capable of targeting to the central nervous system in order to verify its action mechanisms on oxidative stress and cell death in brain of rats subjected to a MSUD chronic model. PBA-loaded nanoparticles treatment was effective in significantly decreasing BCAA concentration in plasma and Leu in the cerebral cortex of MSUD animals. Furthermore, PBA modulate the activity of catalase, superoxide dismutase, glutathione peroxidase and glutathione reductase enzymes, as well as preventing the oxidative damage to lipid membranes and proteins. PBA was also able to decrease the glial fibrillary acidic protein concentrations and partially decreased the reactive species production and caspase-3 activity in MSUD rats. Taken together, the data indicate that the PBA-loaded nanoparticles could be an efficient adjuvant in the MSUD therapy, protecting against oxidative brain damage and neuroinflammation.
Assuntos
Aminoácidos de Cadeia Ramificada/sangue , Córtex Cerebral/efeitos dos fármacos , Doença da Urina de Xarope de Bordo/metabolismo , Nanopartículas/administração & dosagem , Estresse Oxidativo/efeitos dos fármacos , Fenilbutiratos/administração & dosagem , Animais , Catalase/metabolismo , Córtex Cerebral/metabolismo , Glutationa Peroxidase/metabolismo , Doença da Urina de Xarope de Bordo/sangue , Doença da Urina de Xarope de Bordo/induzido quimicamente , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismoRESUMO
In the presented study, a capillary electrophoresis-mass spectrometry method combining high separation efficiency and sensitive detection has been developed and validated, for the first time, to quantify branched chain amino acids (valine, isoleucine, leucine) in commercial food and sport supplement samples and human plasma samples. The separations were performed in a bare fused silica capillary. The background electrolyte was composed of 500 mM formic acid with pH 2.0. The plasma sample pretreatment was realized by simple protein precipitation with acetonitrile. Injection of a short zone of highly basic electrolyte before the sample injection and application of the negative pressure on the separation were accompanied by enhanced resolution of the isobaric amino acids-isoleucine and leucine. The developed method was characterized by favorable validation parameters, such as linearity (r2 > 0.99), accuracy and precision, the limit of detection, lower limit of quantification, or robustness. These parameters were more than sufficient for the quantification of branched chain amino acids in various samples. The determined concentrations of branched chain amino acids in food and sports supplements were in very good agreement with the content declared by the manufacturer. The investigated concentrations of branched chain amino acids were in the range 294.68-359.24 µM for valine, 91.76-95.67 µM for isoleucine, and 196.78-251.24 µM for leucine. These concentrations fall within the physiological limits. The developed CE-MS/MS method represents a suitable alternative to traditional approaches used in branched chain amino acid quality control and bioanalysis.
Assuntos
Aminoácidos de Cadeia Ramificada/análise , Sangue/metabolismo , Suplementos Nutricionais , Eletroforese Capilar/métodos , Espectrometria de Massas/métodos , Adulto , Aminoácidos de Cadeia Ramificada/sangue , Análise Química do Sangue/métodos , Humanos , MasculinoRESUMO
Epidemiological studies indicate that insulin resistance (IR), a hallmark of type 2 diabetes, is associated with an increased risk of major depression. Here, we demonstrated that male mice fed a high-fat diet (HFD) exhibited peripheral metabolic impairments reminiscent of IR accompanied by elevated circulating levels of branched-chain amino acids (BCAAs), whereas both parameters were normalized by chronic treatment with metformin (Met). Given the role of BCAAs in the regulation of tryptophan influx into the brain, we then explored the activity of the serotonin (5-HT) system. Our results indicated that HFD-fed mice displayed impairment in the electrical activity of dorsal raphe 5-HT neurons, attenuated hippocampal extracellular 5-HT concentrations and anxiety, one of the most visible and early symptoms of depression. On the contrary, Met stimulated 5-HT neurons excitability and 5-HT neurotransmission while hindering HFD-induced anxiety. Met also promoted antidepressant-like activities as observed with fluoxetine. In light of these data, we designed a modified HFD in which BCAA dietary supply was reduced by half. Deficiency in BCAAs failed to reverse HFD-induced metabolic impairments while producing antidepressant-like activity and enhancing the behavioral response to fluoxetine. Our results suggest that Met may act by decreasing circulating BCAAs levels to favor serotonergic neurotransmission in the hippocampus and promote antidepressant-like effects in mice fed an HFD. These findings also lead us to envision that a diet poor in BCAAs, provided either alone or as add-on therapy to conventional antidepressant drugs, could help to relieve depressive symptoms in patients with metabolic comorbidities.SIGNIFICANCE STATEMENT Insulin resistance in humans is associated with increased risk of anxiodepressive disorders. Such a relationship has been also found in rodents fed a high-fat diet (HFD). To determine whether insulin-sensitizing strategies induce anxiolytic- and/or antidepressant-like activities and to investigate the underlying mechanisms, we tested the effects of metformin, an oral antidiabetic drug, in mice fed an HFD. Metformin reduced levels of circulating branched-chain amino acids, which regulate tryptophan uptake within the brain. Moreover, metformin increased hippocampal serotonergic neurotransmission while promoting anxiolytic- and antidepressant-like effects. Moreover, a diet poor in these amino acids produced similar beneficial behavioral property. Collectively, these results suggest that metformin could be used as add-on therapy to a conventional antidepressant for the comorbidity between metabolic and mental disorders.
Assuntos
Aminoácidos de Cadeia Ramificada/sangue , Ansiolíticos/uso terapêutico , Antidepressivos/uso terapêutico , Resistência à Insulina/fisiologia , Metformina/uso terapêutico , Aminoácidos de Cadeia Ramificada/antagonistas & inibidores , Animais , Ansiolíticos/farmacologia , Antidepressivos/farmacologia , Ansiedade/sangue , Ansiedade/tratamento farmacológico , Ansiedade/psicologia , Depressão/sangue , Depressão/tratamento farmacológico , Depressão/psicologia , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Masculino , Metformina/farmacologia , Camundongos , Camundongos Endogâmicos C57BLRESUMO
AIMS/HYPOTHESIS: To understand the complex metabolic changes that occur long before the diagnosis of type 2 diabetes, we investigated differences in metabolomic profiles in plasma between prediabetic and normoglycaemic individuals for subtypes of prediabetes defined by fasting glucose, 2 h glucose and HbA1c measures. METHODS: Untargeted metabolomics data were obtained from 155 plasma samples from 127 Mexican American individuals from Starr County, TX, USA. None had type 2 diabetes at the time of sample collection and 69 had prediabetes by at least one criterion. We tested statistical associations of amino acids and other metabolites with each subtype of prediabetes. RESULTS: We identified distinctive differences in amino acid profiles between prediabetic and normoglycaemic individuals, with further differences in amino acid levels among subtypes of prediabetes. When testing all named metabolites, several fatty acids were also significantly associated with 2 h glucose levels. Multivariate discriminative analyses show that untargeted metabolomic data have considerable potential for identifying metabolic differences among subtypes of prediabetes. CONCLUSIONS/INTERPRETATION: People with each subtype of prediabetes have a distinctive metabolomic signature, beyond the well-known differences in branched-chain amino acids. DATA AVAILABILITY: Metabolomics data are available through the NCBI database of Genotypes and Phenotypes (dbGaP, accession number phs001166; www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs001166.v1.p1).
Assuntos
Metabolômica/métodos , Adulto , Idoso , Aminoácidos de Cadeia Ramificada/sangue , Aminoácidos de Cadeia Ramificada/metabolismo , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Jejum/sangue , Hemoglobinas Glicadas/metabolismo , Humanos , Americanos Mexicanos , Pessoa de Meia-Idade , Análise Multivariada , Estado Pré-Diabético/sangue , Estado Pré-Diabético/metabolismo , Texas , Estados Unidos , Adulto JovemRESUMO
Elevations in circulating levels of branched-chain amino acids (BCAAs) are associated with a variety of cardiometabolic diseases and conditions. Restriction of dietary BCAAs in rodent models of obesity lowers circulating BCAA levels and improves whole-animal and skeletal-muscle insulin sensitivity and lipid homeostasis, but the impact of BCAA supply on heart metabolism has not been studied. Here, we report that feeding a BCAA-restricted chow diet to Zucker fatty rats (ZFRs) causes a shift in cardiac fuel metabolism that favors fatty acid relative to glucose catabolism. This is illustrated by an increase in labeling of acetyl-CoA from [1-13C]palmitate and a decrease in labeling of acetyl-CoA and malonyl-CoA from [U-13C]glucose, accompanied by a decrease in cardiac hexokinase II and glucose transporter 4 protein levels. Metabolomic profiling of heart tissue supports these findings by demonstrating an increase in levels of a host of fatty-acid-derived metabolites in hearts from ZFRs and Zucker lean rats (ZLRs) fed the BCAA-restricted diet. In addition, the twofold increase in cardiac triglyceride stores in ZFRs compared with ZLRs fed on chow diet is eliminated in ZFRs fed on the BCAA-restricted diet. Finally, the enzymatic activity of branched-chain ketoacid dehydrogenase (BCKDH) is not influenced by BCAA restriction, and levels of BCAA in the heart instead reflect their levels in circulation. In summary, reducing BCAA supply in obesity improves cardiac metabolic health by a mechanism independent of alterations in BCKDH activity.
Assuntos
Aminoácidos de Cadeia Ramificada/deficiência , Dieta , Miocárdio/metabolismo , Obesidade/metabolismo , Triglicerídeos/metabolismo , Acetilcoenzima A/metabolismo , Aminoácidos de Cadeia Ramificada/sangue , Animais , Glucose/metabolismo , Masculino , Malonil Coenzima A/metabolismo , Metabolômica , Palmitatos/metabolismo , Proteínas Quinases/metabolismo , Ratos , Ratos ZuckerRESUMO
A feared adverse effect of dyslipidaemia therapy by fibrates is myopathy. We examined the effect of fenofibrate (FF) on protein and amino acid metabolism. Rats received a low (50 mg/kg, LFFD) or high (300 mg/kg, HFFD) dose of FF or vehicle daily by oral gavage. Blood plasma, liver, and soleus and extensor digitorum longus muscles were analysed after 10 days. The FF-treated rats developed hepatomegaly associated with increased hepatic carnitine and ATP and AMP concentrations, decreased protein breakdown, and decreased concentrations of DNA and triglycerides. HFFD increased plasma ALT and AST activities. The weight and protein content of muscles in the HFFD group were lower compared with controls. In muscles of the LFFD group there were increased ATP and decreased AMP concentrations; in the HFFD group AMP was increased. In both FF-treated groups there were increased glycine, phenylalanine, and citrulline and decreased arginine and branched-chain keto acids (BCKA) in blood plasma. After HFFD there were decreased levels of branched-chain amino acids (BCAA; valine, leucine and isoleucine), methionine, and lysine and increased homocysteine. Decreased arginine and increased glycine concentrations were found in both muscles in FF-treated animals; in HFFD-treated animals lysine, methionine, and BCAA were decreased. We conclude that FF exerts protein-anabolic effects on the liver and catabolic effects on muscles. HFFD causes signs of hepatotoxicity, impairs energy and protein balance in muscles, and decreases BCAA, methionine, and lysine. It is suggested that increased glycine and decreased lysine and methionine levels are due to activated carnitine synthesis; decreased BCAA and BCKA levels are due to increased BCAA oxidation.
Assuntos
Aminoácidos/metabolismo , Metabolismo Energético/efeitos dos fármacos , Fenofibrato/administração & dosagem , Hipolipemiantes/administração & dosagem , Proteínas/metabolismo , Aminoácidos/efeitos dos fármacos , Aminoácidos de Cadeia Ramificada/sangue , Animais , Carnitina/sangue , Glicina/metabolismo , Hepatomegalia/induzido quimicamente , Hepatomegalia/metabolismo , Humanos , Leucina/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Lisina/metabolismo , Masculino , Metionina/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Oxirredução , Proteínas/efeitos dos fármacos , Ratos , Ratos WistarRESUMO
AIM: Levels of branched-chain amino acids (BCAAs, namely, isoleucine, leucine, and valine) are modulated by dietary intake and metabolic/genetic factors. BCAAs are associated with insulin resistance and increased risk of type 2 diabetes (T2D). Although insulin resistance predicts heart failure (HF), the relationship between BCAAs and HF in T2D remains unknown. METHODS: In this prospective observational study, we measured BCAAs in fasting serum samples collected at inception from 2139 T2D patients free of cardiovascular-renal diseases. The study outcome was the first hospitalization for HF. RESULTS: During 29 103 person-years of follow-up, 115 primary events occurred (age: 54.8 ± 11.2 years, 48.2% men, median [interquartile range] diabetes duration: 5 years [1-10]). Patients with incident HF had 5.6% higher serum BCAAs than those without HF (median 639.3 [561.3-756.3] vs 605.2 [524.8-708.7] µmol/L; P = .01). Serum BCAAs had a positive linear association with incident HF (per-SD increase in logarithmically transformed BCAAs: hazard ratio [HR] 1.22 [95% CI 1.07-1.39]), adjusting for age, sex, and diabetes duration. The HR remained significant after sequential adjustment of risk factors including incident coronary heart disease (1.24, 1.09-1.41); blood pressure, low-density lipoprotein cholesterol, and baseline use of related medications (1.31, 1.14-1.50); HbA1c , waist circumference, triglyceride, and baseline use of related medications (1.28, 1.11-1.48); albuminuria and estimated glomerular filtration rate (1.28, 1.11-1.48). The competing risk of death analyses showed similar results. CONCLUSIONS: Circulating levels of BCAAs are independently associated with incident HF in patients with T2D. Prospective cohort analysis and randomized trials are needed to evaluate the long-term safety and efficacy of using different interventions to optimize BCAAs levels in these patients.
Assuntos
Aminoácidos de Cadeia Ramificada/sangue , Diabetes Mellitus Tipo 2/epidemiologia , Insuficiência Cardíaca/epidemiologia , Adulto , Idoso , Comorbidade , Diabetes Mellitus Tipo 2/sangue , Feminino , Insuficiência Cardíaca/sangue , Hong Kong , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Sistema de RegistrosRESUMO
PURPOSE OF REVIEW: Branched-chain amino acids (BCAAs) are essential amino acids derived from diet. BCAA supplementation has been recommended in elderly and athletes, but recent studies suggest an association between high dietary BCAAs and blood levels of BCAAs with greater risk of cardiometabolic diseases (CMD). This review aims to integrate current epidemiological evidence analyzing the association between BCAAs and related-CMD risk factors. RECENT FINDINGS: Most epidemiological studies consistently show that dietary BCAAs are associated with higher risk of type-2 diabetes (T2D) whereas there is limited evidence related with other cardiovascular risk factors. Evidence also exists showing an association between higher circulating BCAA levels and risk of T2D and cardiovascular disease, and also probably with metabolic syndrome and overweight/obesity. Several clinical trials suggest beneficial cardiometabolic effect of BCAAs supplementation, although with a small sample size and short follow-up. Studies show a weak correlation between dietary BCAAs and circulating BCAA levels. Protein quality sources and whole dietary pattern are key aspects to improve our understanding of the effect of BCAAs as well as factors associated with higher protein needs, such as age or frailty. SUMMARY: Dietary and circulating BCAAs exhibit possible detrimental cardiometabolic effects, but BCAA supplementation may have some positive influence on target groups with nutritional deficiencies.
Assuntos
Aminoácidos de Cadeia Ramificada/administração & dosagem , Aminoácidos de Cadeia Ramificada/sangue , Doenças Cardiovasculares/sangue , Suplementos Nutricionais , Ingestão de Alimentos , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/etiologia , Humanos , Síndrome Metabólica/sangue , Síndrome Metabólica/etiologia , Síndrome Metabólica/prevenção & controle , Obesidade/sangue , Obesidade/etiologia , Obesidade/prevenção & controleRESUMO
BACKGROUND: Branched-chain amino acid (BCAA) concentrations in the blood have been correlated with insulin resistance, but this relation throughout gestation (period in which insulin resistance typically increases) is unclear. OBJECTIVE: The objective of this study was to determine the associations between changes in BCAA concentrations and estimates of insulin resistance throughout gestation. METHODS: Serum BCAA (Leu, Ile, Val) concentrations and insulin resistance/sensitivity [i.e., homeostatic model assessment-2 of insulin resistance (HOMA2-IR), estimated metabolic clearance rate (MCR) of glucose, and estimated first- and second-phase insulin responses] were assessed at early (EP; 8.5 ± 0.2 wk) and/or late (LP; 29.2 ± 0.8 wk) pregnancy in 53 healthy women from the Glowing cohort. Adjusted Spearman correlations were used to evaluate the association between BCAA and insulin resistance/sensitivity measures at EP and LP, adjusted for body fat percentage and gestational weight gain (GWG). A multiple linear regression analysis was used to assess the association between changes in HOMA2-IR and BCAAs throughout gestation. Groups were made post hoc based on the mean percentage change (10% decrease) in Leu throughout gestation, creating a group with a ≥10% decrease in LeuLP-EP (BELOW) and a <10% decrease in LeuLP-EP (ABOVE), and Student's t tests were performed to assess differences between groups. RESULTS: Leu and Ile concentrations positively correlated with HOMA2-IR at both time points, but these relations at EP disappeared/weakened when adjusted for body fat percentage. From EP to LP, the change in Leu (LeuLP-EP) was negatively associated with the change in HOMA2-IR (HOMA2-IRLP-EP) (ß = -0.037, P = 0.006). MCR was lower in the BELOW group compared with the ABOVE group, whereas there was no difference in HOMA2-IR between groups. CONCLUSIONS: In this pregnancy cohort, BCAA concentrations decreased throughout gestation, whereas the mean insulin resistance did not change. These data do not support a connection between changes in blood BCAA concentrations and estimates of insulin resistance in pregnant women. This trial is registered at clinicaltrials.gov as NCT01131117.