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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. [ABSTRACT FROM AUTHOR]

Background: Branched-chain amino acids (BCAAs), including leucine, isoleucine, and valine, are essential amino acids involved in protein synthesis, energy metabolism, and immune regulation. While BCAAs are known to influence cancer biology, their role in leukemia remains unclear. This study employs Mendelian randomization (MR) analysis to explore the causal relationship between BCAA levels and four leukemia subtypes: acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML). Methods: Data from genome-wide association studies (GWAS) were used to select single nucleotide polymorphisms (SNPs) as instrumental variables (IVs) for BCAA levels. The inverse-variance weighted (IVW) method served as the primary analytical approach, with heterogeneity assessed via Cochran's Q test and pleiotropy through MR-Egger intercept. Sensitivity analysis was performed using leave-one-out analysis. Results: A significant inverse association was observed between total BCAA levels, leucine, valine, and ALL risk. Total BCAA levels showed an odds ratio (OR) of 0.16 (95% CI: 0.05–0.54, p=0.003), leucine 0.17 (95% CI: 0.04–0.61, p=0.007), and valine 0.21 (95% CI: 0.07–0.61, p=0.004). No significant associations were found for AML, CLL, or CML. Conclusion: This study suggests that BCAAs, particularly leucine and valine, may protect against ALL, offering insights into leukemia metabolic regulation and potential targets for prevention and therapy. [ABSTRACT FROM AUTHOR]

Background: Branched-chain amino acid (BCAA) has been reported to be associated with obesity, the association of BCAA with visceral fat area (VFA) and subcutaneous fat area (SFA) remained unclear in patients with type 2 diabetes. Methods: This cross-sectional study was conducted in 284 patients with type 2 diabetes mellitus. Enzyme-linked immunospecific assay was used to measure levels of serum BCAA and branched-chain keto acid (BCKA). VFA and SFA were measured with bio-impedance analysis method. The association between BCAA and VFA was calculated using Pearson correlation and multivariable linear regression analysis. Results: There were significant differences in the means of body mass index, waist circumstance, SFA and VFA among the three groups divided by total BCAA tertiles (all p < 0.05). Compared to patients with lower levels of serum BCAA (the lower tertile group), the means of VFA and SFA were significantly larger in the middle and upper tertile groups (all p < 0.05). However, the differences in above obesity parameters were nonsignificant according to various BCKA tertiles. Pearson correlation analysis also demonstrated that BCAA levels were positive associated with each obesity parameter (p < 0.05). Nevertheless, multivariable linear regression analysis showed that levels of serum BCAA were correlated with VFA, BMI and WC (all p < 0.05) rather than SFA after adjusted for other confounders. Conclusions: levels of serum BCAA were more closely correlated with VFA than SFA, prospective studies should be warranted to further explore the mechanism mediating BCAA and visceral fat accumulation in Human beings. Clinical trial number: Not applicable. [ABSTRACT FROM AUTHOR]

Background: The initiation time and formula for supplemental parenteral nutrition after surgery require optimization, especially in older patients undergoing major gastrointestinal surgery. This study aimed to assess the effect of early supplementation with a branched-chain amino acid (BCAA)-enriched formula (BAF) on short-term postoperative outcomes in older patients undergoing gastric surgery. Methods: This single-center, prospective, double-blinded, randomized clinical trial was conducted from March 10, 2020, to September 15, 2022. Patients aged 65–80 years with gastric cancer scheduled for curative resection were assessed for eligibility and randomly allocated to a high-proportion BCAA (HBCAA) (early supplementation with the BAF) or control (routine nutrition) group. The primary outcome was the standardized length of hospital stay (LOS). Results: A total of 150 patients were randomized. Thirteen patients were excluded due to the resection of other organs, presence of metastasis, or withdrawal of consent. Finally, we included 70 and 67 patients in the HBCAA and control groups, respectively (mean age: 70.5 ± 4.2 years; 96 men [70.1%]). The standardized LOS was significantly shorter in the treatment group than in the control group (median [interquartile range]: 8.0 [7.8, 8.0] vs. 8.5 [8.0, 9.0] days; mean difference, 0.38; 95% confidence interval [CI], 0.02–0.74 days; P <.001). Patients in the HBCAA group showed better gastrointestinal function with faster defecation (4.0 [3.6, 5.0] vs. 5.0 [4.0, 5.5] days; mean difference, 0.6 days; 95% CI, 0.26–0.94 days; P <.001) and semi-liquid diet initiation (8.0 [7.5, 8.0] vs. 8.0 [8.0, 8.8] days; mean difference, 0.36 days; 95% CI, 0.03–0.7 days; P <.001) and had lesser weight loss at postoperative day 5 than those in the control group did (3.5 [2.7, 6.5] vs. 4.9 [3.3, 7.6]%; mean difference, 1.23%; 95% CI, 0.27–2.19%; P =.011). Conclusions: In this randomized clinical trial, compared with routine nutrition, early supplementation with a BAF was associated with a shorter standardized LOS in older patients undergoing gastric surgery, suggesting that it may be a favorable strategy for patients with a poor tolerance to external nutrition who are undergoing major surgery. Trial registration: ClinicalTrials.gov; Identifier: ChiCTR2000029635. [ABSTRACT FROM AUTHOR]

Frailty in cirrhosis or advanced chronic liver disease (ACLD) is a relevant prognostic factor. In the present study, we aimed to analyze potential biomarkers associated with frailty and its improvement in patients with ACLD. We analyzed the serum of outpatients with ACLD who participated in a previous study (Román, Hepatol Commun 2024) in which frailty was assessed using the liver frailty index (LFI), and patients who were frail or prefrail were randomized to a multifactorial intervention (home exercise, branched-chain amino acids, and probiotics) or control for 12 months. We determined a biomarker battery of inflammation, bacterial translocation, and liver damage in blood and urine and blood metabolomics by 1H-NMR. Thirty-seven patients were included. According to the LFI, 32 patients were frail or prefrail, and 5 were robust. At baseline, LFI correlated with LBP, sCD163, mtDNA, FGF-21, urinary NGAL, urinary claudin-3, and the metabolites mannose, ethanol, and isoleucine. During the study, patients in the intervention group showed an improvement in LFI and a decrease in CRP, LBP, sCD163, and ccK18 compared to the control group. Metabolomics showed a decrease in dimethyl sulfone and creatinine and an increase in malonate, ornithine, isoleucine, and valine in the intervention group. We conclude that frailty in patients with ACLD is associated with biomarkers of systemic inflammation, bacterial translocation, and liver damage, and alterations of amino acid and short-chain fatty acid metabolism. [ABSTRACT FROM AUTHOR]

Branched-chain amino acids (BCAAs) are essential for muscle protein synthesis and are widely acknowledged for mitigating sarcopenia. Oligonol® (Olg), a low-molecular-weight polyphenol from Litchi chinensis, has also been found to attenuate sarcopenia by improving mitochondrial quality and positive protein turnover. This study aims to investigate the effect of Olg on BCAA-stimulated protein synthesis in sarcopenia. In sarcopenic C57BL/6 mice and senescence-accelerated mouse-prone 8 (SAMP8) mice, BCAAs were significantly decreased in skeletal muscle but increased in blood serum. Furthermore, the expressions of membrane L-type amino acid transporter 1 (LAT1) and branched-chain amino acid transaminase 2 (BCAT2) in skeletal muscle were lower in aged mice than in young mice. The administration of Olg for 8 weeks significantly increased the expressions of membrane LAT1 and BCAT2 in the skeletal muscle when compared with non-treated SAMP8 mice. We further found that BCAA deprivation via LAT1-siRNA in C2C12 myotubes inhibited the signaling of protein synthesis and facilitated ubiquitination degradation of BCAT2. In C2C12 cells mimicking sarcopenia, Olg combined with BCAA supplementation enhanced mTOR/p70S6K activity more than BCAA alone. However, blocked LAT1 by JPH203 reversed the synergistic effect of the combination of Olg and BCAAs. Taken together, changes in LAT1 and BCAT2 during aging profoundly alter BCAA availability and nutrient signaling in aged mice. Olg increases BCAA-stimulated protein synthesis via modulating BCAA transportation and BCAA catabolism. Combining Olg and BCAAs may be a useful nutritional strategy for alleviating sarcopenia. [ABSTRACT FROM AUTHOR]

Aim To investigate the effect of pyruvate and glucose on leucine transamination and 3-methylbutanal production by Lactococcus lactis , including the comparison with cells possessing glutamate dehydrogenase (GDH) activity. Methods and results Lactococcus lactis cells were incubated in chemically defined medium (CDM) with the pH controlled at 5.2 to mimic cheese conditions. Pyruvate supplementation stimulated the production of the key flavour compound 3-methylbutanal by 3–4 times after 72 h of incubation. Concurrently, alanine production increased, demonstrating the involvement of pyruvate in transamination reactions. Glucose-metabolizing cells excreted α-ketoisocaproic acid and produced even 3 times more 3-methylbutanal after 24 h than pyruvate-supplemented cells. Conjugal transfer technique was used to transfer the plasmid pGdh442 carrying the gdh gene encoding for GDH to L. lactis. Introducing GDH did not stimulate the excretion of α-ketoisocaproic acid and the production of 3-methylbutanal. Conclusions These results demonstrate that Lactococcus uses pyruvate to transaminate leucine into α-ketoisocaproic acid which supports 3-methylbutanal production. Surprisingly, GDH activity did not stimulate leucine transamination and 3-methylbutanal production. [ABSTRACT FROM AUTHOR]

Elevated circulating branched‐chain amino acids (BCAA) have been linked with the severity of insulin resistance across numerous populations, implicating heightened BCAA metabolism as a potential therapy for insulin resistance. Recently, the angiotensin II type 1 receptor (AT1R) inhibitor Valsartan (VAL) was identified as a potent inhibitor of branched‐chain alpha‐keto acid dehydrogenase kinase (BCKDK), a negative regulator of BCAA metabolism. This work investigated the effect of VAL on myotube metabolism and insulin sensitivity under both insulin sensitive and insulin resistant conditions. C2C12 myotubes were treated with or without VAL at 8 µM for 24 h, both with and without hyperinsulinemic‐induced insulin resistance. Oxygen consumption and extracellular acidification were used to measure mitochondrial and glycolytic metabolism, respectively. Gene expression was assessed via qRT‐PCR, and insulin sensitivity was assessed via Western blot. Insulin resistance significantly reduced both basal and peak mitochondrial function which were rescued to control levels by concurrent VAL. Changes in mitochondrial function occurred without substantial changes in mitochondrial content or related gene expression. Insulin sensitivity and glycolytic metabolism were unaffected by VAL, as was lipogenic signaling and lipid content. Additionally, both VAL and insulin resistance depressed Bckdha expression. Interestingly, an interaction effect was observed for extracellular isoleucine, valine, and total BCAA (but not leucine), suggesting VAL may alter BCAA utilization in an insulin sensitivity‐dependent manner. Insulin resistance appears to suppress mitochondrial function in a myotube model which can be rescued by VAL. Further research will be required to explore the implications of these findings in more complex models. Significance Statement: The angiotensin II type 1 receptor (AT1R) inhibitor Valsartan rescued reduced mitochondrial function during insulin resistance in a myotube model of skeletal muscle. These findings provide proof‐of‐concept data suggesting Valsartan may provide metabolic benefits beyond blood pressure lowering effects. [ABSTRACT FROM AUTHOR]

Purpose: Autophagy and heat shock protein (HSP) response are proteostatic systems involved in the acute and adaptive responses to exercise. These systems may upregulate sequentially following cellular stress including acute exercise, however, currently few data exist in humans. This study investigated the autophagic and HSP responses to acute intense lower body resistance exercise in peripheral blood mononuclear cells (PBMCs) with and without branched-chain amino acids (BCAA) supplementation. Methods: Twenty resistance-trained males (22.3 ± 1.5 yr; 175.4 ±.7 cm; 86.4 ± 15.6 kg) performed a bout of intense lower body resistance exercise and markers of autophagy and HSP70 were measured immediately post- (IPE) and 2, 4, 24, 48, and 72 h post-exercise. Prior to resistance exercise, 10 subjects were randomly assigned to BCAA supplementation of 0.22 g/kg/d for 5 days pre-exercise and up to 72 h following exercise while the other 10 subjects consumed a placebo (PLCB). Results: There were no difference in autophagy markers or HSP70 expression between BCAA and PLCB groups. LC3II protein expression was significantly lower 2 and 4 h post-exercise compared to pre-exercise. LC3II: I ratio was not different at any time point compared to pre-exercise. Protein expression of p62 was lower IPE, 2, and 4 h post-exercise and elevated 24 h post-exercise. HSP70 expression was elevated 48 and 72 h post-exercise. Conclusions: Autophagy and HSP70 are upregulated in PBMCs following intense resistance exercise with autophagy increasing initially post-exercise and HSP response in the latter period. Moreover, BCAA supplementation did not affect this response. [ABSTRACT FROM AUTHOR]

Background: Diets with high inclusion of corn co-products such as corn fermented protein (CFP) may contain excess Leu, which has a negative impact on feed intake and growth performance of pigs due to increased catabolism of Val and Ile and reduced availability of Trp in the brain for serotonin synthesis. However, we hypothesized that the negative effect of using CFP in diets for weanling pigs may be overcome if diets are fortified with crystalline sources of Val, Trp, and (or) Ile. Methods: Three hundred and twenty weanling pigs were randomly allotted to one of 10 dietary treatments in a completely randomized design, with 4 pigs per pen and 8 replicate pens per treatment. A corn-soybean meal diet and 2 basal diets based on corn and 10% CFP or corn and 20% CFP were formulated. Seven additional diets were formulated by fortifying the basal diet with 20% CFP with Ile, Trp, Val, Ile and Val, Ile and Trp, Trp and Val, or Ile, Trp and Val. A two-phase feeding program was used, with d 1 to 14 being phase 1 and d 15 to 28 being phase 2. Fecal scores were recorded every other day. Blood samples were collected on d 14 and 28 from one pig per pen. On d 14, fecal samples were collected from one pig per pen in 3 of the 10 treatments to determine volatile fatty acids, ammonium concentration, and microbial protein. These pigs were also euthanized and ileal tissue was collected. Results: There were no effects of dietary treatments on any of the parameters evaluated in phase 1. Inclusion of 10% or 20% CFP in diets reduced (P < 0.05) final body weight on d 28, and average daily gain (ADG) and average daily feed intake (ADFI) in phase 2 and for the entire experimental period. However, pigs fed the CFP diet supplemented with Val, Ile, and Trp had final body weight, ADFI, ADG and gain to feed ratio in phase 2 and for the entire experiment that was not different from pigs fed the control diet. Fecal scores in phase 2 were reduced (P < 0.05) if CFP was used. Conclusions: Corn fermented protein may be included by up to 20% in diets for weanling pigs without affecting growth performance, gut health, or hindgut fermentation, if diets are fortified with extra Val, Trp, and Ile. Inclusion of CFP also improved fecal consistency of pigs. [ABSTRACT FROM AUTHOR]

Diabetic neuropathic pain (DNP), one of the most common complications of diabetes, is characterized by bilateral symmetrical distal limb pain and substantial morbidity. To compare the differences is aimed at serum metabolite levels between 81 DNP and 73 T2DM patients without neuropathy and found that the levels of branched‐chain amino acids (BCAA) are significantly lower in DNP patients than in T2DM patients. In high‐fat diet/low‐dose streptozotocin (HFD/STZ)‐induced T2DM and leptin receptor‐deficient diabetic (db/db) mouse models, it is verified that BCAA deficiency aggravated, whereas BCAA supplementation alleviated DNP symptoms. Mechanistically, using a combination of RNA sequencing of mouse dorsal root ganglion (DRG) tissues and label‐free quantitative proteomic analysis of cultured cells, it is found that BCAA deficiency activated the expression of L‐type amino acid transporter 1 (LAT1) through ATF4, which is reversed by BCAA supplementation. Abnormally upregulated LAT1 reduced Kv1.2 localization to the cell membrane, and inhibited Kv1.2 channels, thereby increasing neuronal excitability and causing neuropathy. Furthermore, intraperitoneal injection of the LAT1 inhibitor, BCH, alleviated DNP symptoms in mice, confirming that BCAA‐deficiency‐induced LAT1 activation contributes to the onset of DNP. These findings provide fresh insights into the metabolic differences between DNP and T2DM, and the development of approaches for the management of DNP. [ABSTRACT FROM AUTHOR]

Maple syrup urine disease (MSUD) is a rare, inherited, metabolic disorder characterized by dysfunction of the multi-subunit, mitochondrial enzyme complex branched-chain alpha-keto acid dehydrogenase (BCKDH). BCKDH catalyzes the oxidative decarboxylation of branched-chain amino acids (BCAAs). BCAAs and their neurotoxic alpha-keto intermediates can accumulate in the blood and tissues in the absence of functional BCKDH. We evaluated a lipid nanoparticle (LNP)-based treatment approach to address all possible genetic mutations that can cause MSUD (BCKDHA, BCKDHB, and DBT). In the intermediate MSUD mouse model, which harbors a mutation in the dihydrolipoamide branched-chain transacylase E2 (DBT) subunit of BCKDH, repeated administration of LNP-encapsulated mRNA therapy significantly extended survival and reduced serum leucine levels. We also evaluated our LNP approach in several models of classical MSUD, namely DBT knockout (KO) mice and the new BCKDHA KO and BCKDHB KO mice. The latter two were generated by CRISPR/Cas9 gene editing and contain the highly prevalent classical MSUD-causing mutations seen in the Mennonite and Costa Rican populations. Intravenous LNP-encapsulated mRNA administration extended survival and increased body weight in the DBT KO and BCKDHA KO models of classical MSUD but was not effective in BCKDHB KO mice. Our data provide a promising proof-of-concept that a universal, mutation-independent approach to treating MSUD is possible and viable. [ABSTRACT FROM AUTHOR]

Background: Acute kidney injury (AKI) is a serious complication of cirrhosis. This study analyzed the prognostic effect of AKI in patients with cirrhosis and its risk factors, particularly in relation to amino acid imbalance. Methods: This retrospective study reviewed 808 inpatients with cirrhosis at two institutes in Gifu, Japan. AKI was diagnosed according to the recommendations of the International Club of Ascites. Amino acid imbalance was assessed by measuring serum branched-chain amino acid (BCAA) levels, tyrosine levels, and the BCAA-to-tyrosine ratio (BTR). Factors associated with mortality and AKI development were assessed using the Cox proportional hazards regression model with AKI as a time-dependent covariate and the Fine–Gray competing risk regression model, respectively. Results: Of the 567 eligible patients without AKI at baseline, 27% developed AKI and 25% died during a median follow-up period of 4.7 years. Using a time-dependent covariate, AKI development (hazard ratio [HR], 6.25; 95% confidence interval [CI], 3.98–9.80; p < 0.001) was associated with mortality in patients with cirrhosis independent of potential covariates. In addition, alcohol-associated/-related liver disease, metabolic dysfunction-associated steatohepatitis, Child–Pugh score, and BTR (subdistribution HR 0.78; 95% CI 0.63–0.96; p = 0.022) were independently associated with AKI development in patients with cirrhosis. Similar results were obtained in the multivariate model that included BCAA and tyrosine levels instead of BTR. Conclusions: AKI is common and associated with mortality in Japanese patients with cirrhosis. An amino acid imbalance is strongly associated with the development of AKI in patients with cirrhosis. [ABSTRACT FROM AUTHOR]

Antibiotics are essential for combating pathogens; however, their misuse has led to increased resistance, necessitating the search for effective, low-toxicity alternatives. Surfactin, a cyclic lipopeptide with a C12-C17 β-hydroxy fatty acid chain, exhibits significant antibacterial activity and resists resistance, making it a research focus. Nonetheless, the effects of branched-chain amino acids (BCAAs) on surfactin's structure and activity are not well understood. This study examines the influence of BCAAs (L-valine, L-leucine, and L-isoleucine) on the lipopeptide (surfactin) produced by Bacillus velezensis YA215. Process optimization shows that adding 1 g/L of L-Leu and L-Ile, and 0.5 g/L of L-Val, maximized surfactin production to 18.59%, 19.23%, and 20.64%, respectively. Surfactin content peaked at 36 h with L-Val and L-Ile, yielding 19.72% and 11.37%. In contrast, L-Leu addition peaked at 24 h, yielding 11.33%. Notably, L-Val supplementation resulted in the highest relative surfactin content. Antimicrobial testing demonstrated that BCAAs significantly enhance the antibacterial effects of lipopeptides against Escherichia coli and Staphylococcus aureus, with Val showing the most pronounced effect. The addition of BCAAs notably altered the composition of surfactin fatty acid chains. Specifically, Val increased the proportions of iso C14 and iso C16 β-hydroxy fatty acids from 13.3% and 4.216–23.803% and 8.31%, respectively. Additionally, the amino acid composition at the 7th position of the peptide chain changed significantly, especially with Val addition, which increased the proportion of C14 [Val 7] surfactin by 3.29 times. These structural changes are likely associated with the enhanced antibacterial activity of surfactin. These findings provide valuable insights into the roles of BCAAs in microbial fermentation, underscoring their importance in metabolic engineering to enhance the production of bioactive compounds. [ABSTRACT FROM AUTHOR]

Branched-chain amino acids (BCAAs)—leucine (Leu), isoleucine (Ile), and valine (Val)—are essential nutrients with significant roles in protein synthesis, metabolic regulation, and energy production. This review paper offers a detailed examination of the physico-chemical properties of BCAAs, their industrial synthesis, and their critical functions in various biological processes. The unique isomerism of BCAAs is presented, focusing on analytical challenges in their separation and quantification as well as their solubility characteristics, which are crucial for formulation and purification applications. The industrial synthesis of BCAAs, particularly using bacterial strains like Corynebacterium glutamicum, is explored, alongside methods such as genetic engineering aimed at enhancing production, detailing the enzymatic processes and specific precursors. The dietary uptake, distribution, and catabolism of BCAAs are reviewed as fundamental components of their physiological functions. Ultimately, their multifaceted impact on signaling pathways, immune function, and disease progression is discussed, providing insights into their profound influence on muscle protein synthesis and metabolic health. This comprehensive analysis serves as a resource for understanding both the basic and complex roles of BCAAs in biological systems and their industrial application. [ABSTRACT FROM AUTHOR]

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 (β=-0.028, P = 0.027) and higher high-density lipoprotein cholesterol (HDL-C, β = 0.013, P = 0.006), while BCAAs in red and processed meat or fish were inversely associated with low-density lipoprotein cholesterol (β = 0.025, P = 0.001) and total cholesterol (β = 0.012, P = 0.033), respectively. BCAAs in whole grains and nuts were associated with higher HDL-C (β = 0.011, P = 0.016), and lower TG (β=-0.021, P = 0.041) and diastolic blood pressure (β=-0.003, P = 0.027). Also, BCAAs from soy or vegetables and fruits were inversely associated with arterial stiffness (β=-0.018, P = 0.047) and systolic blood pressure (β=-0.011, P = 0.003), respectively. However, BCAAs in refined grains were positively associated with triglycerides (β = 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. [ABSTRACT FROM AUTHOR]

Background: The association of BCAAs (isoleucine, leucine, and valine) with cardiovascular and cerebrovascular diseases has been widely recognized by researchers, but there is limited evidence to support the relationship between BCAAs and multiple chronic conditions (MCCs) in older adults. This study aimed to explore the correlation between BCAA levels in the diets of older adults and MCCs. Methods: Based on a health management cohort project in Nanshan District of Shenzhen, 4278 individuals over 65 years old were selected as participants via multi-stage stratified sampling from May 2018 to December 2019. Data were collected using a validated semi-quantitative food frequency questionnaire, as well as anthropometric and chronic disease reports. MCC was defined as the coexistence of two or more chronic diseases, namely, hypertension, dyslipidemia, diabetes, CAD, stroke, CKD, and CLD. Multivariate unconditional logistic regression analysis was used to analyze the relationship between dietary BCAAs and MCCs in older adults, and then, gender stratification analysis was performed. A restricted cubic spline model (a fitted smooth curve) was used to determine the dose–response relationship of isoleucine with MCCs. Results: A total of 4278 older adults aged 65 and above were included in this study, with an average age of 72.73 ± 5.49 years. The cohort included 1861 males (43.50%). Regardless of whether confounding factors were corrected, isoleucine was a risk factor for MCCs (OR = 3.388, 95%CI:1.415,8.109). After gender stratification, the relationships between dietary isoleucine and MCCs (OR = 6.902, 95%CI:1.875,25.402) and between leucine (OR = 0.506,95%CI:0.309,0.830) and MCCs were significant in women, but not in men. No significant association between valine and MCCs was observed. In addition, isoleucine was a risk factor for MCCs when its intake was greater than 4.297 g/d. Conclusion: Isoleucine may play an important role in regulating age-related diseases. BCAAs such as isoleucine can be used as risk markers for MCCs in older adults. [ABSTRACT FROM AUTHOR]

Maintaining skeletal muscle mass is important for improving muscle strength and function. Hence, maximizing lean body mass (LBM) is the primary goal for both elite athletes and fitness enthusiasts. The use of amino acids as dietary supplements is widespread among athletes and physically active individuals. Extensive literature analysis reveals that branched-chain amino acids (BCAA), creatine, glutamine and β-alanine may be beneficial in regulating skeletal muscle metabolism, enhancing LBM and mitigating exercise-induced muscle damage. This review details the mechanisms of these amino acids, offering insights into their efficacy as supplements. Recommended dosage and potential side effects are then outlined to aid athletes in making informed choices and safeguard their health. Lastly, limitations within the current literature are addressed, highlighting opportunities for future research. [ABSTRACT FROM AUTHOR]

Aim: 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. Methods: 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. Results: 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. Conclusions: 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; 24: 603–608. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2DM) is a metabolic disorder with intricate pathogenic mechanisms. Despite the availability of various oral medications for controlling the condition, reports of poor glycemic control in type 2 diabetes persist, possibly involving unknown pathogenic mechanisms. In recent years, the gut microbiota have emerged as a highly promising target for T2DM treatment, with the metabolites produced by gut microbiota serving as crucial intermediaries connecting gut microbiota and strongly related to T2DM. Increasingly, traditional Chinese medicine is being considered to target the gut microbiota for T2DM treatment, and many of them are edible. In studies conducted on animal models, edible traditional Chinese medicine have been shown to primarily alter three significant gut microbiotal metabolites: short-chain fatty acids, bile acids, and branched-chain amino acids. These metabolites play crucial roles in alleviating T2DM by improving glucose metabolism and reducing inflammation. This review primarily summarizes twelve edible traditional Chinese medicines that improve T2DM by modulating the aforementioned three gut microbiotal metabolites, along with potential underlying molecular mechanisms, and also incorporation of edible traditional Chinese medicines into the diets of T2DM patients and combined use with probiotics for treating T2DM are discussed. [ABSTRACT FROM AUTHOR]

Background: Mental health disorders are one of the most important and increasing health problems in the youth of today's societies. Some dietary intake and body mass status are factors that affect mental health. This study aimed to investigate the relationship between the intake of branched-chain amino acids (BCAAs) and aromatic amino acids (AAAs) and anthropometric and dietary inflammatory indices with mental health, including depression, anxiety, and stress. Methods: In this case-control study, the data of 138 teenage girls aged 13--18 years were collected. Three-day 24-hour food recall and standard anthropometric methods were used to calculate the dietary inflammation intake score of normal and energy-adjusted diets. Mental health disorders were diagnosed by the DASS-21 questionnaire. Statistical analysis used Student's t-test, correlation, and multiple regression were used to analyze the data based on the study's statistical requirements. Results: Based on the findings, 59 (42%) of the girls had mental disorders, and 79 (58%) were healthy. The average weight of stressed people was significantly higher than that of healthy people, and the BMI of anxious people was significantly higher than that of nonanxious people (P < 0.05). A significant positive correlation was found between stress and weight and energy intake. Additionally, there was a significant negative correlation between BCAAs and mental health. The average intake of BCAAs was significantly lower in patients (P = 0.01). The trend analysis showed significantly lower BCAA levels among the 4th quartile of mental disorders. No significant relationship was observed between DII, AAA, and anthropometric indices. After adjustment of the results, no relationship was observed between mental health and the studied factors. Conclusions: BCAA might be related to mental health. Further studies in different age and sex groups are highly recommended. [ABSTRACT FROM AUTHOR]

The purpose of this study was to investigate the effects of supplementation of whey protein (WP) versus leucine-matched collagen peptides (CP) on muscle thickness MT and performance after a resistance training (RT) program in young adults. Twenty-two healthy untrained participants were randomly assigned to either a WP (n = 11) or leucine-matched CP (n = 11) group and then submitted to a supervised 10-week RT program (3 days/week). The groups were supplemented with an equivalent amount of WP (35 g, containing 3.0 g of leucine) and CP (35 g, containing 1.0 g of leucine and 2.0 g of free leucine) during the intervention period (after each workout and in the evening on nontraining days). MT of the vastus lateralis and biceps brachii, isokinetic peak torque and mean power output of the elbow flexors, and peak power output of the lower body were assessed before and after the RT program. The WP group experienced a greater (interaction, p <.05) increase in the vastus lateralis (effect size, WP = 0.68 vs. CP = 0.38; % Δ, WP = 8.4 ± 2.5 vs. CP = 5.6 ± 2.6%) and biceps brachii muscle thickness (effect size, WP = 0.61 vs. CP = 0.35; % , WP = 10.1 ± 3.8 vs. CP = 6.0 ± 3.2%), with a similar increase in muscle performance (peak torque, mean power output, and peak power output) between groups (time p <.05). Supplementation with WP was superior to leucine content-matched CP supplementation in increasing muscle size, but not strength and power, after a 10-week RT program in young adults. [ABSTRACT FROM AUTHOR]

Summary: Salt stress negatively affects rice growth, development and yield. Metabolic adjustments contribute to the adaptation of rice under salt stress. Branched‐chain amino acids (BCAA) are three essential amino acids that cannot be synthesized by humans or animals. However, little is known about the role of BCAA in response to salt stress in plants.Here, we showed that BCAAs may function as scavengers of reactive oxygen species (ROS) to provide protection against damage caused by salinity. We determined that branched‐chain aminotransferase 2 (OsBCAT2), a protein responsible for the degradation of BCAA, positively regulates salt tolerance.Salt significantly induces the expression of OsBCAT2 rather than BCAA synthesis genes, which indicated that salt mainly promotes BCAA degradation and not de novo synthesis. Metabolomics analysis revealed that vitamin B5 (VB5) biosynthesis pathway intermediates were higher in the OsBCAT2‐overexpressing plants but lower in osbcat2 mutants under salt stress. The salt stress‐sensitive phenotypes of the osbcat2 mutants are rescued by exogenous VB5, indicating that OsBCAT2 affects rice salt tolerance by regulating VB5 synthesis.Our work provides new insights into the enzymes involved in BCAAs degradation and VB5 biosynthesis and sheds light on the molecular mechanism of BCAAs in response to salt stress. [ABSTRACT FROM AUTHOR]

Maple Syrup Urine Disease (MSUD) is a metabolic disease characterized by the accumulation of branched-chain amino acids (BCAA) in different tissues due to a deficit in the branched-chain alpha-ketoacid dehydrogenase complex. The most common symptoms are poor feeding, psychomotor delay, and neurological damage. However, dietary therapy is not effective. Studies have demonstrated that memantine improves neurological damage in neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. Therefore, we hypothesize that memantine, an NMDA receptor antagonist can ameliorate the effects elicited by BCAA in an MSUD animal model. For this, we organized the rats into four groups: control group (1), MSUD group (2), memantine group (3), and MSUD + memantine group (4). Animals were exposed to the MSUD model by the administration of BCAA (15.8 µL/g) (groups 2 and 4) or saline solution (0.9%) (groups 1 and 3) and treated with water or memantine (5 mg/kg) (groups 3 and 4). Our results showed that BCAA administration induced memory alterations, and changes in the levels of acetylcholine in the cerebral cortex. Furthermore, induction of oxidative damage and alterations in antioxidant enzyme activities along with an increase in pro-inflammatory cytokines were verified in the cerebral cortex. Thus, memantine treatment prevented the alterations in memory, acetylcholinesterase activity, 2′,7′-Dichlorofluorescein oxidation, thiobarbituric acid reactive substances levels, sulfhydryl content, and inflammation. These findings suggest that memantine can improve the pathomechanisms observed in the MSUD model, and may improve oxidative stress, inflammation, and behavior alterations. [ABSTRACT FROM AUTHOR]

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%). Drugtreated 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-E1aser293 (þ98%), 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. [ABSTRACT FROM AUTHOR]

The metabolic mechanism of branched-chain amino acids of yeast and the effect of addition of branched-chain amino acids on aroma quality of pineapple wine were investigated. The results showed that adding 400 mg L−1 leucine, isoleucine and valine could increase adenosine triphosphate content, aminotransferase activity and total aroma compounds content of yeast by 80.30 %, 39.94 % and 100.67 % at most, respectively. The total aroma compounds content of pineapple wine fermented with the addition of 400 mg L−1 leucine, 400 mg L−1 isoleucine and 800 mg L−1 valine was increased by 53.80 %, 27.62 %, and 10.70 %, respectively. These results indicated that branched-chain amino acids could promote the growth of yeast to accumulate more adenosine triphosphate content and increased the activity of aminotransferases, thus promoting the entry of amino acids into the Ehrlich pathway to participate in the synthesis of higher alcohols and esters, and improving the aroma and overall quality of pineapple wine. [ABSTRACT FROM AUTHOR]

In the global food industry, plant‐based protein isolates are gaining prominence as an alternative to animal‐based counterparts. However, their nutritional value often falters due to insufficient essential amino acids. To address this issue, our study introduces a sustainable protein isolate derived from yeast cells, achieved through high‐pressure homogenization (HPH) and alkali pH‐shifting treatment. Subjected to HPH pressures ranging from 60 to 120 MPa and 1 to 10 cycles, higher pressure and cycle numbers resulted in enhanced disruption of yeast cells. Combining HPH with alkali pH‐shifting treatment significantly augmented protein extraction. Four cycles of HPH at 100 MPa yielded the optimized protein content, resulting in a yeast protein isolate (YPI) with 75.3 g protein per 100 g powder, including 30.0 g of essential amino acids and 18.4 g of branched‐chain amino acids per 100 g protein. YPI exhibited superior water and oil‐holding capacities compared to pea protein isolate, whey protein isolate (WPI), and soy protein isolate. Although YPI exhibited lower emulsifying ability than WPI, it excelled in stabilizing protein‐stabilized emulsions. For foaming, YPI outperformed others in both foaming ability and stabilizing protein‐based foam. In conclusion, YPI surpasses numerous plant‐based protein alternatives in essential amino acids and branched‐chain amino acids contents, positioning it as an excellent candidate for widespread utilization as a sustainable protein source in the food industry, owing to its exceptional nutritional advantages, as well as emulsifying and foaming properties. Practical Application: This study introduces a sustainable protein isolate derived from yeast cells. YPI exhibited considerable promise as a protein source. Nutritionally, YPI notably surpassed plant‐based protein isolates in EAA and BCAA contents. Functionally, YPI demonstrated superior water‐holding and oil‐holding capacities, as well as an effective emulsion and foam stabilizer. [ABSTRACT FROM AUTHOR]

Background: Dairy 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. Methods: Thirty-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. Results: No 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). Conclusions: Overall, BCAA supplementation in this study improved milk production, whereas BCKA supplementation reduced TG accumulation in the liver of fresh cows. [ABSTRACT FROM AUTHOR]

Alterations in brain energy metabolism have long been proposed as one of several neurobiological processes contributing to delirium. This is supported by previous findings of altered CSF lactate and neuron-specific enolase concentrations and decreased glucose uptake on brain-PET in patients with delirium. Despite this, there are limited data on metabolic alterations found in CSF samples, and targeted metabolic profiling of CSF metabolites involved in energy metabolism has not been performed. The aim of the study was to investigate whether metabolites related to energy metabolism in the serum and CSF of patients with hip fracture are associated with delirium. The study cohort included 406 patients with a mean age of 81 years (standard deviation 10 years), acutely admitted to hospital for surgical repair of a hip fracture. Delirium was assessed daily until the fifth postoperative day. CSF was collected from all 406 participants at the onset of spinal anaesthesia, and serum samples were drawn concurrently from 213 participants. Glucose and lactate in CSF were measured using amperometry, whereas plasma glucose was measured in the clinical laboratory using enzymatic photometry. Serum and CSF concentrations of the branched-chain amino acids, 3-hydroxyisobutyric acid, acetoacetate and β-hydroxybutyrate were measured using gas chromatography-tandem mass spectrometry (GC-MS/MS). In total, 224 (55%) patients developed delirium pre- or postoperatively. Ketone body concentrations (acetoacetate, β-hydroxybutyrate) and branched-chain amino acids were significantly elevated in the CSF but not in serum among patients with delirium, despite no group differences in glucose concentrations. The level of 3-hydroxyisobutyric acid was significantly elevated in both CSF and serum. An elevation of CSF lactate during delirium was explained by age and comorbidity. Our data suggest that altered glucose utilization and a shift to ketone body metabolism occurs in the brain during delirium. [ABSTRACT FROM AUTHOR]

2023. Introduction: Exercise with low carbohydrate availability increases protein degradation, whichmay reduce subsequent performance considerably. The present study aimed to investigate the effect of carbohydrate ingestion during standardized exercise with and without exhaustion on protein degradation and next-day performance. Methods: Seven trained male cyclists ( VO2max 66.8 ± 1.9 mL·kg-1·min-1; mean ± SEM) cycled to exhaustion (-2.5 h) at a power output eliciting 68% of VO2max (W68%). This was followed by repeating 1-min work/1-min recovery intervals at 90% of VO2max (W90%) until exhaustion. During W68%, cyclists consumed a placebo water drink (PLA) the first time and a carbohydrate drink (CHO), 1 g carbohydrate·kg-1·h-1, the second time. The participants performed the same amount of work under the two conditions, separated by at least 1 wk. A standardized diet was provided to the participants so that the two conditions were isoenergetic. To test the impact of carbohydrates on recovery, participants completed a time trial (TT) the next day. Results: Carbohydrate ingestion maintained carbohydrate availability duringW68% andW90%: total carbohydrate oxidation was significantly higher in CHO (P = 0.022), and plasma glucose concentration was maintained compared with PLA (P = 0.025). Next-day performance during TT was better after CHO ingestion (CHO, 41:49 ± 1:38 min; PLA, 42:50 ± 1:46 min; P = 0.020; effect size d = 0.23, small), as was gross efficiency (CHO, 18.6% ± 0.3%; PLA, 17.9% ± 0.3%; P = 0.019). Urinary nitrogen excretion (P = 0.897) and urinary 3-methylhistidine excretion (P = 0.673) did not significantly differ during the study period. Finally, tyrosine and phenylalanine plasma concentrations increased in PLA but not in CHO (P = 0.018). Conclusions: Carbohydrate ingestion during exhaustive exercise reduced deterioration in next-day performance through reduced metabolic stress and development of fatigue. In addition, some parameters point toward less protein degradation, which would preserve muscle function. [ABSTRACT FROM AUTHOR]

Background: Increasing maternal glycaemia across the continuum during pregnancy may predispose offspring to subsequent cardiometabolic risk later in life. However, evidence of long-term impacts of maternal glycemic status on offspring amino acid (AA) profiles is scarce. We aimed to investigate the association between maternal antenatal glycaemia and offspring mid-childhood amino acid (AA) profiles, which are emerging cardiometabolic biomarkers. Methods: Data were drawn from the Growing Up in Singapore Towards healthy Outcomes (GUSTO) study, a multi-ethnic Asian birth cohort. A subset of 422 mother–child dyads from the GUSTO study, who was followed from early pregnancy to mid-childhood, was included. Mothers underwent an oral glucose tolerance test (OGTT) at 26–28 weeks gestation, with fasting and 2-h plasma glucose concentrations measured and gestational diabetes mellitus (GDM) diagnosed per WHO 1999 guidelines. Offspring fasting plasma samples were collected at mean age 6.1 years, from which AA profiles of nine AAs, alanine, glutamine, glycine, histidine, isoleucine, leucine, valine, phenylalanine, and tyrosine were measured. Total branched-chain amino acids (BCAAs) were calculated as the sum of isoleucine, leucine, and valine concentrations. Multi-variable linear regression was used to estimate the association of maternal glycemic status and offspring mid-childhood AA profiles adjusting for maternal age, ethnicity, maternal education, parity, family history of diabetes, ppBMI, child sex, age and BMI z-scores. Results: Approximately 20% of mothers were diagnosed with GDM. Increasing maternal fasting glucose was significantly associated with higher offspring plasma valine and total BCAAs, whereas higher 2-h glucose was significantly associated with higher histidine, isoleucine, valine, and total BCAAs. Offspring born to mothers with GDM had higher valine (standardized mean difference 0.27 SD; 95% CI: 0.01, 0.52), leucine (0.28 SD; 0.02, 0.53), and total BCAAs (0.26 SD; 0.01, 0.52) than their counterparts. Inconsistent associations were found between maternal GDM and other amino acids among offspring during mid-childhood. Conclusions: Increasing maternal fasting and post-OGTT glucose concentrations at 26–28 weeks gestation were significantly associated with mid-childhood individual and total BCAAs concentrations. The findings suggest that elevated maternal glycaemia throughout pregnancy, especially GDM, may have persistent programming effects on offspring AA metabolism which were strongly associated with adverse cardiometabolic profiles at mid-childhood. [ABSTRACT FROM AUTHOR]

Some cellulolytic bacteria cannot transport branched-chain AA (BCAA) and do not express complete synthesis pathways, thus depending on cross-feeding for branched-chain volatile fatty acid (BCVFA) precursors for membrane lipids or for reductive carboxylation to BCAA. Our objective was to assess BCVFA uptake for BCAA synthesis in continuous cultures administered high forage (HF) and low forage (LF) diets without or with corn oil (CO). We hypothesized that BCVFA would be used for BCAA synthesis more in the HF than in LF diets. To help overcome bacterial inhibition by polyunsaturated fatty acids in CO, BCVFA usage for bacterial BCAA synthesis was hypothesized to decrease when CO was added to HF diets. The study was an incomplete block design with 8 dual-flow fermenters used in 4 periods with 8 treatments (n = 4) arranged as a 2 × 2 × 2 factorial. The factors were: HF or LF (67 or 33% forage, 33:67 alfalfa:orchardgrass pellets), without or with supplemental CO (3% of dry matter), and without or with 2.15 mmol/d (5 mg/d 13C) each of isovalerate, isobutyrate, and 2-methylbutyrate for one combined BCVFA treatment. The flow of bacterial BCAA increased by 10.7% by supplementing BCVFA and 9.14% with LF versus HF; similarly, dosing BCVFA versus without BCVFA increased BCAA by 1.98% in total bacterial AA, whereas LF increased BCAA by 1.92% versus HF. Additionally, BCVFA supplementation increased bacterial AA flow by 16.6% when supplemented in HF − CO and 12.4% in LF + CO diets, but not in the HF + CO (−1.5%) or LF − CO (+6.7%) diets (Diet × CO × BCVFA interaction). The recovery of 13C in bacterial AA flow was 31% lower with LF than with HF. Of the total 13C recovered in bacteria, 13.8, 17.3, and 30.2% were recovered in Val, Ile, and Leu, respectively; negligible 13C was recovered in other AA. When fermenters were dosed with BCVFA, nonbacterial and total effluent flows of AA, particularly of alanine and proline, suggest decreased peptidolysis. Increased ruminal outflow of bacterial AA, especially BCAA, but also nonbacterial AA could potentially support postabsorptive responses from BCVFA supplementation to dairy cattle. [ABSTRACT FROM AUTHOR]

Background Natural clearance of Chlamydia trachomatis in women occurs in the interval between screening and treatment. In vitro, interferon-γ (IFN-γ)–mediated tryptophan depletion results in C. trachomatis clearance, but whether this mechanism occurs in vivo remains unclear. We previously found that women who naturally cleared C. trachomatis had lower cervicovaginal levels of tryptophan and IFN-γ compared to women with persisting infection, suggesting IFN-γ–independent pathways may promote C. trachomatis clearance. Methods Cervicovaginal lavages from 34 women who did (n = 17) or did not (n = 17) naturally clear C. trachomatis were subjected to untargeted high-performance liquid chromatography mass-spectrometry to identify metabolites and metabolic pathways associated with natural clearance. Results In total, 375 positively charged metabolites and 149 negatively charged metabolites were annotated. Compared to women with persisting infection, C. trachomatis natural clearance was associated with increased levels of oligosaccharides trehalose, sucrose, melezitose, and maltotriose, and lower levels of indoline and various amino acids. Metabolites were associated with valine, leucine, and isoleucine biosynthesis pathways. Conclusions The cervicovaginal metabolome in women who did or did not naturally clear C. trachomatis is distinct. In women who cleared C. trachomatis , depletion of various amino acids, especially valine, leucine, and isoleucine, suggests that amino acids other than tryptophan impact C. trachomatis survival in vivo. [ABSTRACT FROM AUTHOR]

Maple syrup urine disease (MSUD) is caused by a deficiency in the activity of the branched‐chain α‐ketoacid dehydrogenase (BCKD) complex, promoting the accumulation of the branched‐chain amino acids (BCAA) leucine, isoleucine, and valine, as well as their respective α‐keto acids. MSUD is an autosomal recessive hereditary metabolic disorder characterized by ketoacidosis, ataxia, coma, and mental and psychomotor retardation. The mechanisms involved in the brain damage caused by MSUD are not fully understood. Early diagnosis and treatment, as well as proper control of metabolic decompensation crises, are crucial for patients' survival and for a better prognosis. The recommended treatment consists of a high‐calorie diet with restricted protein intake and specific formulas containing essential amino acids, except those accumulated in MSUD. This treatment will be maintained throughout life, being adjusted according to the patients' nutritional needs and BCAA concentration. Because dietary treatment may not be sufficient to prevent neurological damage in MSUD patients, other therapeutic strategies have been studied, including liver transplantation. With transplantation, it is possible to obtain an increase of about 10% of the normal BCKD in the body, an amount sufficient to maintain amino acid homeostasis and reduce metabolic decompensation crises. However, the experience related to this practice is very limited when considering the shortage of liver for transplantation and the risks related to the surgical procedure and immunosuppression. Thus, the purpose of this review is to survey the benefits, risks, and challenges of liver transplantation in the treatment of MSUD. [ABSTRACT FROM AUTHOR]

Background: It has been reported that weight loss or lean body mass (LBM) loss after gastrectomy for gastric cancer is associated with prognosis and nutritional support alone is insufficient to prevent LBM loss. Branched-chain amino acids (BCAA) play an important role in muscle catabolism, however their clinical effects on suppression of LBM loss in gastric cancer patients undergoing gastrectomy remains elusive. In this current study, we investigated the effect of our original PPN regimen including BCAA (designated to BCAA-regimen) on LBM loss. Methods: We conducted a randomized controlled trial (RCT) at a single institution where patients undergoing gastrectomy were assigned to either receive a five-day early postoperative course of the BCAA-regimen (BCAA group) or conventional nutrition. The primary endpoint was the % reduction in LBM at postoperative day 7. The secondary endpoints included the % reduction in LBM at 1 and 3 months postsurgery. Results: At postoperative day 7, LBM loss in the BCAA group tended to be lower than in the control group (0.16% vs. 1.7%, respectively; P = 0.21), while at 1 month postsurgery, LBM loss in the BCAA group was significantly different to that of the control group (− 0.3% vs. 4.5%, respectively; P = 0.04). At 3 months postgastrectomy, however, LBM loss was similar between the BCAA and the control groups. Conclusion: Our RCT clinical trial clarified that early administration of the postoperative BCAA regimen improved LBM loss at 1 month after surgery in gastric cancer patients undergoing gastrectomy. [ABSTRACT FROM AUTHOR]

Maple syrup urine disease (MSUD) is an inherited metabolic disorder caused by a deficiency in branched-chain alpha-ketoacid dehydrogenase complex (BCKAC). The treatment is a standard therapy based on a protein-restricted diet with low branched-chain amino acids (BCAA) content to reduce plasma levels and, consequently, the effects of accumulating their metabolites, mainly in the central nervous system. Although the benefits of dietary therapy for MSUD are undeniable, natural protein restriction may increase the risk of nutritional deficiencies, resulting in a low total antioxidant status that can predispose and contribute to oxidative stress. As MSUD is related to redox and energy imbalance, melatonin can be an important adjuvant treatment. Melatonin directly scavenges the hydroxy radical, peroxyl radical, nitrite anion, and singlet oxygen and indirectly induces antioxidant enzyme production. Therefore, this study assesses the role of melatonin treatment on oxidative stress in brain tissue and behavior parameters of zebrafish (Danio rerio) exposed to two concentrations of leucine-induced MSUD: leucine 2 mM and 5mM; and treated with 100 nM of melatonin. Oxidative stress was assessed through oxidative damage (TBARS, DCF, and sulfhydryl content) and antioxidant enzyme activity (SOD and CAT). Melatonin treatment improved redox imbalance with reduced TBARS levels, increased SOD activity, and normalized CAT activity to baseline. Behavior was analyzed with novel object recognition test. Animals exposed to leucine improved object recognition due to melatonin treatment. With the above, we can suggest that melatonin supplementation can protect neurologic oxidative stress, protecting leucine-induced behavior alterations such as memory impairment. [ABSTRACT FROM AUTHOR]

The significance of branched‐chain amino acids in diseases was clearly shown over the years. This review aims to describe the available techniques for their analytical determination. The article provides examples of the use of various analytical methods. The methods are divided into two categories: derivatization and non‐derivatization approaches. Separation is achieved through different chromatography or capillary electrophoresis techniques and can be combined with different detectors such as flame ionization, ultraviolet, fluorescence, and mass spectrometry. It compares the application of various derivatization reagents or detection as such for different detectors. [ABSTRACT FROM AUTHOR]

Summary: Micronutrients, particularly amino acids, are thought to play an important role in sleep regulation and maintenance. While tryptophan is a known predictor of sleep, less is known about branched‐chain amino acids (BCAAs), which compete with tryptophan for transport across the blood–brain barrier. The aim of this study was to determine the association between BCAAs and actigraphy‐derived sleep duration, timing and efficiency, and self‐reported trouble sleeping. This study examined data on children and adults collected as part of the Child Health CheckPoint study. Linear mixed models, adjusted for geographic clustering, were used to determine the association between BCAAs and sleep characteristics. Complete‐case analysis was conducted for 741 children aged 11–12 years old (51% females) and 941parents (87% mothers). While BCAAs were significantly associated with children's sleep duration, timing and self‐reported trouble sleeping, no associations were observed in adults, in fully adjusted models. In children, higher levels of BCAAs are associated with shorter sleep duration, delayed sleep timing, and more frequent reports of trouble sleeping. [ABSTRACT FROM AUTHOR]

Background: Several amino acids and their derivatives have been implicated in insulin resistance (IR) and Type 2 Diabetes Mellitus (T2DM). This research sought to establish a relationship between the dietary levels of branched-chain amino acids (BCAA) and the risk of T2DM. Methods: This case-control study was carried out on 4200 participants consisting of 589 people with T2DM and 3611 non-diabetic aged 35 to 70 years residents in Sabzevar, Iran. Data on the economic-social, employment status, medical history, lifestyle, and sleep habits were collected via interview. The food frequency questionnaire (FFQ) was used to check the nutritional status. Participants' dietary BCAA consumption was estimated using Nutritionist IV software. Results: A significant negative association between the incidence of T2DM and the dietary levels of BCAAs after adjustment for age and sex (OR = 0.972, CI 95%:0.648–0.996, P = 0.022). The negative association remained significant after additional adjustments for body mass index (BMI) and physical activity (OR = 0.967, CI 95%: 0.943–0.992, P = 0.010). Interestingly, a positive association was found between T2DM and total BCAAs (OR = 1.067, CI 95%: 1.017–1.119, P = 0.008), Isoleucine (OR = 1.248, CI 95%: 1.043–1.494, P = 0.016), Leucine (OR = 1.165, CI 95%: 1.046–1.299, P = 0.006) and Valine (OR = 1.274, CI 95%: 1.088–1.492, P = 0.003) after further adjustment for calorie intake. Conclusions: Our results demonstrate branched-chain amino acids (BCAAs) including isoleucine, leucine, and valine are negatively associated with the incidence of type 2 diabetes (T2DM) after adjusting for age and sex, BMI, and physical activity. However, adjusting for calorie intake reversed the association between T2DM and BCAAs. These findings suggest that the association between BCAAs and T2DM may be influenced by calorie intake. Future longitudinal studies are warranted. [ABSTRACT FROM AUTHOR]

Background: The potential role of dietary branched-chain amino acids (BCAA) in metabolic health, including cardiovascular disease and diabetes, is evolving, and it is yet to be understood if dietary BCAA intakes are associated with plasma lipid profiles or dyslipidaemia. This study tested the association of dietary BCAA intakes with plasma lipid profiles and dyslipidaemia among Filipino women in Korea. Methods: Energy-adjusted dietary BCAA intakes (isoleucine, leucine, valine, and total BCAA) and fasting blood profiles of triglycerides (TG), total cholesterol (TC), high-density lipoprotein-cholesterol (HDL-C), and low-density lipoprotein-cholesterol (LDL-C) were determined in a sample of 423 women enrolled in the Filipino Women's Diet and Health Study (FiLWHEL). The generalized linear model was applied to estimate least-square (LS) means and 95% confidence intervals (CIs) and compare plasma TG, TC, HDL-C, and LDL-C across tertile distribution of energy-adjusted dietary BCAA intakes at P < 0.05. Results: Mean of energy-adjusted dietary total BCAA intake was 8.3 ± 3.9 g/d. Average plasma lipid profiles were 88.5 ± 47.4 mg/dl for TG, 179.7 ± 34.5 mg/dl for TC, 58.0 ± 13.7 mg/dl for HDL-C, and 104.0 ± 30.5 mg/dl for LDL-C. LS means, and 95% CIs across tertiles of energy-adjusted total BCAA intakes were 89.9 mg/dl, 88.8 mg/dl and 85.8 mg/dl (P-trend = 0.45) for TG, 179.1 mg/dl, 183.6 mg/dl and 176.5 mg/dl (P-trend = 0.48) for TC, 57.5 mg/dl, 59.6 mg/dl and 57.1 mg/dl (P-trend = 0.75) for HDL-C and 103.6 mg/dl, 106.2 mg/dl and 102.3 mg/dl (P-trend = 0.68) for LDL-C. Furthermore, the multivariable-adjusted prevalence ratios and 95% confidence intervals for dyslipidaemia across increasing tertile distribution of energy-adjusted total BCAA intake were; 1.00, 0.67 (0.40, 1.13) and 0.45 (0.16, 1.27; P-trend = 0.03) for the first, second and third tertile, respectively. Conclusions: Higher dietary intakes of BCAA presented a statistically significant inverse trend with the prevalence of dyslipidaemia among Filipino women in this study and testing these associations in longitudinal studies may be necessary to confirm these findings. [ABSTRACT FROM AUTHOR]

We examined postprandial branched-chain amino acid (BCAA), insulin, and glucose responses in blood for 4 h following the consumption of two isonitrogenous doses (2 × 20 g protein) of Greek-style yogurt (GY) and skimmed milk (MILK) in young males. Peak leucine and BCAA concentrations and areas under the curve were greater after GY versus MILK, and time to maximal leucine/BCAA concentrations was similar between conditions. We demonstrated that different protein-matched wholefood dairy products elicit different postprandial aminoacidemic responses. [ABSTRACT FROM AUTHOR]

The pathogenesis of Alzheimer's disease (AD) is complicated and involves multiple contributing factors. Mounting evidence supports the concept that AD is an age-related metabolic neurodegenerative disease mediated in part by brain insulin resistance, and sharing similar metabolic dysfunctions and brain pathological characteristics that occur in type 2 diabetes mellitus (T2DM) and other insulin resistance disorders. Brain insulin signal pathway is a major regulator of branched-chain amino acid (BCAA) metabolism. In the past several years, impaired BCAA metabolism has been described in several insulin resistant states such as obesity, T2DM and cardiovascular disease. Disrupted BCAA metabolism leading to elevation in circulating BCAAs and related metabolites is an early metabolic phenotype of insulin resistance and correlated with future onset of T2DM. Brain is a major site for BCAA metabolism. BCAAs play pivotal roles in normal brain function, especially in signal transduction, nitrogen homeostasis, and neurotransmitter cycling. Evidence from animal models and patients support the involvement of BCAA dysmetabolism in neurodegenerative diseases including Huntington's disease, Parkinson's disease, and maple syrup urine disease. More recently, growing studies have revealed altered BCAA metabolism in AD, but the relationship between them is poorly understood. This review is focused on the recent findings regarding BCAA metabolism and its role in AD. Moreover, we will explore how impaired BCAA metabolism influences brain function and participates in the pathogenesis of AD. [ABSTRACT FROM AUTHOR]

Autism spectrum disorders caused by both genetic and environmental factors are strongly male-biased neuropsychiatric conditions. However, the mechanism underlying the sex bias of autism spectrum disorders remains elusive. Here, we use a mouse model in which the autism-linked gene Cttnbp2 is mutated to explore the potential mechanism underlying the autism sex bias. Autism-like features of Cttnbp2 mutant mice were assessed via behavioral assays. C-FOS staining identified sex-biased brain regions critical to social interaction, with their roles and connectivity then validated by chemogenetic manipulation. Proteomic and bioinformatic analyses established sex-biased molecular deficits at synapses, prompting our hypothesis that male-biased nutrient demand magnifies Cttnbp2 deficiency. Accordingly, intakes of branched-chain amino acids (BCAA) and zinc were experimentally altered to assess their effect on autism-like behaviors. Both deletion and autism-linked mutation of Cttnbp2 result in male-biased social deficits. Seven brain regions, including the infralimbic area of the medial prefrontal cortex (ILA), exhibit reduced neural activity in male mutant mice but not in females upon social stimulation. ILA activation by chemogenetic manipulation is sufficient to activate four of those brain regions susceptible to Cttnbp2 deficiency and consequently to ameliorate social deficits in male mice, implying an ILA-regulated neural circuit is critical to male-biased social deficits. Proteomics analysis reveals male-specific downregulated proteins (including SHANK2 and PSD-95, two synaptic zinc-binding proteins) and female-specific upregulated proteins (including RRAGC) linked to neuropsychiatric disorders, which are likely relevant to male-biased deficits and a female protective effect observed in Cttnbp2 mutant mice. Notably, RRAGC is an upstream regulator of mTOR that senses branched-chain amino acids (BCAA), suggesting that mTOR exerts a beneficial effect on females. Indeed, increased BCAA intake activates the mTOR pathway and rescues neuronal responses and social behaviors of male Cttnbp2 mutant mice. Moreover, mutant males exhibit greatly increased zinc demand to display normal social behaviors. Mice carrying an autism-linked Cttnbp2 mutation exhibit male-biased social deficits linked to specific brain regions, differential synaptic proteomes and higher demand for BCAA and zinc. We postulate that lower demand for zinc and BCAA are relevant to the female protective effect. Our study reveals a mechanism underlying sex-biased social defects and also suggests a potential therapeutic approach for autism spectrum disorders. [ABSTRACT FROM AUTHOR]

Sleep disorder is a relatively common problem that causes chronic conditions such as obesity, diabetes, and cardiovascular diseases. It is believed that diet regulates sleep. So, investigating the relationship between branched-chain amino acids (BCAAs) and aromatic amino acids intake with sleep quality based on age, gender and Body Mass Index (BMI) is important. A total of 172 males and females aged 18–65 participated in this study. The questionnaires were given online to them, included demographic information, food frequency questionnaire (FFQ), International Physical Activity Questionnaire, and Pittsburgh Sleep Quality Index. The Chalder fatigue scale (CFQ) was also used to measure the extent and severity of fatigue. The intake of amino acids was investigated by FFQ. The relationship between amino acids intake and sleep quality was investigated using Pearson's test. The results showed that intake of energy, macronutrients, and some micronutrients had a significant relationship with the quality of sleep of men compared to that of women (P < 0.05). No difference in sleep duration was observed between the two genders. There was a significant, positive association between sleep duration and the intake of BCAA (CC = 0.205, P = 0.031) and aromatic amino acids (CC = 0.22, P = 0.02) in the participants with normal BMI. Significant differences were seen in the intake of BCAA according to BMI which these differences were between lean and obese people, lean and overweight people, obese and normal, and overweight people. It demonstrated that in individuals with normal BMI, amino acids, protein, and carbohydrate intake may affect sleep duration and with modification of these factors sleep quality may get better. More study is needed to confirm these findings. [ABSTRACT FROM AUTHOR]

Metabolic and molecular interactions between branched-chain amino acid (BCAA) and lipid metabolism are evident in insulin-resistant tissues. However, it remains unclear whether insulin resistance is a prerequisite for these relationships and whether BCAAs or their metabolic intermediates can modulate hepatic lipid oxidation and synthesis. We hypothesized that BCAAs can alter hepatic oxidative function and de novo lipogenesis, independent of them being anaplerotic substrates for the mitochondria. Mice (C57BL/6NJ) were reared on a low-fat (LF), LF diet plus 1.5X BCAAs (LB), high-fat (HF) or HF diet plus 1.5X BCAAs (HB) for 12 wk. Hepatic metabolism was profiled utilizing stable isotopes coupled to mass spectrometry and nuclear magnetic resonance, together with fed-to-fasted changes in gene and protein expression. A greater induction of lipid oxidation and ketogenesis on fasting was evident in the BCAA-supplemented, insulin-sensitive livers from LB mice, whereas their rates of hepatic de novo lipogenesis remained lower than their LF counterparts. Onset of insulin resistance in HF and HB mice livers blunted these responses. Whole body turnover of BCAAs and their ketoacids, their serum concentrations, and the ketogenic flux from BCAA catabolism, all remained similar between fasted LF and LB mice. This suggested that the impact of BCAAs on lipid metabolism can occur independent of them or their degradation products fueling anaplerosis through the liver mitochondria. Furthermore, the greater induction of lipid oxidation in the LB livers accompanied higher mitochondrial NADH/NAD+ ratio and higher fed-to-fasting phosphorylation of AMPKa and ACC. Taken together, our results provide evidence that BCAA supplementation, under conditions of insulin sensitivity, improved the feeding-to-fasting induction of hepatic lipid oxidation through changes in cellular redox, thus providing a favorable biochemical environment for flux through b-oxidation and lower de novo lipogenesis. [ABSTRACT FROM AUTHOR]

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]

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]