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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 FROM AUTHOR]

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.. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: End-stage liver diseases (ESLDs) are a significant global health challenge due to their high prevalence and severe health impacts. Despite the severe outcomes associated with ESLDs, therapeutic options remain limited. Targeting the activation of hepatic stellate cells (HSCs), key drivers of extracellular matrix accumulation during liver injury presents a novel therapeutic approach. In ESLDs patients, branched-chain amino acids (BCAAs, leucine, isoleucine and valine) levels are decreased, and supplementation has been proposed to attenuate liver fibrosis and improve regeneration. However, their effects on HSCs require further investigation. Objective: To evaluate the efficacy of BCAAs and their metabolites, branched-chain α-keto acids (BCKAs), in modulating HSCs activation in human and rat models. Methods: Primary HSCs from rats and cirrhotic and non-cirrhotic human livers, were cultured and treated with BCAAs or BCKAs to assess their effects on both preventing (from day 1 of isolation) and reversing (from day 7 of isolation) HSCs activation. Results: In rat HSCs, leucine and BCKAs significantly reduced fibrotic markers and cell proliferation. In human HSCs, the metabolite of isoleucine decreased cell proliferation around 85% and increased the expression of branched-chain ketoacid dehydrogenase. The other metabolites also showed antifibrotic effects in HSCs from non-cirrhotic human livers. Conclusion: BCAAs and their respective metabolites inhibit HSC activation with species-specific responses. Further research is needed to understand how BCAAs influence liver fibrogenesis. BCKAs supplementation could be a strategic approach for managing ESLDs, considering the nutritional status and amino acid profiles of patients. The antifibrotic effects of BCAAs and BCKAs in various conditions are depicted for human HSCs (left) and rat HSCs (right) The symbol ‘↓’ indicates a downregulation or a decrease. α-SMA alpha-smooth muscle actin, BCAAs branched-chain amino acids, BCKAs branched-chain keto acids, HSCs hepatic stellate cells, KMV α-keto-β-methylvalerate. Figure created with Biorender.com [ABSTRACT FROM AUTHOR]

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.

Summary Branched‐chain amino acids (BCAAs), including leucine, isoleucine, and valine, are essential for maintaining physiological functions and metabolic homeostasis. However, chronic elevation of BCAAs causes metabolic diseases such as obesity, type 2 diabetes (T2D), and metabolic‐associated fatty liver disease (MAFLD). Adipose tissue, skeletal muscle, and the liver are the three major metabolic tissues not only responsible for controlling glucose, lipid, and energy balance but also for maintaining BCAA homeostasis. Under obese and diabetic conditions, different pathogenic factors like pro‐inflammatory cytokines, lipotoxicity, and reduction of adiponectin and peroxisome proliferator‐activated receptors γ (PPARγ) disrupt BCAA metabolism, leading to excessive accumulation of BCAAs and their downstream metabolites in metabolic tissues and circulation. Mechanistically, BCAAs and/or their downstream metabolites, such as branched‐chain ketoacids (BCKAs) and 3‐hydroxyisobutyrate (3‐HIB), impair insulin signaling, inhibit adipogenesis, induce inflammatory responses, and cause lipotoxicity in the metabolic tissues, resulting in multiple metabolic disorders. In this review, we summarize the latest studies on the metabolic regulation of BCAA homeostasis by the three major metabolic tissues—adipose tissue, skeletal muscle, and liver—and how dysregulated BCAA metabolism affects glucose, lipid, and energy balance in these active metabolic tissues. We also summarize therapeutic approaches to restore normal BCAA metabolism as a treatment for metabolic diseases. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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..

This study investigates the effect of daily consumption of wheat biscuits enriched with plant proteins in postprandial metabolic responses of women with overweight/obesity who follow an energy-restricted diet. Thirty apparently healthy women participated in a 12-week randomized controlled trial and were assigned either to a control (CB) or an intervention (PB) group. Participants consumed daily either a conventional (CB) or an isocaloric wheat biscuit enriched with plant proteins (PB) containing high amounts of amino acids with appetite-regulating properties, i.e., BCAAs and L-arg. At baseline and the end of the intervention, a mixed meal tolerance test was performed. The responses of glucose, insulin, ghrelin, GLP-1, and glicentin were evaluated over 180 min. After 12 weeks, both groups experienced significant decreases in body weight, fat mass, and waist circumference. In the PB group, a trend towards higher weight loss was observed, accompanied by lower carbohydrate, fat, and energy intakes (p < 0.05 compared to baseline and CB group), while decreases in fasting insulin and the HOMA-IR index were also observed (p < 0.05 compared to baseline). In both groups, similar postprandial glucose, ghrelin, and GLP-1 responses were detected, while iAUC for insulin was lower (p < 0.05). Interestingly, the iAUC of glicentin was greater in the PB group (p < 0.05 compared to baseline). Subjective appetite ratings were beneficially affected in both groups (p < 0.05). Consumption of wheat biscuits enriched in plant proteins contributed to greater weight loss, lower energy intake, and insulin resistance and had a positive impact on postprandial glicentin response, a peptide that can potentially predict long-term weight loss and decreased food intake. [ABSTRACT FROM AUTHOR]

Objectives Insulin resistance is associated with elevations in plasma branched-chain amino acids (BCAAs). BCAAs compete with aromatic amino acids including tryptophan for uptake into β cells. To explore relationships between BCAAs and tryptophan metabolism, adiposity, and glucose tolerance, we compared urine metabolites in overweight/obese youth with type 2 diabetes (T2D) with those in nondiabetic overweight/obese and lean youth. Methods Metabolites were measured in 24-hour and first-morning urine samples of 56 nondiabetic adolescents with overweight/obesity, 42 adolescents with T2D, and 43 lean controls, aged 12 to 21 years. Group differences were assessed by Kruskal Wallis or ANOVA. Results Groups were comparable for age, pubertal status, and ethnicity. Youth with T2D were predominantly female and had highest percent body fat. BCAAs, branched-chain ketoacids (BCKAs), tryptophan, and kynurenine were higher in urine of subjects with T2D. There were no differences between lean controls and nondiabetic youth with overweight/obesity. T2D was associated with diversion of tryptophan from the serotonin to the kynurenine pathway, with higher urinary kynurenine/serotonin ratio and lower serotonin/tryptophan and 5-HIAA/kynurenine ratios. Urinary BCAAs, BCKAs, tryptophan, and ratios reflecting diversion to the kynurenine pathway correlated positively with metrics of body fat and hemoglobin A1c. Increases in these metabolites in the obese T2D group were more pronounced and statistically significant only in adolescent girls. Conclusion Increases in urinary BCAAs and BCKAs in adolescent females with T2D are accompanied by diversion of tryptophan metabolism from the serotonin to the kynurenine pathway. These adaptations associate with higher risks of T2D in obese adolescent females than adolescent males. [ABSTRACT FROM AUTHOR]

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.

Inborn error of metabolism disorders (IEMs) are a family of diseases resulting from single-gene mutations that lead to the accumulation of metabolites that are usually toxic or interfere with normal cell function. The etiological link between metabolic alteration and the symptoms of IEMs is still elusive. Several metabolites, which accumulate in IEMs, were shown to self-assemble to form ordered structures. These structures display the same biophysical, biochemical, and biological characteristics as proteinaceous amyloid fibrils. Here, we have demonstrated, for the first time, the ability of each of the branched-chain amino acids (BCAAs) that accumulate in maple syrup urine disease (MSUD) to self-assemble into amyloid-like fibrils depicted by characteristic morphology, binding to indicative amyloid-specific dyes and dose-dependent cytotoxicity by a late apoptosis mechanism. We could also detect the presence of the assemblies in living cells. In addition, by employing several in vitro techniques, we demonstrated the ability of known polyphenols to inhibit the formation of the BCAA fibrils. Our study implies that BCAAs possess a pathological role in MSUD, extends the paradigm-shifting concept regarding the toxicity of metabolite amyloid-like structures, and suggests new pathological targets that may lead to highly needed novel therapeutic opportunities for this orphan disease. [ABSTRACT FROM AUTHOR]

Advanced chronic liver disease (ACLD) represents a complex and multifactorial clinical entity characterized by liver dysfunction and associated complications. In recent years, the significance of nutritional status in ACLD prognosis has gained considerable attention. This review article delves into the multifactorial pathogenesis of malnutrition in ACLD and its profound consequences for health outcomes. We explore the clinical implications of secondary sarcopenia in ACLD and highlight the critical relevance of frailty in both decompensated and compensated ACLD. A specific focus of this review revolves around branched-chain amino acids (BCAAs) and their pivotal role in managing liver disease. We dissect the intricate relationship between low Fischer's ratio and BCAA metabolism in ACLD, shedding light on the molecular mechanisms involved. Furthermore, we critically evaluate the existing evidence regarding the effects of BCAA supplementation on outcomes in ACLD patients, examining their potential to ameliorate the nutritional deficiencies and associated complications in this population. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2DM) still holds the title as one of the most debilitating chronic diseases with rising prevalence and incidence, including its complications such as retinal, renal, and peripheral nerve disease. In order to develop novel molecules for diagnosis and treatment, a deep understanding of the complex molecular pathways is imperative. Currently, the existing agents for T2DM treatment target only blood glucose levels. Over the past decades, specific building blocks of proteins—branched-chain amino acids (BCAAs) including leucine, isoleucine, and valine—have gained attention because they are linked with insulin resistance, pre-diabetes, and diabetes development. In this review, we discuss the hypothetical link between BCAA metabolism, insulin resistance, T2DM, and its microvascular complications including diabetic retinopathy and diabetic nephropathy. Further research on these amino acids and their derivates may eventually pave the way to novel biomarkers or therapeutic concepts for the treatment of diabetes and its accompanied complications. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Metabolic Syndrome (MetS) is characterized by risk factors such as abdominal obesity, hypertriglyceridemia, low high-density lipoprotein cholesterol (HDL-C), hypertension, and hyperglycemia, which contribute to the development of cardiovascular disease and type 2 diabetes. Here, we aim to identify candidate metabolite biomarkers of MetS and its associated risk factors to better understand the complex interplay of underlying signaling pathways. Methods: We quantified serum samples of the KORA F4 study participants (N = 2815) and analyzed 121 metabolites. Multiple regression models adjusted for clinical and lifestyle covariates were used to identify metabolites that were Bonferroni significantly associated with MetS. These findings were replicated in the SHIP-TREND-0 study (N = 988) and further analyzed for the association of replicated metabolites with the five components of MetS. Database-driven networks of the identified metabolites and their interacting enzymes were also constructed. Results: We identified and replicated 56 MetS-specific metabolites: 13 were positively associated (e.g., Val, Leu/Ile, Phe, and Tyr), and 43 were negatively associated (e.g., Gly, Ser, and 40 lipids). Moreover, the majority (89%) and minority (23%) of MetS-specific metabolites were associated with low HDL-C and hypertension, respectively. One lipid, lysoPC a C18:2, was negatively associated with MetS and all of its five components, indicating that individuals with MetS and each of the risk factors had lower concentrations of lysoPC a C18:2 compared to corresponding controls. Our metabolic networks elucidated these observations by revealing impaired catabolism of branched-chain and aromatic amino acids, as well as accelerated Gly catabolism. Conclusion: Our identified candidate metabolite biomarkers are associated with the pathophysiology of MetS and its risk factors. They could facilitate the development of therapeutic strategies to prevent type 2 diabetes and cardiovascular disease. For instance, elevated levels of lysoPC a C18:2 may protect MetS and its five risk components. More in-depth studies are necessary to determine the mechanism of key metabolites in the MetS pathophysiology. [ABSTRACT FROM AUTHOR]

Ketone bodies are an endogenous fuel source generated primarily by the liver to provide alternative energy for extrahepatic tissues during prolonged fasting and exercise. Skeletal muscle is an important site of ketone body oxidation that occurs through a series of reactions requiring the enzyme succinyl-CoA:3-ketoacid-CoA transferase (SCOT/Oxct1). We have previously shown that deleting SCOT in the skeletal muscle protects against obesity-induced insulin resistance by increasing pyruvate dehydrogenase (PDH) activity, the rate-limiting enzyme of glucose oxidation. However, it remains unclear whether inhibiting muscle ketone body oxidation causes hypoglycemia and affects fuel metabolism in the absence of obesity. Here, we show that lean mice lacking skeletal muscle SCOT (SCOTSkM-/-) exhibited no overt phenotypic differences in glucose and fat metabolism from their human a-skeletal actin-Cre (HSACre) littermates. Of interest, we found that plasma and muscle branched-chain amino acid (BCAA) levels are elevated in SCOTSkM-/- lean mice compared with their HSACre littermates. Interestingly, this alteration in BCAA catabolism was only seen in SCOTSkM-/- mice under low-fat feeding and associated with decreased expression of mitochondrial branchedchain aminotransferases (BCATm/Bcat2), the first enzyme in BCAA catabolic pathway. Loss- and gain-of-function studies in C2C12 myotubes demonstrated that suppressing SCOT markedly diminished BCATm expression, whereas overexpressing SCOT resulted in an opposite effect without influencing BCAA oxidation enzymes. Furthermore, SCOT overexpression in C2C12 myotubes significantly increased luciferase activity driven by a Bcat2 promoter construct. Together, our findings indicate that SCOT regulates the expression of the Bcat2 gene, which, through the abundance of its product BCATm, may influence circulating BCAA concentrations. NEW & NOTEWORTHY Most studies investigated ketone body metabolism under pathological conditions, whereas the role of ketone body metabolism in regulating normal physiology has been relatively understudied. To address this gap, we used lean mice lacking muscle ketone body oxidation enzyme SCOT. Our work demonstrates that deleting muscle SCOT has no impact on glucose and fat metabolism in lean mice, but it disrupts muscle BCAA catabolism and causes an accumulation of BCAAs by altering BCATm. [ABSTRACT FROM AUTHOR]

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

Aim: Diabetic cardiomyopathy (DbCM), a complex metabolic disease, greatly threatens human health due to therapeutic limitations. Multi-omics approaches facilitate the elucidation of its intrinsic pathological changes., Methods: Metabolomics, RNA-seq, proteomics, and assay of transposase-accessible chromatin (ATAC-seq) were utilized to elucidate multidimensional molecular alterations in DbCM., Results: In the heart and plasma of mice with DbCM, metabolomic analysis demonstrated significant differences in branched-chain amino acids (BCAAs) and lipids. Subsequent RNA-seq and proteomics showed that the key genes, including BCKDHB, PPM1K, Cpt1b, Fabp4, Acadm, Acadl, Acadvl, HADH, HADHA, HADHB, Eci1, Eci2, PDK4, and HMGCS2, were aberrantly regulated, contributing to the disorder of BCAAs and fatty acids. ATAC-seq analysis underscored the pivotal role of epigenetic regulation by revealing dynamic shifts in chromatin accessibility and a robust positive correlation with gene expression patterns in diabetic cardiomyopathy mice. Furthermore, motif analysis identified that KLF15 as a critical transcription factor in DbCM, regulating the core genes implicated with BCAAs metabolism., Conclusion: Our research delved into the metabolic alterations and epigenetic landscape and revealed that KLF15 may be a promising candidate for therapeutic intervention in DbCM.

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.

Chronic fatigue and central fatigue with malaise significantly impair quality of life. Inattention caused by central fatigue is closely related to attention deficit/hyperactivity disorder (ADHD) symptoms, but the neurochemical mechanism of central fatigue remains hypothetical. The serotonin hypothesis of central fatigue was proposed first, serving as the central dogma for the molecular and neural mechanisms of central fatigue, and underpinning many studies. The tryptophan hypothesis was proposed because tryptophan released into the synaptic cleft of neurons in the brain coincides with and responds sensitively to development of fatigue. Tryptophan is highly bioactive, with brain concentrations of 50 to 200 times that of serotonin. The tryptophan-kynurenic acid-synergy hypothesis posits that central fatigue is not monocausal but a synergistic effect between tryptophan itself and its catabolite kynurenic acid. Central fatigue is associated with mental health problems and is a cause of inattention, thereby warranting scrutiny for its relationship with ADHD. Fatigability in ADHD is mediated by tryptophan, in which abnormal enhancement of the tryptophan-kynurenine-kynurenic acid pathway causes an imbalance in monoamine nervous system function. Notably, noradrenergic neuronal dysfunction is associated with the characteristic inattention of ADHD. Neutral amino acids such as branched-chain amino acids (BCAAs) can assist recovery from attentional and cognitive decline caused by central fatigue. Since they are transported by the same L-amino acid transporter as tryptophan, BCAAs compete with tryptophan to inhibit its brain uptake. Controlling central fatigue this way may improve attentional cognitive performance. [ABSTRACT FROM AUTHOR]

Simple Summary: Human chronic liver disease is reported to be associated with alterations in amino acids metabolism, with a decrease in serum branched-chain amino acids and an increase in aromatic amino acids. A decreased Fischer ratio (branched to aromatic amino acids ratio) has showed prognostic significance and is a therapeutic target in human cirrhosis. In dogs, few studies have been performed, and the Fischer ratio seems to be reduced in animals with congenital portosystemic shunts. The aim of this study was to evaluate serum amino acids in dogs with chronic hepatic inflammation compared with healthy dogs. The serum amino acids in dogs with chronic hepatitis were also evaluated in relation to their histological severity. Eighteen amino acidic metabolites were measured using the leftover serum samples of 16 dogs with histological chronic hepatitis and 25 healthy dogs. Several amino acid concentrations were significantly different between dogs diagnosed with chronic hepatitis and healthy controls. In human medicine, aromatic amino acids seem to increase during chronic hepatitis, whereas isoleucine decreases. The Fischer ratio was significantly reduced if higher grades of fibrosis were present. Even if total serum proteins did not significantly differ between groups, we observed qualitative imbalances in serum amino acids among dogs presenting with chronic hepatitis. 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. [ABSTRACT FROM AUTHOR]

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.

Non-alcoholic fatty liver disease (NAFLD) is the steatosis of liver parenchyma unrelated to alcoholism, autoimmunity, and viral infection. It is also a metabolism-related syndrome, which has an unseparated relationship with adipose tissue dysfunction and obesity. Hepatic encephalopathy (HE) is one of the severe complications of chronic liver disease and one of the end-stage syndromes of liver disease. Some researchers have suggested that NAFLD, like other forms of liver injury, may be related to the metabolic disorder of branched-chain amino acids (BCAAs), which have been approved to be associated with HE influencing ammonia and energy metabolism. However, several studies have revealed the relationship among amino acids in serum, HE, and chronic liver disease; there are few studies on the contents of amino acids in brain tissues of an animal model with NAFLD. In the present research, we established a NAFLD mouse model with C57BL/6 mice and determined the contents of 13 amino acids in brain tissues of model mice by HPLC-FLD derivatization method using ortho-phthalaldehyde (OPA) to explore the relationship between the contents of amino acids in brain tissues and the progression of NAFLD. Moreover, the study showed that the changes of amino acid contents in the brain of the C57BL/6 mice were associated with the advancement of NAFLD, and this change might be related to the mechanism of HE. [ABSTRACT FROM AUTHOR]

Branched chain amino acids' (BCAAs) beneficial role in the management of hepatic encephalopathy is already well established, whereas a number of randomized clinical trials (RCTs) have showed promising results examining BCAA supplementation in the management of other aspects of liver cirrhosis. Current results in the light of BCAAs' biochemical properties make them an attractive supplementation option, in addition to standard pharmaceutical treatment of cirrhosis. The aim of this systematic review is to summarize the current literature and assess the efficacy of BCAA supplementation in patients with liver cirrhosis. Major electronic databases and grey literature sources were searched up to October 4th, 2021 for RCTs assessing the supplementation of BCAA against an active comparator, diet or placebo in patients with liver cirrhosis. Twenty RCTs fulfilled selection criteria. Relative to other interventions BCAAs showed beneficial effect regarding muscle mass (SMD 0.21, 95% CI 0.01 to 0.4, I 2 0%), but no effect regarding fat mass. Furthermore, BCAAs were associated with significant increase in plasma albumin concentration (SMD 0.52, CI 95% 0.18 to 0.86, I 2 84.99%), reduction in occurrence of serious cirrhotic complications (logOR −046, CI 95% −0.78 to −0.13, I 2 0%) and increase in body mass index (WMD 0.24, CI 95% 0.08 to 0.40, I 2 0%). On the other hand, no significant effect was noted concerning the incidence of mortality. Supplementation with BCAA seems to improve significant prognostic factors for patients with cirrhosis, with potential positive impact in mortality. Heterogeneity of study findings attributed to many factors limit overall conclusion and results require further assessment. [ABSTRACT FROM AUTHOR]

Branched-chain amino acids (BCAAs), including leucine, isoleucine, and valine, are essential for maintaining physiological functions and metabolic homeostasis. However, chronic elevation of BCAAs causes metabolic diseases such as obesity, type 2 diabetes (T2D), and metabolic-associated fatty liver disease (MAFLD). Adipose tissue, skeletal muscle, and the liver are the three major metabolic tissues not only responsible for controlling glucose, lipid, and energy balance but also for maintaining BCAA homeostasis. Under obese and diabetic conditions, different pathogenic factors like pro-inflammatory cytokines, lipotoxicity, and reduction of adiponectin and peroxisome proliferator-activated receptors γ (PPARγ) disrupt BCAA metabolism, leading to excessive accumulation of BCAAs and their downstream metabolites in metabolic tissues and circulation. Mechanistically, BCAAs and/or their downstream metabolites, such as branched-chain ketoacids (BCKAs) and 3-hydroxyisobutyrate (3-HIB), impair insulin signaling, inhibit adipogenesis, induce inflammatory responses, and cause lipotoxicity in the metabolic tissues, resulting in multiple metabolic disorders. In this review, we summarize the latest studies on the metabolic regulation of BCAA homeostasis by the three major metabolic tissues-adipose tissue, skeletal muscle, and liver-and how dysregulated BCAA metabolism affects glucose, lipid, and energy balance in these active metabolic tissues. We also summarize therapeutic approaches to restore normal BCAA metabolism as a treatment for metabolic diseases., (© 2024 The Author(s). Obesity Reviews published by John Wiley & Sons Ltd on behalf of World Obesity Federation.)

The growing interest in metabolomics has spread to the search for suitable predictive biomarkers for complications related to the emerging issue of pediatric obesity and its related cardiovascular risk and metabolic alteration. Indeed, several studies have investigated the association between metabolic disorders and amino acids, in particular branched-chain amino acids (BCAAs). We have performed a revision of the literature to assess the role of BCAAs in children and adolescents' metabolism, focusing on the molecular pathways involved. We searched on Pubmed/Medline, including articles published until February 2022. The results have shown that plasmatic levels of BCAAs are impaired already in obese children and adolescents. The relationship between BCAAs, obesity and the related metabolic disorders is explained on one side by the activation of the mTORC1 complex—that may promote insulin resistance—and on the other, by the accumulation of toxic metabolites, which may lead to mitochondrial dysfunction, stress kinase activation and damage of pancreatic cells. These compounds may help in the precocious identification of many complications of pediatric obesity. However, further studies are still needed to better assess if BCAAs may be used to screen these conditions and if any other metabolomic compound may be useful to achieve this goal. [ABSTRACT FROM AUTHOR]

Background and Aim: Circulating amino acids are modified by sex, body mass index (BMI) and insulin resistance (IR). However, whether the presence of genetic variants in branched-chain amino acid (BCAA) catabolic enzymes modifies circulating amino acids is still unknown. Thus, we determined the frequency of two genetic variants, one in the branched-chain aminotransferase 2 (BCAT2) gene (rs11548193), and one in the branched-chain ketoacid dehydrogenase (BCKDH) gene (rs45500792), and elucidated their impact on circulating amino acid levels together with clinical, anthropometric and biochemical parameters.Methods and Results: We performed a cross-sectional comparative study in which we recruited 1612 young adults (749 women and 863 men) aged 19.7 ± 2.1 years and with a BMI of 24.9 ± 4.7 kg/m2. Participants underwent clinical evaluation and provided blood samples for DNA extraction and biochemical analysis. The single nucleotide polymorphisms (SNPs) were determined by allelic discrimination using real-time polymerase chain reaction (PCR). The frequencies of the less common alleles were 15.2 % for BCAT2 and 9.83 % for BCKDH. The subjects with either the BCAT2 or BCKDH SNPs displayed no differences in the evaluated parameters compared with subjects homozygotes for the most common allele at each SNP. However, subjects with both SNPs had higher body weight, BMI, blood pressure, glucose, and circulating levels of aspartate, isoleucine, methionine, and proline than the subjects homozygotes for the most common allele (P < 0.05, One-way ANOVA).Conclusion: Our findings suggest that the joint presence of both the BCAT2 rs11548193 and BCKDH rs45500792 SNPs induces metabolic alterations that are not observed in subjects without either SNP. [ABSTRACT FROM AUTHOR]

The pandemic of the coronavirus disease (COVID-19) caused by SARS-CoV-2 affects millions of people worldwide. There are still many unknown aspects to this infection which affects the whole world. In addition, the potential impacts caused by this infection are still unclear. Amino acid metabolism, in particular, contains significant clues in terms of the development and prevention of many diseases. Therefore, this study aimed to compare amino acid profile of COVID-19 and healthy subject. In this study, the amino acid profiles of patients with asymptomatic, mild, moderate, and severe/critical SARS-CoV-2 infection were scanned with LC–MS/MS. The amino acid profile encompassing 30 amino acids in 142 people including 30 control and 112 COVID-19 patients was examined. 20 amino acids showed significant differences when compared to the control group in COVID-19 patient groups with different levels of severity in the statistical analyses conducted. It was detected that the branched-chain amino acids (BCAAs) changed in correlation with one another, and l-2-aminobutyric acid and l-phenylalanine had biomarker potential for COVID-19. Moreover, it was concluded that l-2-aminobutyric acid could provide prognostic information about the course of the disease. We believe that a new viewpoint will develop regarding the diagnosis, treatment, and prognosis as a result of the evaluation of the serum amino acid profiles of COVID-19 patients. Determining l-phenylalanine and l-2-aminobutyric levels can be used in laboratories as a COVID-19-biomarker. Also, supplementing COVID patients with taurine and BCAAs can be beneficial for treatment protocols. [ABSTRACT FROM AUTHOR]

Background and Aims: Coronary heart disease is a major global health concern. Further, severity of this condition is greatly influenced by myocardial ischemia/reperfusion (I/R) injury. Branched-chain amino acids (BCAAs) have cardioprotective effects against I/R via mammalian target of rapamycin (mTOR) activity, wherein Leu is considered to particularly regulate mTOR activation. However, the mechanism underlying cardioprotective effects of Leu via mTOR activity is not fully elucidated. Here, we aimed to study the signaling pathway of cardioprotection and mitochondrial function induced by Leu treatment.Methods and Results: Cardiac myocytes isolated from adult male Wistar rats were incubated and exposed to simulated I/R (SI/R) injury by replacing the air content. Cardiac myocytes were treated with Leu and subsequently, their survival rate was calculated. To elucidate the signaling pathway and mitochondrial function, immunoblots and mitochondrial permeability transition pore were examined. Cell survival rate was decreased with SI/R but improved by 160 μM Leu (38.5 ± 3.6% vs. 64.5 ± 4.2%, respectively, p < 0.001). Although rapamycin (mTOR inhibitor) prevented this cardioprotective effect induced by Leu, wortmannin (PI3K inhibitor) did not interfere with this effect. In addition, we indicated that overexpression of Opa-1 and mitochondrial function are ameliorated via Leu-induced mitochondrial biogenesis. In contrast, knockdown of Opa-1 suppressed Leu-induced cardioprotection.Conclusion: Leu treatment is critical in rendering a cardioprotective effect exhibited by BCAAs via mTOR signaling. Furthermore, Leu improved mitochondrial function. [ABSTRACT FROM AUTHOR]

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

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.

Circulating branched chain amino acid (BCAA) levels are elevated in obese humans and genetically obese rodents. However, the relationship of BCAAs to insulin resistance in diet-induced obese mice, a commonly used model to study glucose homeostasis, is still ill-defined. Here we examined how high-fat high-sucrose (HFHS) or high-fat diet (HFD) feeding, with or without BCAA supplementation in water, alters the metabolome in serum/plasma and tissues in mice and whether raising circulating BCAA levels worsens insulin resistance and glucose intolerance. Neither HFHS nor HFD feeding raised circulating BCAA levels in insulin-resistant diet-induced obese mice. BCAA supplementation raised circulating BCAA and branched-chain α-keto acid levels and C5-OH/C3-DC acylcarnitines (AC) in muscle from mice fed an HFHS diet or HFD, but did not worsen insulin resistance. A set of short- and long-chain acyl CoAs were elevated by diet alone in muscle, liver, and white adipose tissue (WAT), but not increased further by BCAA supplementation. HFD feeding reduced valine and leucine oxidation in WAT but not in muscle. BCAA supplementation markedly increased valine oxidation in muscle from HFD-fed mice, while leucine oxidation was unaffected by diet or BCAA treatment. Here we establish an extensive metabolome database showing tissue-specific changes in mice on 2 different HFDs, with or without BCAA supplementation. We conclude that mildly elevating circulating BCAAs and a subset of ACs by BCAA supplementation does not worsen insulin resistance or glucose tolerance in mice. This work highlights major differences in the effects of BCAAs on glucose homeostasis in diet-induced obese mice versus data reported in obese rats and in humans. [ABSTRACT FROM AUTHOR]

Purpose of Review: Dietary interventions (DI) aimed at improving overweight and metabolic abnormalities in metabolic dysfunction-associated fatty liver disease (MAFLD) and at reducing malnutrition and sarcopenia in cirrhosis should become part of routine care in hepatology. This review focuses on recent advances in this field. Recent Findings: In patients with MAFLD, a gradual reduction, respectively, of 7–10% of body weight if overweight or of 3–5% if lean, obtained by moderately reducing caloric intake, is effective to improve liver disease. Intermittent energy restriction might be an alternative to continuous energy restriction with higher adherence. Qualitative dietary adjustments should include increased intake of unprocessed foods including fruits and vegetables, whole grains, fiber, and unsaturated fatty acids (FAs), for example, through a Mediterranean diet. Refined carbohydrates (CHOs), saturated FA (SFAs), red meat, and processed meat should be limited. DI studies in HIV-infected subjects with MAFLD are very limited, and this is a field for future research. In patients with cirrhosis, DI should aim at correcting malnutrition and improving skeletal muscle mass. Daily diet contents should aim at achieving 30–35 kcal/kg of body weight, including 1.2–1.5 g/kg proteins, and oral or enteral supplementation might be used in patients unable to achieve these targets. In some studies, branched-chain amino acids (BCAAs) proved to be effective in improving muscle mass and were associated with a lower risk of hepatic encephalopathy. Obesity requires adjustment of the above-mentioned targets, and its management is challenging. Studies looking at the efficacy of DI recommended by the existing guidelines on clinical endpoints are a field for future research. Summary: Dietary interventions are able to improve MAFLD and show potential to reduce complications in liver disease. Despite its key importance, there are many barriers limiting the implementation of DI in patients with chronic liver disease. Patients' empowerment is crucial and should be the focus of specific educational programs. In addition, liver clinics would benefit from multidisciplinary teams involving experts in nutrition, physical exercise, primary care physicians, and psychologists when needed. [ABSTRACT FROM AUTHOR]

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Abdualkader, Karwi, Lopaschuk and Al Batran.)

Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a growing health concern due to its increasing prevalence worldwide. Metabolic homeostasis encompasses the stable internal conditions vital for efficient metabolism. This equilibrium extends to the intestinal microbiota, whose metabolic activities profoundly influence overall metabolic balance and organ health. The metabolites derived from the gut microbiota metabolism can be defined as microbiota-related co-metabolites. They serve as mediators between the gut microbiota and the host, influencing various physiological processes. The recent redefinition of the term MASLD has highlighted the metabolic dysfunction that characterize the disease. Metabolic dysfunction encompasses a spectrum of abnormalities, including impaired glucose regulation, dyslipidemia, mitochondrial dysfunction, inflammation, and accumulation of toxic byproducts. In addition, MASLD progression has been linked to dysregulation in the gut microbiota and associated co-metabolites. Short-chain fatty acids (SCFAs), hippurate, indole derivatives, branched-chain amino acids (BCAAs), and bile acids (BAs) are among the key co-metabolites implicated in MASLD progression. In this review, we will unravel the relationship between the microbiota-related metabolites which have been associated with MASLD and that could play an important role for developing effective therapeutic interventions for MASLD and related metabolic disorders.

Branched-chain amino acids (BCAAs), including leucine, valine, and isoleucine, play crucial roles in regulating metabolic balance and maintaining physiological functions in the body. Extensive studies have been focused on their implications in obesity, diabetes, and cardiovascular diseases. Nevertheless, accumulating evidence suggests that BCAAs metabolism also plays significant roles in tumorigenesis and progression. In this review, we overview recent progress of the study on BCAAs metabolism including its relationship with epigenetic regulation. Particularly, we discuss the metabolic reprogramming and metabolic sensing of BCAAs and its intermediate metabolites in tumor cells and microenvironment to decipher their functions. An enhanced understanding of the roles and mechanism of BCAAs metabolism in tumorigenesis and progression will contribute to development of novel therapeutic strategies against tumor.

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 regulators of protein metabolism. However, elevated levels of BCAAs and their metabolites are linked to insulin resistance. We previously demonstrated that the leucine metabolite, α-ketoisocaproate (KIC), inhibited insulin-stimulated glucose transport in myotubes. Like KIC, inflammatory factors are implicated in the development of insulin resistance. Here, we analyzed the effect of KIC and inflammatory factors (homocysteine [50 μM], TNF-α [10 ng/ml], and interleukin 6 (IL-6) [10 ng/ml]) on myotubes. Although KIC suppressed insulinstimulated glucose transport, addition of the inflammatory factors did not worsen this effect. Depletion of branched-chain aminotransferase 2, the enzyme that catalyzes the conversion of leucine into KIC, abrogated the effect of KIC and the inflammatory factors. The effect of insulin on AKTS473 and S6K1T389 phosphorylation was not modified by treatments. There were no treatment effects on glycogen synthase phosphorylation. Depletion of E1α subunit of branched-chain α-keto acid dehydrogenase, the enzyme that catalyzes the oxidative decarboxylation of KIC, suppressed insulin-stimulated glucose transport, especially in cells incubated in KIC. Thus, defects in BCAA catabolism are contributory to insulin resistance of glucose transport in myotubes, especially in the presence of KIC. Interventions that increase BCAA catabolism may promote muscle glucose utilization and improve insulin resistance and its sequelae. [ABSTRACT FROM AUTHOR]