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Abstract A high-fat diet (HFD) induces obesity and insulin resistance, which may exacerbate amyloid-β peptide (Aβ) pathology during Alzheimer’s disease (AD) progression. Branched-chain amino acids (BCAAs) accumulate in obese or insulin-resistant patients and animal models. However, roles of accumulated BCAAs and their metabolites, branched-chain keto acids (BCKAs), in the HFD-induced deterioration of AD and the underlying mechanisms remains largely unclear. In this study, APPswe/PSEN1dE9 (APP/PS1) transgenic mice were fed a HFD for 6 months, and the BCAAs content of the HFD was adjusted to 200% or 50% to determine the effects of BCAAs. The HFD-fed APP/PS1 mice accumulated BCAAs and BCKAs in the serum and cortex, which was accompanied by more severe cognitive deficits and AD-related pathology. The additional or restricted intake of BCAAs aggravated or reversed these phenomena. Importantly, BCAAs and BCKAs repressed microglial phagocytosis of Aβ in vivo and in BV2 cells, which might be relevant for triggering receptor expressed on myeloid cells 2 (TREM2) dysfunction and autophagy deficiency. We found that BCAAs and BCKAs could bind to TREM2 in silico, in pure protein solutions and in the cellular environment. These molecules competed with Aβ for binding to TREM2 so that the response of TREM2 to Aβ was impaired. Moreover, BCAAs and BCKAs decreased TREM2 recycling in an mTOR-independent manner, which might also lead to TREM2 dysfunction. Our findings suggest that accumulated BCAAs and BCKAs contribute to the HFD-induced acceleration of AD progression through hypofunctional TREM2-mediated disturbances in Aβ clearance in microglia. Lowering BCAAs and BCKAs levels may become a potential dietary intervention for AD.

Abstract Elevated concentrations of amino acids (AAs) are commonly observed in patients with nonalcoholic fatty liver disease (NAFLD). Individuals with hypopituitarism (HP) are at a heightened risk of developing NAFLD due to factors such as visceral obesity, increased insulin resistance (IR), and disturbances in lipid metabolism. However, the changes in AAs concentrations associated with HP remain poorly understood. Therefore, our study aimed to investigate whether individuals with HP, who were not receiving growth hormone replacement therapy (GHRT), exhibited altered AAs compared to controls (CTs), and whether these AAs were associated with IR, the presence of NAFLD, and the Metabolic Syndrome (MetS) score. The AAs profiles of 133 young males with HP (age: 24.5 ± 5.9; 57 with NAFLD and 76 without NAFLD) and 90 age and BMI-matched CTs were analyzed using untargeted metabolomics. The results revealed that most AAs were found to be elevated in subjects with HPs compared to CTs. Glutamate, glutamine, norleucine, and branched-chain amino acids (BCAAs) (leucine and valine) were correlated with the homeostasis model assessment of insulin resistance (HOMA-IR), with glutamate and norleucine showing independent linkage. Glutamate and proline levels were specifically associated with MetS score, while alanine and proline linked to NAFLD. Given that elevated glutamate and BCAAs levels have higher prevalence of NAFLD, we hypothesized that the changes in AAs observed in HPs may be attributed to the impact of NAFLD and IR.

Summary: Background & Aims: Branched-chain amino acids (BCAAs), and the marine omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), prevent physical decline in older people. However, their combined effect on physical function in heart failure (HF) is unclear. This study aimed to investigate the association of BCAAs and EPA/DHA with exercise tolerance in people with HF. Methods: In total, 124 patients with HF were prospectively enrolled, and their serum BCAA and EPA/DHA levels, dietary pattern, and 6-minute walking distance (6-MWD) were assessed. Results: Lower 6-MWD quantiles contained more female patients than higher 6-MWD quantiles. Patients with a shorter 6-MWD were older and had a smaller leg circumference, higher B-type natriuretic peptide concentrations, and lower BCAA and EPA/DHA levels than those with longer 6-MWD (all P < 0.05). Patients with a shorter 6-MWD had an imbalanced dietary pattern with low intakes of oily fish, soy products, and vegetables. Meanwhile, their estimated nutrient intakes were high in saturated fatty acids and sucrose and low in polyunsaturated fatty acids and dietary fiber (all P < 0.05). According to multivariate analysis, low EPA/DHA concentrations (per 50 μg/mL decrease) [odds ratio, 95% confidence interval: 1.479 (1.025–2.137)], low dietary fiber intake (per 1 g/1000kcal decrease) [1.524 (1.098–2.119)], and high sucrose intake (per 1 g/1000kcal increase) [1.170 (1.040–1.310)] were independently associated with short 6-MWD (the lowest quantile of 6-MWD,

Abstract Maladaptive changes of metabolic patterns in the lumbar dorsal root ganglion (DRG) are critical for nociceptive hypersensitivity genesis. The accumulation of branched-chain amino acids (BCAAs) in DRG has been implicated in mechanical allodynia and thermal hyperalgesia, but the exact mechanism is not fully understood. This study aimed to explore how BCAA catabolism in DRG modulates pain sensitization. Wildtype male mice were fed a high-fat diet (HFD) for 8 weeks. Adult PP2Cmfl/fl mice of both sexes were intrathecally injected with pAAV9-hSyn-Cre to delete the mitochondrial targeted 2 C-type serine/threonine protein phosphatase (PP2Cm) in DRG neurons. Here, we reported that BCAA catabolism was impaired in the lumbar 4–5 (L4-L5) DRGs of mice fed a high-fat diet (HFD). Conditional deletion of PP2Cm in DRG neurons led to mechanical allodynia, heat and cold hyperalgesia. Mechanistically, the genetic knockout of PP2Cm resulted in the upregulation of C-C chemokine ligand 5/C-C chemokine receptor 5 (CCL5/CCR5) axis and an increase in transient receptor potential ankyrin 1 (TRPA1) expression. Blocking the CCL5/CCR5 signaling or TRPA1 alleviated pain behaviors induced by PP2Cm deletion. Thus, targeting BCAA catabolism in DRG neurons may be a potential management strategy for pain sensitization.

BackgroundBranched-chain amino acids (BCAAs) are widely used as sports nutrition supplements. However, their impact on the rate of force development (RFD), an indicator of explosive muscle strength, has not yet been validated. This study aimed to assess the impact of BCAA supplementation on the RFD in college basketball players during simulated games.MethodsThis study employed a randomized, controlled crossover, double-blind design. Participants received either BCAAs (0.17 g/kg combined with 0.17 g/kg isocaloric glucose) or a placebo (0.34 g/kg isocaloric glucose) orally 30 min before beginning the exercise protocol. The RFD was quantified using the isometric mid-thigh pull (IMTP) test. Additional outcome measures, including strength and jump tests, agility and sprinting tests, and physiological responses, were also assessed. A two-way repeated measures ANOVA was employed to evaluate the impact of supplements (BCAAs and placebo) on RFD and other related outcome measures.ResultsAnalysis of the 50 ms RFD demonstrated significant main effects of BCAA supplementation (p = 0.003). The BCAAs group consistently exhibited higher levels of 50 ms RFD compared to the placebo group across rounds 1 to 4. For example, in round 1, the 50 ms RFD was 3702.3 ± 1223.2 N/S in the BCAAs group versus 2931.3 ± 888.8 N/S in the placebo group (p = 0.045). Although no significant between-group differences were observed for the 100, 150, 200, and 250 ms RFD measurements, the BCAAs group consistently showed superior values across all time points. The results of other outcome indicators also suggested that supplementation with BCAAs was indeed effective.ConclusionThe results indicate that BCAA supplementation can enhance RFD in basketball players, particularly at the 50 ms RFD. Our research design provides reliable insights into the effects of BCAAs on athletic performance. Further studies of similar design with larger sample sizes are necessary to confirm and extend these findings.Clinical trial registrationChinese Clinical Trial Registry, ChiCTR2400091314 (https://www.chictr.org.cn).

Amaranthus is considered a superfood with high nutraceutical value. It is a functional food composed of bioactive compounds crucial for sports nutrition including secondary metabolites, tocopherols, sterols, squalene, trace elements, polyphenols, peptides, polyunsaturated fatty acids, antioxidants, proteins, fat, carbohydrates, fibers, minerals, and vitamins making it a versatile supplement source. Notably, it is rich in amino acids, including branched-chain amino acids (BCAAs), natural enhancer of nitric oxide levels for improved circulation, endurance, strength, and stamina in athletes. It has been found to improve aerobic capacity, muscle recovery, and improved body composition. It is rich in fiber making it a beneficial prebiotic for athletes to maintain gastrointestinal health after intense training. Being rich in antioxidants and gluten-free, it’s ideal for special diets to reduce fat and increase muscle mass. A comprehensive overview of the ergogenic potential of Amaranthus and further research promises insights into developing Amaranthus-based dietary supplements for enhancing sports performance..

Elevated levels of circulating branched-chain amino acids (BCAAs) and their associated metabolites have been strongly linked to insulin resistance and type 2 diabetes. Despite extensive research, the precise mechanisms linking increased BCAA levels with these conditions remain elusive. In this review, we highlight the key organs involved in maintaining BCAA homeostasis and discuss how obesity and insulin resistance disrupt the intricate interplay among these organs, thus affecting BCAA balance. Additionally, we outline recent research shedding light on the impact of tissue-specific or systemic modulation of BCAA metabolism on circulating BCAA levels, their metabolites, and insulin sensitivity, while also identifying specific knowledge gaps and areas requiring further investigation. Finally, we summarize the effects of BCAA supplementation or restriction on obesity and insulin sensitivity.

The association of thyroid function with essential and non-essential amino acids is understudied, despite their common metabolic roles. Thus, our aim was to evaluate the association of thyroid function with the levels of branched-chain amino acids (BCAAs—leucine, isoleucine, and valine) and of alanine in the general population. We utilized data from the São Paulo research center of ELSA-Brasil, a longitudinal population-based cohort study. Thyroid parameters included thyroid stimulating hormone (TSH), free T4 and free T3 levels, and the FT4:FT3 ratio. BCAAs and alanine were analyzed on a fully automated NMR platform. The current analysis included euthyroid participants and participants with subclinical hyperthyroidism and hypothyroidism. We used Pearson’s coefficient to quantify the correlation between thyroid-related parameters and amino acids. Linear regression models were performed to analyze whether thyroid parameters were associated with BCAAs and alanine levels. We included 4098 participants (51.3 ± 9.0 years old, 51.5% women) in this study. In the most adjusted model, higher levels of TSH were associated with higher levels of alanine, FT4 levels were inversely associated with isoleucine levels, FT3 levels were statistically significant and positively associated with valine and leucine, and the T3:T4 ratio was positively associated with all amino acids. We observed that subclinical hypothyroidism was positively associated with isoleucine and alanine levels in all models, even after full adjustment. Our findings highlight the association of subclinical hypothyroidism and thyroid-related parameters (including TSH, free T4, free T3, and FT4:FT3 ratio) with BCAAs and alanine. Further studies are needed to explore the mechanisms underlying this association. These insights contribute to our understanding of the influence of thyroid-related parameters on BCAA and alanine metabolism.

Ranunculus asiaticus L. is an ornamental geophyte. In commercial practice, it is mainly propagated by rehydrated tuberous roots. Vernalization before planting is a common practice to overcome the natural dormancy of tuberous roots; however, little is known about the mechanisms underlying the plant’s response to low temperatures. We investigated the influence of three preparation procedures of tuberous roots, only rehydration (control, C), and rehydration plus vernalization at 3.5 °C for 2 weeks (V2) and for 4 weeks (V4), on plant growth, leaf photosynthesis, flowering, and metabolism in plants of two hybrids, MBO (early flowering, pale orange flower) and MDR (medium earliness, bright orange flower), grown in pots in an unheated greenhouse. We reported the responses observed in the aerial part in a previous article in this journal. In this paper, we show changes in the underground organs in carbohydrate, amino acids, polyphenols, and protein levels throughout the growing cycle in the different plant stages: pre-planting, vegetative growth, and flowering. The metabolic profile revealed that the two hybrids had different responses to the root preparation procedure. In particular, MBO synthesized GABA and alanine after 2 weeks and sucrose after 4 weeks of vernalization. In contrast, MDR was more sensitive to vernalization; in fact, a higher synthesis of polyphenols was observed. However, both hybrids synthesized metabolites that could withstand exposure to low temperatures.

Objectives: Tirzepatide, a dual GIP and GLP-1 receptor agonist, delivered superior glycemic control and weight loss compared to selective GLP-1 receptor (GLP-1R) agonism in patients with type 2 diabetes (T2D). These results have fueled mechanistic studies focused on understanding how tirzepatide achieves its therapeutic efficacy. Recently, we found that treatment with tirzepatide improves insulin sensitivity in humans with T2D and obese mice in concert with a reduction in circulating levels of branched-chain amino (BCAAs) and keto (BCKAs) acids, metabolites associated with development of systemic insulin resistance (IR) and T2D. Importantly, these systemic effects were found to be coupled to increased expression of BCAA catabolic genes in thermogenic brown adipose tissue (BAT) in mice. These findings led us to hypothesize that tirzepatide may lower circulating BCAAs/BCKAs by promoting their catabolism in BAT. Methods: To address this question, we utilized a murine model of diet-induced obesity and employed stable-isotope tracer studies in combination with metabolomic analyses in BAT and other tissues. Results: Treatment with tirzepatide stimulated catabolism of BCAAs/BCKAs in BAT, as demonstrated by increased labeling of BCKA-derived metabolites, and increases in levels of byproducts of BCAA breakdown, including glutamate, alanine, and 3-hydroxyisobutyric acid (3-HIB). Further, chronic administration of tirzepatide increased levels of multiple amino acids in BAT that have previously been shown to be elevated in response to cold exposure. Finally, chronic treatment with tirzepatide led to a substantial increase in several TCA cycle intermediates (α-ketoglutarate, fumarate, and malate) in BAT. Conclusions: These findings suggest that tirzepatide induces a thermogenic-like amino acid profile in BAT, an effect that may account for reduced systemic levels of BCAAs in obese IR mice.

Alzheimer’s disease is an incurable chronic neurodegenerative disorder and the leading cause of dementia, imposing a growing economic burden upon society. The disease progression is associated with gradual deposition of amyloid plaques and the formation of neurofibrillary tangles within the brain parenchyma, yet severe dementia is the culminating phase of the enduring pathology. Converging evidence suggests that Alzheimer’s disease-related cognitive decline is the outcome of an extremely complex and persistent pathophysiological process. The disease is characterized by distinctive abnormalities apparent at systemic, histological, macromolecular, and biochemical levels. Moreover, besides the well-defined and self-evident characteristic profuse neurofibrillary tangles, dystrophic neurites, and amyloid-beta deposits, the Alzheimer’s disease-associated pathology includes neuroinflammation, substantial neuronal loss, apoptosis, extensive DNA damage, considerable mitochondrial malfunction, compromised energy metabolism, and chronic oxidative stress. Likewise, distinctive metabolic dysfunction has been named a leading cause and a hallmark of Alzheimer’s disease that is apparent decades prior to disease manifestation. State-of-the-art metabolomics studies demonstrate that altered branched-chain amino acids (BCAAs) metabolism accompanies Alzheimer’s disease development. Lower plasma valine levels are correlated with accelerated cognitive decline, and, conversely, an increase in valine concentration is associated with reduced risk of Alzheimer’s disease. Additionally, a clear BCAAs-related metabolic signature has been identified in subjects with obesity, diabetes, and atherosclerosis. Also, arginine metabolism is dramatically altered in Alzheimer’s disease human brains and animal models. Accordingly, a potential role of the urea cycle in the Alzheimer’s disease development has been hypothesized, and preclinical studies utilizing intervention in the urea cycle and/or BCAAs metabolism have demonstrated clinical potential. Continual failures to offer a competent treatment strategy directed against amyloid-beta or Tau proteins-related lesions, which could face all challenges of the multifaceted Alzheimer’s disease pathology, led to the hypothesis that hyperphosphorylated Tau and deposited amyloid-beta proteins are just hallmarks or epiphenomena, but not the ultimate causes of Alzheimer’s disease. Therefore, approaches targeting amyloid-beta or Tau are not adequate to cure the disease. Accordingly, the modern scientific vision of Alzheimer’s disease etiology and pathogenesis must reach beyond the hallmarks, and look for alternative strategies and areas of research.

In humans, chronic liver disease may cause alterations in amino acids (AAs) metabolism, with serum branched-chain AAs (BCAAs) decreasing and aromatic AAs (AAAs) increasing. A reduced Fischer ratio (BCAAs/AAAs) has been found to be associated with hepatic fibrosis and is useful for assessing prognosis in human patients. In veterinary medicine, few studies have been performed, and in contrast to human patients, dogs with different kinds of hepatopathy tend to show both increased AAAs and BCAAs. In dogs, the association between histological scores and serum AAs has not been previously investigated. The aim of this study was to evaluate serum AAs in dogs with chronic hepatitis (CH) compared with a healthy control group (C) and, among CH dogs, in relation to their histological fibrosis and necroinflammatory activity scores. Leftover serum samples of 16 dogs with histological CH and 25 healthy dogs were employed. Serum AAs were measured by high performance liquid chromatography. Proline and the AAAs phenylalaine and tyrosine progressively increased with the histological severity. In contrast, cysteine, tryptophan and BCAA isoleucine progressively reduced. Lysine and the BCAAs leucine and valine showed a non-linear trend with the histological findings. The BCAAs/AAAs ratio was significatively reduced if higher grades of liver fibrosis were present.

El consumo de proteína y especialmente aminoácidos esenciales juega un papel fundamental en la dieta, ya que suple las necesidades de nitrógeno del organismo y favorece el mantenimiento de estructuras corporales. En los últimos años, la nutrición y la tecnología de los alimentos están experimentando una profunda transformación debido al desarrollo del concepto de alimentos funcionales y nutracéuticos. Tanto las proteínas funcionales como los péptidos bioactivos están cobrando gran importancia ya que, además de su papel nutricional por ser fuente de aminoácidos, son capaces de ejercer diferentes efectos biológicos específicos sobre el sistema inmune, el sistema cardiovascular o el tracto gastrointestinal. Los aminoácidos de cadena ramificada (BCAAs denominación por las siglas en inglés) como lo son la Leucina, Isoleucina y Valina son considerados útiles para el tratamiento y predicción de algunas enfermedades, el presente artículo de revisión, se recopila información acerca de los aminoácidos de cadena ramificada y su uso positivo en el tratamiento de diferentes patologías como enfermedades neurológicas, hepáticas, cardiometabólicas, cáncer, además de su uso en deportistas. Se tuvieron en cuenta los siguientes criterios de inclusión: 1. La búsqueda se realizó en reconocidas bases de datos, 2. Se incluyeron artículos desde el 2006 a la fecha, 3. Se realizó la búsqueda con palabras como aminoácidos de cadena ramificada y efecto en diferentes patologías, con la inclusión de artículos donde se menciona el consumo humano de los mismos, se excluyeron artículos donde los aminoácidos no intervengan de manera positiva en su consumo y tratamiento de enfermedades.

Branched-chain amino acids (BCAAs) are involved in immune system’s metabolic pathways and play fundamental role in gut health. Our aim was to assess BCAA plasma levels in patients with ulcerative colitis (UC) and associations of plasma BCAAs with disease-related parameters. This was a case-control study in adult patients with UC and BMI-matched controls. A total of 150 volunteers were screened between May 2016 and June 2017; 43 patients and 34 healthy controls were enrolled. Medical and dietary history (3 × 24 h recalls, MedDiet score), anthropometric measurements, blood and fecal samples were collected. We measured BCAAs in plasma with gas chromatography-mass spectrometry. In patients, fecal calprotectin, lactoferrin, lysozyme and defensin were quantified. Dietary pattern was similar in patients and controls. Plasma-free BCAA profiles did not differ between groups. Regression analysis showed that i) valine was inversely associated with calprotectin (p = 0.007) and ii) isoleucine with age (p = 0.031), after adjusting for age, sex, PMS and smoking. Leucine was negatively associated with age (p = 0.015) after adjusting for age, sex and PMS, but this association vanished when smoking was introduced. No correlation was observed between total BCAAs with any of the parameters. Plasma-free valine is negatively associated with calprotectin in patients with UC.

Arbuscular mycorrhizal fungi (AMF) are a promising tool to improve plant nutrient use efficiency (NUE) and tolerance against abiotic stresses. Moreover, AMF can potentially increase plant productivity and reduce the negative externalities of the agricultural sector. Our study aimed to elucidate whether AMF (containing Rhizoglomus irregulare and Funneliformis mosseae) could positively affect not only tomato growth and productivity but also the nutritional and nutraceutical quality of yellow-pigmented type (‘Giagiù’) and red-pigmented type (‘Lucariello’) tomatoes (Solanum lycopersicum L.). These cherry tomatoes are landraces of the Protected Designation of Origin (PDO) ‘Pomodorino del Piennolo del Vesuvio’ (PPV), one of the most typical agricultural products of the Campania region (Southern Italy). AMF rose fruit yield by increasing the number of fruits per plant (+49% and +29% in ‘Giagiù’ and ‘Lucariello’, respectively) but not of the fruit mean mass. AMF increased lycopene (+40%), total ascorbic acid (TAA; +41%), alanine (+162%), gamma-Aminobutyric acid (GABA; +101%) and branched-chain amino acids (BCAAs; +53%) in ‘Lucariello’. In ‘Giagiù’, AMF increased calcium (+63%), zinc (+45%), ASP (+70%), GABA (+53%) and the essential amino acids arginine (+58%) and lysine (+45%), also indicating a genotype-specific response. In both landraces, AMF improved nutrient uptake and biosynthesis of important molecules involved in the control the oxidative stress and cellular pH. In addition to the beneficial effects of human health, the molecules influenced by the AMF treatment are expected to extend the shelf life of tomato fruits, thus further promoting the useful agronomic application of AMF for premium tomatoes marketed fresh or in pendulums (‘piennoli’).

High glucose-induced cardiomyocyte death is a common symptom in advanced-stage diabetic patients, while its metabolic mechanism is still poorly understood. The aim of this study was to explore metabolic changes in high glucose-induced cardiomyocytes and the heart of streptozotocin-induced diabetic rats by 1H-NMR-based metabolomics. We found that high glucose can promote cardiomyocyte death both in vitro and in vivo studies. Metabolomic results show that several metabolites exhibited inconsistent variations in vitro and in vivo. However, we also identified a series of common metabolic changes, including increases in branched-chain amino acids (BCAAs: leucine, isoleucine and valine) as well as decreases in aspartate and creatine under high glucose condition. Moreover, a reduced energy metabolism could also be a common metabolic characteristic, as indicated by decreases in ATP in vitro as well as AMP, fumarate and succinate in vivo. Therefore, this study reveals that a decrease in energy metabolism and an increase in BCAAs metabolism could be implicated in high glucose-induced cardiomyocyte death.