Branched-chain amino acid synthesis is coupled to TOR activation early in the cell cycle in yeast.

How cells coordinate their metabolism with division determines the rate of cell proliferation. Dynamic patterns of metabolite synthesis during the cell cycle are unexplored. We report the first isotope tracing analysis in synchronous, growing budding yeast cells. Synthesis of leucine, a branched-chain amino acid (BCAA), increases through the G1 phase of the cell cycle, peaking later during DNA replication. Cells lacking Bat1, a mitochondrial aminotransferase that synthesizes BCAAs, grow slower, are smaller, and are delayed in the G1 phase, phenocopying cells in which the growth-promoting kinase complex TORC1 is moderately inhibited. Loss of Bat1 lowers the levels of BCAAs and reduces TORC1 activity. Exogenous provision of valine and, to a lesser extent, leucine to cells lacking Bat1 promotes cell division. Valine addition also increases TORC1 activity. In wild-type cells, TORC1 activity is dynamic in the cell cycle, starting low in early G1 but increasing later in the cell cycle. These results suggest a link between BCAA synthesis from glucose to TORC1 activation in the G1 phase of the cell cycle.

The role of dopamine in visual imagery-An experimental pharmacological study.

Mental imagery enables people to simulate experiences in their minds without the presence of an external stimulus. The underlying biochemical mechanisms are poorly understood but there is vague evidence that dopamine may play a significant role. A better understanding at the biochemical level could help to unravel the mechanisms of mental imagery and related phenomena such as aphantasia (= lack of voluntary mental imagery), but also opens up possibilities for interventions to enhance or restore mental imagery. To test the hypothesis that acute dopamine depletion leads to a decrease in the strength of mental imagery, N = 22 male participants will be administered an amino acid mixture containing branched-chain amino acids (BCAAs) and tryptophan (TRP) to transiently reduce dopamine synthesis and further N = 22 male participants will receive a placebo. Plasma prolactin (PRL) levels are determined as a peripheral marker of brain dopamine function. The strength of mental imagery will be measured before and after ingestion of the BCAA/TRP mixture using the method of mental imagery priming. Additional exploratory analyses will use genetic data to investigate possible effects of variations on dopaminergic gene loci (e.g., DAT1) on dopamine levels and strength of mental imagery. The results show […].

Bcat1 is controlled by Tsc2/mTORC1 pathway at expression levels and its deficiency together with Bcat2 inactivation suppresses the growth of a Tsc2-/- tumor cell line.

The tuberous sclerosis complex (TSC) gene products (TSC1/TSC2) negatively regulate mTORC1. Although mTORC1 inhibitors are used for the treatment of TSC, incomplete tumor elimination and the adverse effects from long-term administration are problems that need to be solved. Branched-chain amino acid (BCAA) metabolism is involved in the growth of many tumor cells via the mTORC1 pathway. However, it remains unclear how BCAA metabolism affects the growth of mTORC1-dysregulated tumors. We show here that the expression of branched-chain amino transferase1 (Bcat1) was suppressed in Tsc2-deficient murine renal tumor cells either by treatment with rapamycin or restoration of Tsc2 expression suggesting that Bcat1 is located downstream of Tsc2-mTORC1 pathway. We also found that gabapentin, a Bcat1 inhibitor suppressed the growth of Tsc2-deficient tumor cells and increased efficacy when combined with rapamycin. We investigate the functional importance of Bcat1 and the mitochondrial isoform Bcat2 by inhibiting each enzyme separately or both together by genome editing and shRNA in Tsc2-deficient cells. We found that deficiency of both enzymes, but not either alone, inhibited cell growth, indicating that BCAA-metabolic reactions support Tsc2-deficient cell proliferation. Our results indicate that inhibition of Bcat1 and Bcat2 by specific drugs should be a useful method for TSC treatment.

Transition from fetal to postnatal state in the heart: Crosstalk between metabolism and regeneration.

Cardiovascular disease is the leading cause of mortality worldwide. Myocardial injury resulting from ischemia can be fatal because of the limited regenerative capacity of adult myocardium. Mammalian cardiomyocytes rapidly lose their proliferative capacities, with only a small fraction of adult myocardium remaining proliferative, which is insufficient to support post-injury recovery. Recent investigations have revealed that this decline in myocardial proliferative capacity is closely linked to perinatal metabolic shifts. Predominantly glycolytic fetal myocardial metabolism transitions towards mitochondrial fatty acid oxidation postnatally, which not only enables efficient production of ATP but also causes a dramatic reduction in cardiomyocyte proliferative capacity. Extensive research has elucidated the mechanisms behind this metabolic shift, as well as methods to modulate these metabolic pathways. Some of these methods have been successfully applied to enhance metabolic reprogramming and myocardial regeneration. This review discusses recently acquired insights into the interplay between metabolism and myocardial proliferation, emphasizing postnatal metabolic transitions.

Emerging drugs for the treatment of sarcopenia in cirrhosis of the liver.

INTRODUCTION: Malnutrition and sarcopenia are common and impact the prognosis in patients with liver cirrhosis. The etiology is multifactorial and includes periods of reduced caloric intake, increased catabolism and direct molecular mechanisms that inhibit muscle synthesis. Although these conditions are widely acknowledged, and there is a growing interest in their diagnosis, robust evidence regarding the treatment and reversibility of these conditions is still lacking. AREAS COVERED: We have explored the current evidence on the pharmacological treatment of sarcopenia in patients with cirrhosis. Additionally, we have searched for drugs already in use and ongoing trials for other chronic diseases. EXPERT OPINION: The current guidelines recommend the use of a protein-adequate diet and moderate physical activity for treating sarcopenia in patients with cirrhosis. Currently, robust evidence is derived only from the supplementation of Branched-Chain Amino Acids, capable of increasing muscle mass and function. There are many drugs targeting various pathways that contribute to sarcopenia. However, evidence is sporadic and insufficient to suggest their use in clinical practice.Novel drugs specifically designed to enhance muscle mass and function should be developed. Finally, gender significantly influences the type of muscle alteration and therapeutic mechanisms; therefore, future studies should be designed taking gender differences into consideration.

Association between Branched-Chain amino acids and Epilepsy: A Mendelian randomized study.

BACKGROUND: Branched-chain amino acids (BCAAs) have been affected epilepsy, yet conclusions remain inconclusive, lacking causal evidence regarding whether BCAAs affect epilepsy. Systematic exploration of the causal relationship between BCAAs and epilepsy could hand out new ideas for the treatment of epilepsy. METHODS: Utilizing bidirectional Mendelian randomization (MR) study, we investigated the causal relationship between BCAA levels and epilepsy. BCAA levels from genome-wide association studies (GWAS), including total BCAAs, leucine levels, isoleucine levels, and valine levels, were employed. Causal relationships were explored applying the method of inverse variance-weighted (IVW) and MR-Egger, followed by sensitivity analyses of the results to evaluate heterogeneity and pleiotropy. RESULTS: Through strict genetic variant selection, we find some related SNPs, total BCAA levels (9), leucine levels (11), isoleucine levels (7), and valine levels (6) as instrumental variables for our MR analysis. Following IVW and sensitivity analysis, total BCAAs levels (OR = 1.14, 95 % CI = 1.019 âˆ¼ 1.285, P = 0.022) and leucine levels (OR = 1.15, 95 % CI = 1.018 âˆ¼ 1.304, P = 0.025) had significant correlation with epilepsy. CONCLUSIONS: There exists a causal relationship between the levels of total BCAAs and leucine with epilepsy, offering the new ideas into epilepsy potential mechanisms, holding significant implications for its prevention and treatment.

MASLD in persons with HIV is associated with high cardiometabolic risk as evidenced by altered advanced lipoprotein profiles and targeted metabolomics.

BACKGROUND: Metabolic dysfunction associated steatotic liver disease (MASLD) is associated with increased cardiovascular disease (CVD) risk in persons with HIV (PWH). The lipidomic and metabolomic alterations contributing to this risk are poorly understood. We aimed to characterize the advanced lipoprotein and targeted metabolomic profiles in PWH and assess if the presence and severity of MASLD influence these profiles. METHODS: This is a cross-sectional analysis of a prospectively enrolled multicenter cohort. PWH without alcohol abuse or known liver disease underwent vibration-controlled transient elastography for controlled attenuation parameter (CAP) and liver stiffness measurement (LSM). Lipidomic and metabolomic profiling was undertaken with nuclear magnetic resonance (NMR) spectroscopy. Hepatic steatosis was defined as CAP ≥ 263 dB/m and clinically significant fibrosis (CSF) as LSM ≥ 8 kPa. Logistic regression models assessed associations between MASLD, CSF and lipidomic and metabolic parameters. RESULTS: Of 190 participants (71% cisgender male, 96% on antiretroviral therapy), 58% had MASLD and 12% CSF. Mean (SD) age was 48.9 (12.1) years and body mass index (BMI) 29.9 (6.4) kg/m2. Compared to PWH without MASLD (controls), PWH with MASLD had lower HDL-C but higher total triglyceride, VLDL-C, branched-chain amino acids, GlycA, trimethylamine N-oxide levels, Lipoprotein-Insulin Resistance and Diabetes Risk Indices. There were no significant differences in these parameters between participants with MASLD with or without CSF. In a multivariable regression analysis, MASLD was independently associated with changes in most of these parameters after adjustment for age, gender, race/ethnicity, type 2 diabetes mellitus, BMI, and lipid lowering medications use. CONCLUSIONS: MASLD in PWH is independently associated with altered advanced lipoprotein and targeted metabolic profiles, indicating a higher CVD risk in this population.

Identification of putative allosteric inhibitors of BCKDK via virtual screening and biological evaluation.

Abnormal accumulation of branched-chain amino acids (BCAAs) can lead to metabolic diseases and cancers. Branched-chain α-keto acid dehydrogenase kinase (BCKDK) is a key negative regulator of BCAA catabolism, and targeting BCKDK provides a promising therapeutic approach for diseases caused by BCAA accumulation. Here, we screened PPHN and POAB as novel putative allosteric inhibitors by integrating allosteric binding site prediction, large-scale ligand database virtual screening, and bioactivity evaluation assays. Both of them showed a high binding affinity to BCKDK, with Kd values of 3.9 µM and 1.86 µM, respectively. In vivo experiments, the inhibitors demonstrated superior kinase inhibitory activity and notable antiproliferative and proapoptotic effects on diverse cancer cells. Finally, bulk RNA-seq analysis revealed that PPHN and POAB suppressed cell growth through a range of signalling pathways. Taken together, our findings highlight two novel BCKDK inhibitors as potent therapeutic candidates for metabolic diseases and cancers associated with BCAA dysfunctional metabolism.

Effects of branched-chain amino acids on changes in body composition during the recovery period following tonsillectomy.

PURPOSE: In recent decades studies have examined body weight changes following tonsillectomy. In nutrition science, the focus has shifted from body mass index to body composition analysis. However, no studies have explored body composition changes post-tonsillectomy. In oncology and digestive surgeries, the potential benefits of branched-chain amino acids (BCAAs) have been investigated; however, their effects on pharyngeal surgery remain unknown. Therefore, the aim of the present study was to investigate the body composition changes after tonsillectomy and to explore the potential benefits of branched-chain amino acids. METHODS: This prospective interventional controlled study enrolled 48 patients who were randomly assigned to a control group (CG) and an experimental group (EG). These groups were further divided into active and inactive subgroups on the basis of their activity levels. The EG consumed 2 × 4 mg of BCAA daily. Body composition was measured using bioimpedance (InBody 270) on the day of surgery and again on days 7 and 21 postoperatively. RESULTS: Both groups experienced similar weight loss; however, significant differences in body composition emerged. The CG showed significant muscle mass loss (from 30,29 to 28,51 kg), whereas active EG members maintained muscle mass (from 35,33 to 35,40 kg); inactive EG members increased muscle mass (from 26,70 to 27,56 kg) and reduced body fat percentage (from 31.94% to 29.87%). The general health status (InBody score) remained stable or improved in the EG (from 75,13 to 75,96); however, it decreased in the CG (from 75,42 to 72,67). CONCLUSION: The negative effects of tonsillectomy on body composition are mitigated by BCAA supplementation.

Leucine drives LAT1-related SNAIL upregulation in glucose-starved pancreatic cancer cells.

Pancreatic cancer, a highly fibrotic and hypovascular tumor, is thought to have unique metabolic characteristics in surviving and proliferating in malnutritional microenvironments. In this study, we compared the differences in the ability of pancreatic cancer cells to adapt to glucose-free conditions with liver cancer cells, which are representative of hypervascular tumors. Three pancreatic cancer cells and two liver cancer cells were used to examine the transcriptional expression levels of molecules involved in intracellular amino acid uptake, epithelial-mesenchymal transition (EMT), and cancer stemness under glucose deprivation. The results showed that the proliferative activity of pancreatic cancer cells under glucose deprivation was significantly lower than that of liver cancer cells, but the expression levels of amino acid transporters were significantly higher. Among them, L-type amino acid transporter 1 (LAT1) upregulation was unique in concert with increased expression of the EMT regulator SNAIL and the cancer stemness marker doublecortin-like kinase 1. LAT1 knockdown canceled the upregulation of SNAIL in glucose-starved pancreatic cancer cells, suggesting a mechanistic link between the two molecules. When LAT1 was stimulated by its substrate leucine, the SNAIL expression was upregulated dose-dependently. Collectively, pancreatic cancer cells reprogrammed metabolism to adapt to energy crises involving leucine-induced SNAIL upregulation.

High doses of rosuvastatin induce impaired branched-chain amino acid catabolism and lead to insulin resistance.

NEW FINDINGS: What is the central question of this study? Is there a risk of developing diabetes associated with statin treatment? What is the underlying mechanism of the increased incidence rate of new-onset diabetes in patients treated with rosuvastatin? What is the main finding and its importance? Rosuvastatin therapy reduced intraperitoneal glucose tolerance and changed the catabolism of branched-chain amino acid (BCAAs) in white adipose tissue and skeletal muscle. Protein phosphatase 2Cm knockdown completely abolished the effects of insulin and rosuvastatin on glucose absorption. This study provides mechanistic support for recent clinical data on rosuvastatin-related new-onset diabetes and underscores the logic for intervening in BCAA catabolism to prevent the harmful effects of rosuvastatin. ABSTRACT: Accumulating evidence indicates that patients treated with rosuvastatin have an increased risk of developing new-onset diabetes. However, the underlying mechanism remains unclear. In this study, we administered rosuvastatin (10 mg/kg body weight) to male C57BL/6J mice for 12 weeks and found that oral rosuvastatin dramatically reduced intraperitoneal glucose tolerance. Rosuvastatin-treated mice showed considerably higher serum levels of branched-chain amino acids (BCAAs) than control mice. They also showed dramatically altered expression of BCAA catabolism-related enzymes in white adipose tissue and skeletal muscle, including downregulated mRNA expression of BCAT2 and protein phosphatase 2Cm (PP2Cm) and upregulated mRNA expression of branched-chain ketoacid dehydrogenase kinase (BCKDK). The levels of BCKD in the skeletal muscle were reduced in rosuvastatin-treated mice, which was associated with lower PP2Cm protein levels and increased BCKDK levels. We also investigated the effects of rosuvastatin and insulin administration on glucose metabolism and BCAA catabolism in C2C12 myoblasts. We observed that incubation with insulin enhanced glucose uptake and facilitated BCAA catabolism in C2C12 cells, which was accompanied by elevated Akt and glycogen synthase kinase 3 ß (GSK3ß) phosphorylation. These effects of insulin were prevented by co-incubation of the cells with 25 µM rosuvastatin. Moreover, the effects of insulin and rosuvastatin administration on glucose uptake and Akt and GSK3ß signaling in C2C12 cells were abolished when PP2Cm was knocked down. Although the relevance of these data, obtained with high doses of rosuvastatin in mice, to therapeutic doses in humans remains to be elucidated, this study highlights a potential mechanism for the diabetogenic effects of rosuvastatin, and suggests that BCAA catabolism could be a pharmacological target for preventing the adverse effects of rosuvastatin.

Dietary branched-chain amino acids intake, glycemic markers, metabolic profile, and anthropometric features in a community-based sample of overweight and obese adults.

BACKGROUND: Existing research provides conflicting evidence regarding the relationship between estimated branched-chain amino acid (BCAA) intake and metabolic, glycemic markers, and anthropometric characteristics. This research seeks to examine the association between estimated dietary BCAA consumption and glycemic, and metabolic markers, as well as anthropometric parameters in adults classified as overweight or obese. METHODS: In this cross-sectional analysis, we gathered data from 465 overweight and obese individuals aged between 18 and 37 years. To evaluate dietary data, we employed the food frequency questionnaire, and the BCAA content in foods was determined via the United States Department of Agriculture website. We utilized ELISA kits to measure fasting blood glucose (FBS) and lipid profile markers, and additionally calculated low-density lipoprotein (LDL) and insulin sensitivity markers. We assessed sociodemographic status, physical activity (PA), and anthropometric attributes through a method recognized as both valid and reliable. For statistical analysis, we conducted analyses of covariance (ANCOVA), making adjustments for variables including sex, PA, age, energy, and body mass index (BMI). RESULTS: Upon adjusting for confounders, those in the highest tertiles of BCAA intake exhibited an increase in weight, BMI, waist circumference (WC), waist-to-hip ratio (WHR), and fat-free mass (FFM). Conversely, they demonstrated reduced fat mass (FM) (%) and FM (kg) compared to their counterparts in the lowest tertiles (P < 0.05). Additionally, there was a noted association between greater estimated BCAA intake and reduced LDL levels. Nonetheless, our findings did not reveal a significant relationship between dietary BCAA and glycemic indices. CONCLUSIONS: From our findings, an increased estimated intake of BCAA seems to correlate with diminished serum LDL concentrations. To gain a more comprehensive understanding of this association, it is imperative that further experimental and longitudinal studies be conducted.

Disrupted cardiac fibroblast BCAA catabolism contributes to diabetic cardiomyopathy via a periostin/NAP1L2/SIRT3 axis.

BACKGROUND: Periostin is an extracellular matrix protein that plays a critical role in cell fate determination and tissue remodeling, but the underlying role and mechanism of periostin in diabetic cardiomyopathy (DCM) are far from clear. Thus, we aimed to clarify the mechanistic participation of periostin in DCM. METHODS: The expression of periostin was examined in DCM patients, diabetic mice and high glucose (HG)-exposed cardiac fibroblasts (CF). Gain- and loss-of-function experiments assessed the potential role of periostin in DCM pathogenesis. RNA sequencing was used to investigate the underlying mechanisms of periostin in DCM. RESULTS: A mouse cytokine antibody array showed that the protein expression of periostin was most significantly upregulated in diabetic mouse heart, and this increase was also observed in patients with DCM or HG-incubated CF. Periostin-deficient mice were protected from diabetes-induced cardiac dysfunction and myocardial damage, while overexpression of periostin held the opposite effects. Hyperglycemia stimulated the expression of periostin in a TGF-ß/Smad-dependent manner. RNA sequencing results showed that periostin upregulated the expression of nucleosome assembly protein 1-like 2 (NAP1L2) which recruited SIRT3 to deacetylate H3K27ac on the promoters of the branched-chain amino acid (BCAA) catabolism-related enzymes BCAT2 and PP2Cm, resulting in BCAA catabolism impairment. Additionally, CF-derived periostin induced hypertrophy, oxidative injury and inflammation in primary cardiomyocytes. Finally, we identified that glucosyringic acid (GA) specifically targeted and inhibited periostin to ameliorate DCM. CONCLUSION: Overall, manipulating periostin expression may function as a promising strategy in the treatment of DCM.

The impact of branched-chain amino acid supplementation on measures of glucose homeostasis in individuals with hepatic disorders: A systematic review of clinical studies.

BACKGROUND: Branched chain amino acid (BCAA) supplementation may influence glucose metabolism in individuals with an impaired glyceamic profile. This systematic review investigated the effects of isolated BCAA supplementation on measures of glucose homeostasis in individuals with hepatic disorders. METHODS: We searched PubMed, Web of Science, Cochrane Library and Scopus for published clinical trials that investigated the effects of isolated BCAA supplementation on measures of glucose homeostasis, including serum glucose and insulin, glycated haemoglobin (HbA1c) levels and homeostatic model assessment for insulin resistance (HOMA-IR) scores. RESULTS: Eleven trials met the inclusion criteria. Only one study revealed a decrease in serum glucose from BCAA supplementation compared to three studies that showed increases. Five studies demonstrated no significant changes in serum glucose, and two studies displayed no changes in HbA1c following BCAA supplementation. Serum levels of insulin were decreased in three studies, remained unchanged in one, and increased in the remaining three studies. BCAA supplementation reduced HOMA-IR scores in two studies, increased HOMA-IR scores in another two, or resulted in no changes in two other studies. CONCLUSIONS: BCAA supplementation in isolation had no effect on overall glucose homeostasis in individuals with hepatic disorders, although some improvements on serum insulin levels and HOMA-IR scores were observed. Overall, there is little evidence to support the utilisation of BCAA supplementation as a potential nutritional strategy for improving measures of glucose homeostasis in individuals with hepatic disorders.

Meta-analysis links dietary branched-chain amino acids to metabolic health in rodents.

BACKGROUND: The role of dietary branched chain amino acids (BCAAs) and their effect on metabolic health is complex. How dietary BCAA levels and their interaction with background nutrition affect health is unclear. Here, we used meta-analysis and meta-regression, together with the nutritional modelling, to analyse the results of rodent studies that increased the level of dietary BCAAs and measured circulating levels, outcomes related to metabolic health, body mass and food intake. RESULTS: Across all studies, increasing dietary BCAAs resulted in increased levels of circulating BCAAs. These effects, however, were heavily moderated by background dietary levels whereby on high BCAA diets, further increases were not reflected in the blood. Impaired glucose tolerance was associated with elevated dietary BCAAs, with the greatest effect occurring with a simultaneous increase in total protein intake. Effects of dietary BCAAs on plasma glucose, insulin, or HOMA emerged only when dietary macronutrient background was considered. We found that elevated dietary BCAAs increases % body fat, with largest increases in adiposity occurring when BCAAs are increased on a high protein, low carbohydrate dietary background. Finally, we found that increased dietary BCAAs were associated with increased food intake when the background diet was low in BCAAs. CONCLUSION: Our data highlights the interaction between BCAAs and background nutrition. We show that the effects of BCAAs on metabolic health cannot be studied in isolation but must be considered as part of complex mixture of dietary components.

A prospective clinical study evaluating short-term changes in body composition and quality of life after gastrectomy in elderly patients receiving postoperative exercise and nutritional therapies.

BACKGROUND: Muscle mass loss after gastrectomy is associated with a negative impact on quality of life (QOL) and long-term prognosis following gastric cancer treatment, especially in elderly patients. We conducted a prospective study to examine short-term changes in body composition and QOL after gastrectomy in elderly patients with gastric cancer who received exercise and nutritional therapies. METHODS: Patients over aged 65 years of age who underwent gastrectomies for gastric cancer were enrolled in our study. Patients received exercise and nutritional therapies with branched-chain amino acid (BCAA)-rich supplements during 1 month after surgery. Body composition was evaluated using InBody S10 before surgery, and at 1 week and 1 month postoperatively. Other variables including QOL status (EQ-5D-5 L), serum albumin level, hand grip strength, and gait speed were evaluated at the same time. RESULTS: Eighteen patients were analyzed. The mean loss of skeletal muscle mass index (SMI) was 4.6% (1 week) and 2.1% (1 month) compared to the preoperative period. QOL scores showed almost the same degree of recovery at 1 month after gastrectomy as preoperative scores. Serum albumin levels, hand grip strength, and gait speed decreased at 1 week and then increased at 1 month after surgery, similar to the changes seen in SMI. CONCLUSIONS: Multidisciplinary approaches play key role in the surgical treatment of elderly patients. Postoperative exercise and nutritional therapies with BCAA-rich supplements may benefit elderly patients after gastrectomy by reducing loss of SMI and decreases in QOL. TRIAL REGISTRATION: UMIN Clinical Trials Registry; UMIN000034374 (registration date: 10/10/2018).

Community-based exercise and nutritional interventions to improve frailty syndrome among older adults: A quasi-experimental study.

This study aimed to explore the efficacy of single and combined effects of exercise and branched-chain amino acid (BCAA) supplements on improving frailty and quality of life in older adults. In total, 120 study participants were allocated into a combined exercise-and-BCAA supplementation group, an exercise-only group, a BCAA supplementation-only group, and a control group. Results showed that Fried's frailty score significantly decreased in the combined exercise-and-BCAA supplementation group (ß= -1.73, p<0.001), exercise-only group (ß= -1.68, p<0.001), and BCAA supplementation-only group (ß= -0.73, p=0.005) compared to the control group. Moreover, the combination of exercise and BCAA supplements and the exercise-only program produced significant improvements in frailty compared to the BCAA supplement-only group and control group (p<0.05). Exercise should be a critical approach for older adults to improve frailty. Healthcare professionals in geriatric care should incorporate exercise programs as frailty management and prevention for older adults.

Pancreatic cancer: branched-chain amino acids as putative key metabolic regulators?

Branched-chain amino acids (BCAA) are essential amino acids utilized in anabolic and catabolic metabolism. While extensively studied in obesity and diabetes, recent evidence suggests an important role for BCAA metabolism in cancer. Elevated plasma levels of BCAA are associated with an increased risk of developing pancreatic cancer, namely pancreatic ductal adenocarcinoma (PDAC), a tumor with one of the highest 1-year mortality rates. The dreadful prognosis for PDAC patients could be attributable also to the early and frequent development of cancer cachexia, a fatal host metabolic reprogramming leading to muscle and adipose wasting. We propose that BCAA dysmetabolism is a unifying component of several pathological conditions, i.e., obesity, insulin resistance, and PDAC. These conditions are mutually dependent since PDAC ranks among cancers tightly associated with obesity and insulin resistance. It is also well-established that PDAC itself can trigger insulin resistance and new-onset diabetes. However, the exact link between BCAA metabolism, development of PDAC, and tissue wasting is still unclear. Although tissue-specific intracellular and systemic metabolism of BCAA is being intensively studied, unresolved questions related to PDAC and cancer cachexia remain, namely, whether elevated circulating BCAA contribute to PDAC etiology, what is the biological background of BCAA elevation, and what is the role of adipose tissue relative to BCAA metabolism during cancer cachexia. To cover those issues, we provide our view on BCAA metabolism at the intracellular, tissue, and whole-body level, with special emphasis on different metabolic links to BCAA intermediates and the role of insulin in substrate handling.

Dietary intake of branched-chain amino acids in relation to general and abdominal obesity.

PURPOSE: Despite the huge evidence on the link between dietary protein intake and obesity, limited studies have examined the role of individual amino acids in this regard. This study aimed to investigate the association between dietary total and individual BCAAs intake and odds of general and abdominal obesity in a large group of adults. METHODS: This cross-sectional study was conducted among 8691 adults aged 18-55 years in Isfahan, Iran. Dietary BCAAs were assessed using a validated dish-based 106-item semi-quantitative food frequency questionnaire (DS-FFQ). Information about weight and waist circumference was collected through a self-reported validated questionnaire. General obesity was defined as body mass index (BMI) ≥ 30 kg/m2, and abdominal obesity was defined as waist circumference (WC) ≥ 88 cm for women and ≥ 102 cm for men. RESULTS: Mean age of study participants was 36.8 ± 8.1 years. Prevalence of general obesity was 9.2% in men and 9.7% in women and that of abdominal obesity was 13.3% and 36.2% in men and women, respectively. We found that participants in the top tertile of total BCAAs intake had higher odds of general obesity compared with those in the bottom tertile (OR: 1.42; 95% CI: 1.09-1.84). Such significant association was seen in men (OR: 1.57; 95% CI: 1.05-2.34), but not in women (OR: 1.33; 95% CI: 0.94-1.89) in our stratified analysis. We found no significant association between total BCAAs intake and odds of abdominal obesity. Stratified by sex, no significant association was observed between total BCAAs intake and odds of abdominal obesity [for men: (OR: 1.10; 95% CI: 0.74-1.65) and for women: (OR: 1.08; 95% CI: 0.84-1.38)]. Assessing the association with individual BCAAs, a significant positive association was observed between dietary intake of valine (OR: 1.42; 95% CI: 1.10-1.84), leucine (OR: 1.43; 95% CI: 1.10-1.86), and isoleucine (OR: 1.42; 95% CI: 1.09-1.84) with general obesity. We observed no significant association between dietary intake of individual BCAAs intake and odds of abdominal obesity. CONCLUSION: Dietary BCAAs intake was associated with an increased odds of general obesity, in particular among men. No significant association was observed between dietary BCAAs and abdominal obesity. LEVEL OF EVIDENCE: Level V, descriptive cross-sectional study.

Metabolic flux analysis of branched-chain amino and keto acids (BCAA, BCKA) and ß-hydroxy ß-methylbutyric acid across multiple organs in the pig.

Branched-chain amino acids (BCAA) and their metabolites the branched-chain keto acids (BCKA) and ß-hydroxy ß-methylbutyric acid (HMB) are involved in the regulation of key signaling pathways in the anabolic response to a meal. However, their (inter)organ kinetics remain unclear. Therefore, branched-chain amino acids (BCAA) [leucine (Leu), valine (Val), isoleucine (Ile)], BCKA [α-ketoisocaproic acid (KIC), 3-methyl-2-oxovaleric acid (KMV), 2-oxoisovalerate (KIV)], and HMB across organ net fluxes were measured. In multi-catheterized pigs (n = 12, ±25 kg), net fluxes across liver, portal drained viscera (PDV), kidney, and hindquarter (HQ, muscle compartment) were measured before and 4 h after bolus feeding of a complete meal (30% daily intake) in conscious state. Arterial and venous plasma were collected and concentrations were measured by LC- or GC-MS/MS. Data are expressed as mean [95% CI] and significance (P < 0.05) from zero by the Wilcoxon Signed Rank Test. In the postabsorptive state (in nmol/kg body wt/min), the kidney takes up HMB (3.2[1.3,5.0]) . BCKA is taken up by PDV (144[13,216]) but no release by other organs. In the postprandial state, the total net fluxes over 4 h (in µmol/kg body wt/4 h) showed a release of all BCKA by HQ (46.2[34.2,58.2]), KIC by the PDV (12.3[7.0,17.6]), and KIV by the kidney (10.0[2.3,178]). HMB was released by the liver (0.76[0.49,1.0]). All BCKA were taken up by the liver (200[133,268]). Substantial differences are present in (inter)organ metabolism and transport among the BCAA and its metabolites BCKA and HMB. The presented data in a translation animal model are relevant for the future development of optimized clinical nutrition.NEW & NOTEWORTHY Branched-chain amino acids (BCAA) and their metabolites the branched-chain keto acids (BCKA) and ß-hydroxy ß-methylbutyric acid (HMB) are involved in the regulation of key signaling pathways in the anabolic response to a meal. Substantial differences are present in (inter)organ metabolism and transport among the BCAA and its metabolites BCKA and HMB. The presented data in a translation animal model are relevant for the future development of optimized clinical nutrition.