The Complex Relation of Branched-Chain Amino Acids and Inflammation in the Obesity and Diabetes Context.

Diabetes and branched-chain amino acids: What is the link?

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.

Background and objectivesCirculating branched chain amino acids (BCAAs) increase the risk of type 2 diabetes (T2D). The genetic variants in the BCAA metabolic pathway influence the individual metabolic ability of BCAAs and may affect circulating BCAA levels together with dietary intakes. So, we investigated whether genetic predisposition to impaired BCAA metabolism interacts with dietary BCAA intakes on the risk of type 2 diabetes and related parameters.MethodsWe estimated dietary BCAA intakes among 434 incident T2D cases and 434 age-matched controls from The Harbin Cohort Study on Diet, Nutrition and Chronic Non-Communicable Diseases. The genetic risk score (GRS) was calculated on the basis of 5 variants having been identified in the BCAA metabolic pathway. Multivariate logistic regression models and general linear regression models were used to assess the interaction between dietary BCAAs and GRS on T2D risk and HbA1c.ResultsDietary BCAAs significantly interact with metabolism related GRS on T2D risk and HbA1c (p for interaction = 0.038 and 0.015, respectively). A high intake of dietary BCAAs was positively associated with diabetes incidence only among high GRS (OR 2.40, 95% CI 1.39, 4.12, P for trend = 0.002). Dietary BCAAs were associated with 0.14% elevated HbA1c (p = 0.003) and this effect increased to 0.21% in high GRS (p = 0.003). Furthermore, GRS were associated with 9.19 μmol/L higher plasma BCAA levels (p = 0.006, P for interaction = 0.015) only among the highest BCAA intake individuals.ConclusionsOur study suggests that genetic predisposition to BCAA metabolism disorder modifies the effect of dietary BCAA intakes on T2D risk as well as HbA1c and that higher BCAA intakes exert an unfavorable effect on type 2 diabetes risk and HbA1c only among those with high genetic susceptibility.

The aim of this study was to evaluate the effect of strenuous exercise on the functions of peritoneal macrophages in rats and to test the hypothesis that branched-chain amino acid (BCAA) supplementation will be beneficial to the macrophages of rats from strenuous exercise. Forty male Wistar rats were randomly divided into five groups: (C) Control, E) Exercise, (E1) Exercise with one week to recover, (ES) Exercise + Supplementation and (ES1) Exercise + Supplementation with 1 week to recover. All rats except those of the sedentary control were subjected to four weeks of strenuous exercise. Blood hemoglobin, serum testosterone and BCAA levels were tested. Peritoneal macrophages functions were also determined at the same time. The data showed that hemoglobin, testosterone, BCAA levels, and body weight in group E decreased significantly as compared with that of group C. Meanwhile, phagocytosis capacity (decreased by 17.07%, p = 0.031), reactive oxygen species (ROS) production (decreased by 26%, p = 0.003) and MHC II mRNA (decreased by 22%, p = 0.041) of macrophages decreased in the strenuous exercise group as compared with group C. However, the chemotaxis of macrophages did not change significantly. In addition, BCAA supplementation could slightly increase the serum BCAA levels of rats from strenuous exercise (increased by 6.70%, p > 0.05). Moreover, the body weight, the blood hemoglobin, the serum testosterone and the function of peritoneal macrophages in group ES did not change significantly as compared with group E. These results suggest that long-term intensive exercise impairs the function of macrophages, which is essential for microbicidal capability. This may represent a novel mechanism of immunosuppression induced by strenuous exercise. Moreover, the impaired function of macrophage induced by strenuous exercise could not be ameliorated by BCAA supplementation in the dosing and timing used for this study.

Branched-chain amino acid-enriched supplements as therapy for liver disease: Rasputin lives

The branched chain amino acids (BCAA), leucine, isoleucine and valine, are essential for mammalians, and they play a positive role in exercise capacity, muscle development, and a lean body phenotype. BCAA supplementation is commonly paired with exercise in order to promote muscle growth, increase resistance to fatigue and reduce muscle soreness. On the other hand, elevated serum BCAA is strongly and positively correlated with the development of insulin resistance, coronary heart disease, and type II diabetes, and is predictive of patient response to therapeutics and intervention outcomes. We have previously shown that defective BCAA catabolism in mice impaired glucose metabolism in the heart and increased susceptibility to stress-induced cardiac damage. In this study we sought to determine the effects of elevated BCAA levels on skeletal muscle performance and response to exercise training using mouse models with systemically elevated BCAA levels. Supplementation of BCAA (1.5mg/g bodyweight/day, ratio of Leu:Ile:Val = 1.5:0.8:1) was administered to mice with impairment of BCAA catabolism due to the deletion of mitochondrial-localized protein phosphatase 2C (KO), a key enzyme in activating BCAA catabolism, and their littermate controls (CON). Mice were subjected to one week of daily exercise training via forced treadmill running and an exercise capacity test was performed at the beginning and end of training. Baseline maximum running time was decreased in the KO compared to CON (mean 73.4 and 82.5 min, respectively). One week of training resulted in increased exercise capacity in CON with an attenuated increase in KO mice (mean 136 and 112 min, respectively). BCAA supplementation did not further improve exercise capacity in CON (mean 131 min) and abrogated the response to training in KO (mean 70.1 min). Reduced exercise capacity positively correlated with elevated serum BCAA levels. Additionally, KO supplemented with BCAAs demonstrated elevated serum succinate, alanine and glutamate levels, which are metabolic markers of physiological stress. We conclude that short term supplementation of BCAA has no benefit for exercise capacity and accumulation of BCAAs has a negative effect on endurance exercise capacity.

The elevated branched-chain amino acids (BCAAs) have been strongly associated with the development of metabolic diseases in recent years. It remains unclear whether the altered BCAA metabolism plays a functional role in mediating the beneficial effects of exercise against metabolic dysfunctions. Diet-induced obese (DIO) mice underwent an aerobic exercise regimen with or without BCAA supplementation. Fibroblast growth factor 21 (FGF21) was either knocked down or overexpressed specifically in the liver using an adeno-associated virus. Various metabolic phenotypes were assessed. HepG2 cells were cultured and treated with varying concentrations of BCAAs. Aerobic exercise significantly reduced circulating BCAA levels in obese mice (leucine: -15.21%; isoleucine: -18.13%; valine: -20.83%), concomitant with decreased body weight (-8.89%), better glycaemic control and improved hepatic steatosis. Notably, BCAA supplementation restored plasma BCAA levels and counteracted the metabolic benefits of aerobic exercise. Exercise upregulated hepatic FGF21 expression (+66.67%), which was abolished by BCAA supplementation (-63.67%). Deletion of hepatic FGF21 eliminated the metabolic benefits of exercise, while over-expression of hepatic FGF21 mitigated the metabolic dysfunctions induced by BCAA supplementation in exercised mice. BCAAs suppressed hepatic FGF21 expression likely through the general control nonderepressible (GCN2)-activating transcription factor 4 (ATF4) pathway. Long-term aerobic exercise mitigates obesity and associated metabolic disorders by reducing BCAA abundances and subsequently FGF21 induction. The causal relationship between dietary BCAA intake and the anti-obesity effects of exercise provides novel insight into the metabolic interplay between exercise and BCAAs, underscoring the potential of integrating exercise with precise nutrient modulation as an effective strategy to improve metabolic health.

Branched-Chain Amino Acids Prevent Hepatocarcinogenesis and Prolong Survival of Patients With Cirrhosis

The branched chain amino acids (BCAA), leucine, isoleucine and valine, are essential for mammals, and they play a positive role in exercise capacity, muscle development, and a lean body phenotype. BCAA supplementation is commonly paired with exercise in order to promote muscle growth, increase resistance to fatigue and reduce muscle soreness. Conversely, elevated serum BCAA is strongly and positively correlated with the development of insulin resistance, coronary heart disease, and type II diabetes, and is predictive of patient response to therapeutics and intervention outcomes. We have previously shown that defective BCAA catabolism in mice impaired glucose metabolism in the heart and increased susceptibility to stress-induced cardiac damage. In this study we sought to determine the effects of elevated BCAA levels on skeletal muscle performance and response to exercise training using mouse models with systemically elevated BCAA levels. Here we assess the hypothesis that defective BCAA catabolism negatively impacts exercise capacity and endurance through deregulation of substrate utilization in the skeletal muscle using a mouse model with systemically elevated BCAA levels. Impairment of BCAA catabolism due to the deletion of mitochondrial-localized protein phosphatase 2C (PP2Cm), a key enzyme in activating BCAA catabolism, leads to elevated BCAA levels in mice. To study this, PP2Cm-knock out (KO) mice and their littermate controls were subjected to high-intensity and low-intensity exercise capacity tests via forced treadmill running. PP2Cm-KO mouse has a 20% reduction in exercise capacity. Reduced exercise capacity positively correlated with elevated serum BCAA levels. Additionally, KO animals supplemented with BCAAs demonstrated elevated serum succinate, alanine and glutamate levels, which are metabolic markers of physiological stress. We conclude that the inability to catabolize BCAAs has a negative effect on exercise capacity and endurance.

Type 2 diabetes (T2D) is a worldwide epidemic associated with metabolic disorders and intestinal microbiota alterations. Polysaccharides have been considered to be beneficial to the prevention and alleviation of T2D. In the present study, ultra-performance liquid chromatography-triple-time-of-flight-based metabolomics and proteomics and 16S rRNA sequencing methods were employed to evaluate the effects of glucomannans from Dendrobium officinale stem, konjac, and Aloe vera leaves on host metabolism and intestinal microbiota regulation in type 2 diabetic rats and potential mechanisms. The metabolism of amino acids was significantly disturbed in the type 2 diabetic rats, especially the upregulated branched-chain amino acid (BCAA) metabolism. Host-derived BCAA metabolism was significantly decreased in type 2 diabetic rats. However, the levels of BCAAs in host circulation and gene abundance of BCAA biosynthesis in gut microbiota were significantly increased in diabetic rats, which suggested that the disturbed intestinal microbiota might be responsible for the increased circulation of BCAAs in T2D. Glucomannan treatment decreased the abundance of microbial BCAA biosynthesis-related genes and ameliorated the host BCAA metabolism. Also, glucomannan with a higher molecular weight and a lower ratio of mannose/glucose possessed better antidiabetic effects. In summary, the antidiabetic effects of glucomannans might be associated with the amelioration of BCAA metabolism by modulating intestinal microbiota.

Background: Branched chain amino acid (BCAA) metabolism plays roles in various cellular processes, including energy homeostasis, anabolic signaling, and production of glutamate, the primary excitatory neurotransmitter. Emerging evidence also suggests BCAA metabolism has relationships to inflammatory and hypoxic cellular responses. Recent work in adult and adolescent clinical populations has suggested that BCAA dietary supplementation may improve outcomes associated with traumatic brain injury. Given these links, examining the putative mechanisms and potential therapeutic applications of modulating dietary BCAA content in the context of inflammatory and hypoxic developmental brain injury may reveal mechanisms for intervention in affected infants. Summary: Inflammatory and hypoxic brain injuries influence the dynamics of BCAA metabolism in the fetal brain. Inflammatory insults to the developing brain may increase BCAA catabolism downstream of the branched chain ketoacids (BCKAs). The effect of altered BCAA metabolism on the pathophysiology of inflammatory developmental brain injury is currently unclear but may play a role in microglial response. Hypoxic brain injury seems to increase BCAA concentration in the fetal brain, possibly because of re-amination of BCKAs to the parent BCAAs, or via increased protein breakdown during hypoxia. Key Messages: The apparent relationship between aberrant BCAA metabolism and inflammation or hypoxia warrants consideration of BCAA supplementation or restriction as a strategy for attenuating developmental brain injury that is associated with these pathologic events. This approach could entail alterations of maternal diet during pregnancy or the feeding of infant formula that is fortified with or restricted in BCAA. These types of interventions have been safely and effectively employed in cases of inborn errors of BCAA metabolism, suggesting feasibility in infant populations. Both in vitro and preclinical work is necessary to elucidate how BCAA supplementation or restriction may affect the sequelae of inflammatory and hypoxic developmental brain injury.

Increased levels of serum branched-chain amino acids (BCAA) is associated with obesity, insulin resistance (IR), and type 2 diabetes (T2D). However, the mechanisms that trigger perturbations in BCAA homeostasis, and whether elevated BCAA causes obesity and other metabolic impairments or is a consequence of them is not clear. Young knock-in mice bearing the human T2D-linked R1788W variant in the cytoskeletal protein ankyrin-B (AnkB) show normal body weight and composition. These mice display increased glucose uptake by white adipose tissue (WAT) due to deficient internalization of the glucose transporter GLUT4. We reported that sustained elevation in glucose disposal in WAT leads to the onset of increased adiposity, lipotoxicity, systemic inflammation, and IR in AnkB mutant mice with age or in young animals fed Western diets. Non-obese R1788W AnkB mice also exhibit transcriptional changes consistent with lower BCAA catabolism in WAT. Here, we show that AnkB deficits impair BCAA catabolism in WAT prior to the onset of obesity. Lean R1788W AnkB mice show reduction in surface levels of the BCAA transporter Asct2 and BCAA uptake together with downregulation of BCAA catabolic enzymes in WAT. These deficits are concomitant with elevations in serum levels of BCAA and related acylcarnitines. Reduced expression of BCAA catabolic enzymes was also observed in WAT of lean WAT-specific AnkB KO mice. In contrast, AnkB deficiency did not alter BCAA oxidation in skeletal muscle (SKM), brown adipose tissue, or liver. Studies in control and R1788W AnkB mice fed isocaloric low and high fat (HFD) diets enriched in BCAA suggest that BCAA elevation triggers mitochondrial dysfunction, impairments in insulin secretion by the pancreas and in insulin signaling in SKM. Our data indicates that elevated circulating BCAA impair glucose tolerance and insulin sensitivity independently of obesity, and that these deleterious effects are potentiated by HFD. Disclosure J. Tzeng: None. A. Aguillard: None. D. Lorenzo: None. Funding American Diabetes Association (1-19-JDF-081 to D.L.)

Branched-chain amino acids (BCAA) and nitrate have become increasingly popular mainly for their potential effect on individuals' health and secondary as ergogenic aids. The purpose of this narrative review was to incorporate the current scientific evidence of BCAA and nitrate supplementation on athletic performance and health. The current recommendations of BCAA and nitrate supplementation are discussed, as well as possible health complications associated with its intake. Pubmed, Scopus, and Web of Science were searched for articles on the effects of BCAA and nitrate supplementation in humans. The positive effect of BCAAs supplementation on athletic performance does not appear to be fully established. BCAAs supplementation seems to be recommended for all athletes who exercise vigorously daily, as it enhances their recovery after causing exercise-induced muscle damage. BCAAs supplementation reduces the feeling of delayed muscle pain, which follows because of muscle damage. Limited scientific data suggest a potentially beneficial effect of BCAAs on reducing central fatigue. Several clinical conditions could benefit from BCAAs' consumption. However, there are no reliable markers to evaluate or quantify their requirements. There are no exact consumption protocols and absolute recommendations, mainly because BCAAs are also obtained through the consumption of animal protein. Dietary nitrates lower blood pressure, reduce the cost of exercise oxygen, and, at least sometimes, enhance exercise capacity. Taking supplements for 2-6 days (or up to 15 days) can increase athletic performance during high-intensity exercise. The duration of continuous maximum exercise for which nitrates appear to be ergogenic is between 5-30 min. There is limited evidence that nitrates are beneficial in prolonged exercise performance (40 min), at least when administered short term. Supplementation of approximately 5-9 mmol of nitrate/day for 1-15 days may have beneficial effects on normal exercise responses, although the exact dose-response relationship has not yet been established. Five to 9 mmol of nitrates can be easily consumed in the normal diet and there is currently no evidence to adequately document that taking additional nitrates produces greater benefits. The effectiveness of acute nitrate supplementation is likely to depend on many factors, such as sex, health, hypoxia, diet, and level of fitness/training experience of the subjects. Nitrate needs are most likely met by ingesting approximately 250-500 g of leafy and root vegetables per day; however, dietary supplements might represent a more convenient and accurate way of covering an athlete's nitrate needs.

Dietary Luffa cylindrica (L.) Roem promotes branched-chain amino acid catabolism in the circulation system via gut microbiota in diet-induced obese mice

Impact of Branched Chain Amino Acid Supplementation on Hepatic Mitochondrial Metabolism in Mice with Non-alcoholic Fatty Liver Disease (P08-136-19)