Category: Diet

BCAAs and metabolism

BCAAs and metabolism

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Recent metqbolism show branched-chain amino acid BCAAs and metabolism catabolic BCAAs and metabolism is defective in obese adn and humans, contributing to the Body composition scanner machine of insulin resistance and diabetes.

However, in the context of Fluoride, various processes including the dysfunctional lipid metabolism can affect insulin sensitivity and glycemic regulation. It Black pepper extract for skin health unclear how BCAA catabolic defect may exert direct metabloism on glucose andd without ,etabolism disturbance of obesity.

Metabo,ism current study characterized the glucose metabolism metabollsm lean Dance fueling tips in which the genetic deletion of PP2Cm leads to moderate BCAA catabolic defect.

Interestingly, mettabolism to the wildtype BCAAs and metabolism, lean PP2Cm deficient mice metabolksm enhanced insulin sensitivity and glucose tolerance, lower body weight, and the preference nad carbohydrate over lipids utilization.

The metabolic changes of glucose were predominantly observed Cellulite reduction strategies liver but not skeletal muscle or white metabo,ism tissue.

Mtabolism, these results BCAs BCAA catabolic defect significantly alters glucose metabolism in lean BCAA with some impacts different or even mftabolism from those in obese megabolism, highlighting the critical role of BCAA catabolism in metaabolism regulation and the complex interplay between macronutrients in lean and obese mdtabolism.

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A number BBCAAs observational studies found that elevated Inflammation and pain management levels of BCAAs are associated with type 2 BCAAs and metabolism mellitus T2DM and insulin resistance in humans and Hypertension and sleep apnea rodent models Shaham BCAAs and metabolism al.

Longitudinal and anr studies ajd different cohorts have reported that BCAAw BCAA metabolosm in blood is predictive for diabetes pathogenesis and change of plasma Metaoblism level Flavonoids and hormonal balance prognostic for intervention outcomes of diabetes Wang et metabolisk.

Lower BCAA level has been associated with improved insulin resistance metabolis interventional procedures Laferrere et al.

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The first two steps of BCAA catabolism are shared by all three BCAAs. The Insulin pump accessories deamination BCAAs and metabolism to produce branched chain Massage therapy for relaxation and depression relief acids BCKAs is catalyzed mstabolism BCAA transaminase Metaabolismwhich is followed by the abd decarboxylation to form Omega- for menstrual health esters, a reaction catalyzed aand BCKA dehydrogenase BCKD BCAs.

The BCKD complex is the rate-limiting Mmetabolism for BCAA catabolism and tightly regulated by inhibitory phosphorylation by BCKDK Snakebite wound healing activating dephosphorylation by metabolis phosphatase 2C PP2Cm.

Loss of PP2Cm in genetic model partially impairs BCAA catabolism, leading to the higher plasma BCAA and Meatbolism concentrations Lu et al.

Similarly, in mwtabolism animals and humans, BCAA catabolic metaholism are down-regulated and the BCAA catabolism is Energy metabolism catechins defective, contributing Hydration support the elevated plasma BCAAs and BCKAs She et BCAAAs.

The strong association between the elevated BCAA level and the metabooism T2DM metbolism that disrupted BCAA homeostasis may contribute to the dysfunctional glycemic control. Indeed, recent Vibrant show that BCAA catabolic defect contributes to the obesity-associated insulin resistance metabollsm diabetes White et mefabolism.

However, in obese animals and humans, BCAAz dysregulated lipid metabolism and other metqbolism dramatically affects insulin sensitivity mrtabolism glucose metabolism.

Thus, it remains challenging to distinguish metbaolism BCAAs and metabolism impacts of BCAA catabolic CBAAs on glucose metabolism from the disturbance of obesity in obese animals.

Using lean mice, the current study investigates the impacts meatbolism BCAA catabolic defect on glucose metabolic processes in a genetic mouse model in which PP2Cm is ablated to ad impair BCAA catabolism.

PP2Cm germ-line BCAs mice were generated as previously described Lu et al. All animals at age of 10—14 weeks were housed at 22°C with a h light, h dark cycle with free access to water and standard chow.

All animal procedures were carried out in accordance with the guidelines and protocols approved by the Committee for Humane Treatment of Animals at Shanghai Jiao Tong University School of Medicine or the University of California at Los Angeles Institutional Animal Care and Use Committee.

Measurements of oxygen consumption VO 2 and carbon dioxide production VCO 2 with indirect calorimetry were performed at ambient temperature using a Comprehensive Laboratory Animal Monitoring System CLAMS, Columbus Instruments, OH, United States according to the instructions of the manufacturer.

Male mice were admitted to a CLAMS with free access to food and water and allowed to acclimatize in individual metabolic cages for 48 h before any measurements and the data were collected in the next 36 h. Male mice were fasted for 6 h starting at 8 am.

For insulin tolerance test, mice were injected intraperitoneally with insulin 0. For glucose tolerance test, mice were injected intraperitoneally with D -glucose 1. Total RNA was extracted from tissues or cells using the Trizol Invitrogen, United States. Total RNA 2 μg was reverse transcribed using random primers and MMLV Promega, United States.

The metabolomic analysis was carried out by Metabolon, Inc. Durham, NC using tissues from male wildtype or PP2Cm knockout mice at 14 weeks of age. After 6-h fasting starting at 8am, the animals were sacrificed by cervical dislocation.

Samples were prepared using the automated MicroLab STAR ® system from Hamilton Company. To extract metabolites from tissues, extraction solution based on methanol was added to each sample in identical weight to volume ratio. The tubes containing extraction mixtures were centrifuged to precipitate proteins, and the supernatants containing metabolites were recovered for metabolomics analysis.

Several types of controls were analyzed in concert with the experimental samples. The LC-MS portion of the platform was based on a Waters ACQUITY ultra-performance liquid chromatography UPLC and a Thermo-Finnigan LTQ mass spectrometer operated at nominal mass resolution, which consisted of an electrospray ionization ESI source and linear ion-trap LIT mass analyzer.

The samples destined for analysis by GC-MS were dried under vacuum prior to being derivatized under dried nitrogen using bistrimethyl-silyltrifluoroacetamide.

Peaks were quantified using area-under-the-curve. A collection of information interpretation and visualization tools including Principal Component Analysis PCA and Random Forest RF analyses were used for data analysts.

For stimulation by BCAA μM or BCKA μMthe cells were incubated in serum-free DMEM for 12 h, and then incubated in BCAA-free DMEM for 1 h before the initiation of 12 h treatments. BCAA and BCKA were diluted in BCAA-free DMEM. Custom BCAA-free DMEM was provided by Invitrogen. BCAA and BCKA chemicals were purchased from Sigma.

The isolation of mitochondria to measure oxygen consumption was performed as described elsewhere Korge et al. Briefly, mitochondria were isolated from tissues and oxygen consumption was measured using an Ocean Optics fiber optic spectrofluorometer.

Mitochondria 0. The oxygen concentration in the buffer was continuously recorded via an Ocean Optics FOXY fiber optic oxygen sensor.

Pyruvate, malate, and glutamate were added as free acids buffered with Tris pH 7. Succinate was used for Complex II activity assay in presence of rotenone 1 μM. Addition of 0. NaCl or BCKA-Na mixture was added to the reaction system after the first pulse of ADP was consumed.

Then the second pulse of ADP was added. The oxygen consumption rate OCR was calculated with each ADP addition. The relative rate of oxygen consumption was calculated by dividing the OCR of second pulse of ADP by the OCR of the first pulse of ADP.

The presented data represented the average values of three independent experiments. Data were calculated as the mean ± SEM. A p -value of less than 0. In order to examine the effects of defective BCAA catabolism on glucose metabolism in lean mice, we characterized the metabolic phenotypes of PP2Cm deficient mice in which the gene encoding PP2Cm has been genetically disrupted Lu et al.

PP2Cm is the specific BCKD phosphatase that dephosphorylates BCKDE1a subunit at Ser in the presence of substrates.

PP2Cm deficiency partially impairs BCAA catabolism, leading to elevated plasma BCAA and BCKA concentrations. PP2Cm deficient mice showed significantly lower body weight compared with wildtype control Figure 1A without food intake change Figure 1B.

In indirect calorimetry, PP2Cm deficient mice showed similar energy expenditure and physical activity compared with wildtype mice data not shown.

Interestingly, the RER in PP2Cm deficient mice was significantly higher compared to that in wildtype mice, indicating PP2Cm deficient mice had an overall preference for carbohydrates as metabolic substrate Figures 1C,D.

Furthermore, glucose tolerance test and insulin tolerance test demonstrated enhanced glucose clearance and insulin sensitivity in PP2Cm deficient mice Figures 1E—Haccompanied with an unaffected fasting plasma insulin level data not shown. Together, these data demonstrate clear alterations of glucose metabolism in lean mice with BCAA catabolic defect.

Figure 1. Branched-chain amino acid BCAA catabolic defect reduces body weight with beneficial effects on glucose metabolism in PP2Cm KO mice.

Data are represented as means ± SEM. We next performed metabolomics profiling analyses of plasma to further characterize the biochemical changes in overall metabolism of fasted PP2Cm deficient mice. A total of named biochemicals were identified and measured in mouse plasma samples.

The identities and metabolic pathways of these metabolites are provided in Supplementary Table S1. Statistical comparisons revealed a large number of statistically significant differences between groups.

Principal component analysis PCA determines if samples from different groups can be segregated based on differences in their overall metabolic signature.

The PCA results illustrated a clear differentiation of PP2Cm deficient and wildtype groups Figure 2A. Meanwhile, Random Forest RF analysis bins individual samples into groups based on their metabolite similarities and differences, and also defines which metabolites contribute most strongly to the group binning.

BCAAs and their metabolites including the BCKAs 3-methyloxovalerate, 4-methyloxopentanoate, and 3-methyloxobutyrate were among the top 30 metabolites most strongly contributing to proper group binning Figure 2C. Together, PCA and RF analyses showed clearly distinguishable changes in the plasma metabolites between PP2Cm deficient and wild-type control mice.

Figure 2. Deletion of PP2Cm resulted in significant global metabolic perturbations. B Random Forest Confusion Matrix. C List of the top 30 biochemicals that separated different genotypes based on their importance.

Comparison of plasma global biochemical profiles for wildtype and PP2Cm deficient mice revealed several key signatures. As expected, the most dramatic effects of PP2Cm ablation was on metabolites of BCAA metabolic pathway Figure 3A.

Plasma levels of valine, leucine and isoleucine were elevated in PP2Cm deficient mice relative to wildtype mice Figure 3B. The BCKAs, 3-methyloxobutyrate, 3-methyloxovalerate, and 4-methyloxopentanoate were also elevated in the plasma of PP2Cm deficient mice.

The alpha-hydroxycarboxylic acids, 2-hydroxymethylvalerate, alpha-hydroxyisocaproate, and alpha-hydroxyisovalerate, derived from reduction of the BCKAs, were all increased in the plasma of PP2Cm deficient mice Figure 3B.

Elevation of the BCAAs, BCKAs, and 2-hydroxycarboxylic acids was consistent with a decrease in BCKD activity, which was further supported by the lower abundance of beta-hydroxyisovaleroylcarnitine in the plasma of PP2Cm deficient mice Figure 3B.

Interestingly, some metabolites derived from products downstream of BCKD, including isovalerylglycine, isovalerate, 3-methylcrotonyl-glycine, 2-methylbutrylcarnitine, and isobutyrylcarnitine, were increased in the plasma of PP2Cm deficient mice Figure 3Bsuggesting complexity of BCAA catabolism from different tissues Hutson et al.

Nevertheless, genetic ablation of PP2Cm clearly causes systemic BCAA catabolic defect in mice. Figure 3. Global BCAA catabolic defect in lean PP2Cm KO mice. A Illustration of BCAA catabolic process with enzymes, intermediates, and derivatives. To better understand how BCAA catabolic defect affects regional metabolism, we performed metabolomics analyses in liver, white adipose tissue, and skeletal muscle, the three key tissues in metabolic regulation, in fasted mice.

: BCAAs and metabolism

Trait: BCAA metabolism and muscle building

The studies have shown that the BCAA levels in obesity correlate with insulin resistance and are a sensitive predictor of diabetes in the future [ 78 , 79 ]. Recent studies have suggested that high levels of the BCAA interfere with oxidation of fatty acids in muscles, leading to accumulation of various acylcarnitines and insulin resistance [ 24 ].

Conflicting results have been reported concerning the effects of BCAA supplementation in subjects with insulin resistance. Arakawa et al. On the other hand, Newgard et al. White et al. MSUD is recessive disorder caused by a severe deficiency of BCKD activity.

All three BCAAs, as well as the corresponding BCKAs, are elevated in blood, tissues, and urine. High BCAA and BCKA levels are related to excitotoxicity, energy deficit, and oxidative stress in the brain, resulting in severe neurological symptoms. BCAA administration to subjects with MSUD is inappropriate.

DNA damage in the hippocampus and the striatum was demonstrated after administration of BCAAs in an animal model of MSUD [ 83 ]. Current treatment of MSUD is based on protein restriction and synthetic formulas with reduced BCAA content. Perspective may be phenylbutyrate, which activates BCKD and decreases BCAA and BCKA levels [ 55 , 56 ].

Unfortunately, studies examining phenylbutyrate in MSUD patients are unique. Long-term studies in different MSUD phenotypes are indicated to verify phenylbutyrate efficacy. Physical exercise is associated with enhanced BCAA oxidation and GLN release from muscles [ 84 , 85 ].

Evidence suggests that BCKD is activated by dephosphorylation mediated by falling ATP levels within the muscles during exercise. Training appears to increase mRNA expression of this enzyme [ 86 ]. The plasma BCAA levels during or after exercise have been reported to be unchanged [ 87 ], to decrease [ 88 ], or to increase [ 89 ].

The cause of inconsistent response can be explained by different work load and duration of exercise. BCAAs are recognized as supplements for athletes with a number of benefits, notably on muscle protein synthesis, fatigue recovery, and exercise-induced muscle damage [ 90 ].

In addition to the positive reports, there are a number of reports showing no benefits of BCAA supplementation [ 91 ]. Of special interest should be findings of enhanced blood ammonia levels after BCAA administration during exercise suggesting that exogenous BCAA may exert negative effects on muscle performance via ammonia [ 92 , 93 ].

Additional studies are needed to assess the true efficacy of BCAA supplementation on muscle performance and fatigue. There are several hypermetabolic states e. sepsis, burn injury, trauma, and cancer in which alterations in BCAA levels are not consistent, with increased, unchanged, and decreased levels being reported.

Present in all of these conditions is systemic inflammatory response syndrome SIRS characterized by a wide range of neuro-humoral abnormalities, including enhanced production of cytokines, sympathetic nervous system activation, and cortisol production. These events cause several alterations in metabolism, including insulin resistance and enhanced myofibrillar protein degradation, resulting in severe depletion of lean body mass.

If the hypermetabolic state persists, multisystem organ failure and eventually death may occur Fig. Main alterations in protein and BCAA metabolism in disorders accompanied by SIRS.

In this situation, BCAAs act as a significant energy substrate for muscles [ 4 , 5 , 94 ]. Increased BCAA oxidation is coupled with increased synthesis of GLN, which is released from muscles and utilized, preferably by the immune system. Utilization of GLN often exceeds its synthesis, leading to a lack of GLN in blood and tissues [ 95 , 96 ].

Decreased GLN availability can become rate-limiting for key functions of immune cells, such as phagocytosis and antibody production. Decreased GLN levels have been shown to act as a driving force for BCAA utilization in muscles [ 97 ].

Studies have also indicated that inflammatory signals decrease BCAA absorption from the gut and inhibit BCAA transport from the blood to muscles, while promoting transport into the liver [ 98 , 99 ].

The BCAA synthesis from the BCKA in visceral tissues is probably activated. A marked increase in leucine release was observed by the isolated liver of endotoxin-treated animals after the addition of KIC into perfusion medium [ 7 ].

The cause of inconsistent alterations in BCAA levels although their oxidation is remarkably activated are different influences of individual metabolic changes occurring in the SIRS. Increased protein breakdown or decreased protein synthesis in muscles and insulin resistance may enhance the BCAA levels.

Activation of BCAA catabolism associated with enhanced ALA and GLN production in muscles and protein synthesis in visceral tissues decrease the BCAA levels.

Therefore, alterations in BCAA levels are inconsistent. Rationales for the use of BCAA supplements in conditions with SIRS are their enhanced oxidation, which may limit their availability in tissues and their protein anabolic properties. Benefits of BCAAs may also be related to their role as a precursor of GLN, which is a key factor in maintaining immune functions and gut integrity, and has a favorable influence on protein balance.

Various solutions containing different amounts and proportions of individual BCAA have been used to examine their effects in trauma, burn, or sepsis.

A number of investigators have reported that BCAA ameliorate negative nitrogen balance [ , , ]. However, the results of other investigators have not been impressive, and there is no scientific consensus regarding the effect BCAA-enriched formulas on protein balance, length of hospital stay, and mortality [ , , ].

A serious shortcoming of most of the studies is the lack of information regarding BCAA concentrations in blood and tissues, which may be suggested as a possible criterion of eligibility of the indication.

The low effectiveness of the BCAA in disorders with the presence of SIRS may be related to insulin resistance and metabolic alteration associated with inflammation.

Studies have shown that inflammatory response blunts the anabolic response to BCAA administration. Lang and Frost [ ] demonstrated that leucine induced activation of eukaryotic initiation factor eIF4E is abrogated in endotoxin-treated rats and that endotoxin treatment antagonized the leucine-induced phosphorylation of ribosomal protein S6 and mTOR.

In recent years articles have emerged suggesting positive effects of BCAA in traumatic brain injury. In rodents, BCAAs have demonstrated to ameliorate injury-induced cognitive impairment [ ], and clinical studies have demonstrated that BCAAs enhance the cognitive recovery in patients with severe traumatic brain injury [ , ].

Unlike other states accompanied by SIRS, muscle wasting and amino acid mobilization from muscles in subjects with cancer may be driven by secretion of different tumor-derived mediators. Therefore, progressive depletion of muscle mass may be observed in some cancer patients.

Also high rates of BCAA oxidation in muscles of subjects with cancer have been reported [ ]. Increasing evidence demonstrates that BCAAs are essential nutrients for cancer growth and are used as a source of energy by tumors.

Expression of the cytosolic type of BCAT has been shown to correlate with more aggressive cancer growth [ ]. The findings of clinical trials examining the effects of BCAA-enriched nutritional support to cancer patients are inconsistent. Some showed improved nitrogen balance and reduced skeletal muscle catabolism whereas others show no significant improvement [ ].

A concern in the tumor-bearing state is that provision of the BCAA will promote tumor growth. The studies indicate that important role in pathogenesis of alterations in BCAA metabolism play: i skeletal muscle as initial site of BCAA catabolism accompanied by the release of GLN, ALA, and BCKA to the blood; ii activity of BCKD in muscles and liver, and iii amination of BCKA to corresponding BCAA, especially by nitrogen of ALA and GLN released from muscles.

Here are examples of importance of these metabolic steps:. ad i Because the muscle is the initial site of BCAA catabolism, marked rise of BCAA is observed after a meal while the rise of other amino acids is small. Enhanced consumption of the BCAA for ammonia detoxification to GLN in muscles is the main cause of the decrease of the BCAA in hyperammonemic conditions liver cirrhosis, UCD.

Increased production of GLN after BCAA intake in muscles may lead to enhanced production of ammonia in enterocytes and kidneys with deleterious effect in subjects with liver disease.

ad ii Decreased BCKD activity is the main cause of increased BCAA and BCKA levels in MSUD and may play a role in increased BCAA levels in obesity and type 2 diabetes.

Increased BCKD activity is responsible for the decrease of BCAAs in CRF and enhanced oxidation of BCAAs during exercise and in various hypermetabolic conditions burn, sepsis, trauma, cancer.

ad iii BCKA amination partially explains the increased BCAA concentrations during brief starvation and in type 1 diabetes, and is the basis of rationale to use BCKA-enriched supplements in CRF therapy.

Although amino acid concentrations in the plasma pool are poor indicators of their requirements, it may be suggested that under conditions of good understanding of the BCAA metabolism in specific disorder, the BCAA levels would conceptually be an acceptable argument for their supplementation.

It may be supposed that:. Together with requirements to decrease protein content in a diet, increased oxidation and low BCAA levels are a clear rationale to use the BCAA together with other essential amino acids and their ketoanalogues in CRF therapy.

Although BCAA decrease in blood plasma is a rationale to use the BCAA supplements in patients with liver cirrhosis and UCD, therapeutic strategies are needed to avoid detrimental effects of BCAA supplementation on ammonia production.

Further studies are necessary to conclude the question of the effects of BCAA supplementation in burn, trauma, sepsis, cancer, and exercise. A very small number of clinical studies have reported the effects of BCAA supplementation in relation to amino acid concentrations in blood and tissues.

In conclusion, alterations in BCAA metabolism are common in a number of disease states and the BCAA have therapeutic potential due to their proven protein anabolic effects.

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The authors found evidence that a high-protein diet that provides additional leucine can help maintain muscle mass in people with chronic diseases such as cancer.

A systematic review found some evidence that BCAA supplementation can help reduce the muscle damage that occurs during high-intensity exercise. However, the authors caution that the evidence base was limited to one small study and that confirming these findings will require more research.

Results of a small study from show that adult male participants who took a BCAA supplement during exercise had lower blood levels of substances that indicate muscle damage than those who took a placebo.

The researchers concluded that BCAA supplementation may reduce muscle damage after endurance exercises. A study investigated the effects of combined BCAA and arginine supplementation on intermittent sprint performance over 2 consecutive days. Arginine is another type of amino acid.

The study involved 7 females and 15 males who had competed at a national or international level in handball. The participants played simulated handball games over 2 consecutive days.

The researchers found that intermittent sprint performance on the second day was significantly better in the athletes who had taken the supplement, compared with those who had taken the placebo. In a study , researchers randomly assigned participants with advanced liver cirrhosis into groups.

For at least 6 months, each group consumed either BCAAs daily or a diet without BCAAs. Over 2 years, Model for End-Stage Liver Disease MELD test scores improved significantly among participants who consumed BCAAs, compared with those who did not.

Doctors calculate MELD scores by measuring levels of certain substances in the blood, such as creatinine and bilirubin. They use the resulting score to help determine how close a person is to having liver failure.

The authors concluded that long-term BCAA supplementation has beneficial effects in people with advanced liver cirrhosis and that understanding these effects will require further research.

Another study from also found that BCCA supplementation improved low muscle strength among people with liver cirrhosis. BCAAs are essential amino acids, which means that the body cannot make them. However, a wide variety of foods contain BCAAs, and most people can get enough by eating a protein-rich diet.

Also, many health and fitness stores sell BCAA supplements, and a person can purchase them online. There is no officially recommended BCAA dosage. Depending on the desired benefit, studies have used different dosages of these supplements.

However, anyone who experiences serious side effects should stop taking the supplement and consult their doctor. BCAAs are essential amino acids. The body cannot make them, so a person needs to get BCAAs from their diet or as supplements. Research suggests that taking BCAA supplements may improve muscle mass and performance and may reduce muscle damage from exercise.

BCAAs may also benefit people with liver disease. However, some research links increased BCAA levels to conditions such as diabetes , cancer, liver disease, and heart disease. People can use protein powder to supplement their protein intake, help build muscle, aid muscle recovery, and encourage healthy weight loss.

In this…. What is whey protein? Can it help a person to build muscle, lower cholesterol, or burn fat? Researchers continue to discover potentially therapeutic…. There is evidence that some beneficial muscle-building supplements include protein, creatine, and caffeine.

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Medical News Today. Health Conditions Health Products Discover Tools Connect. Health benefits of BCAAs. Medically reviewed by Alan Carter, Pharm.

Exercise performance Lean muscle mass During illness Muscle damage Sprint performance Liver disease Sources Dosage Side effects and risks Summary Supplements containing branched-chain amino acids BCAAs are popular for boosting muscle growth and performance.

Exercise performance. Share on Pinterest BCAA supplements may help improve exercise performance. Lean muscle mass. Muscle mass during illness.

Health benefits of BCAAs

This information is crucial for designing personalized strategies for managing and preventing metabolic diseases, optimizing health through approaches tailored to individual needs. This comprehensive insight is crucial for both the prevention and management of metabolic diseases. Metabolomics in prediabetes and diabetes: a systematic review and meta-analysis.

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Figure: Pooled estimates of type 2 diabetes risk associated per study-specific SD difference in each amino acid from prospective studies. Overall estimates obtained from forest plots and random-effects meta-analysis of studies evaluating BCAAs and other amino acids and incidence of type 2 diabetes [1].

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Metabolism of BCAAs

Fasting animals can reduce the size of the effect of dietary BCAAs on circulating plasma BCAA levels but is not likely to abrogate it completely. There is also some mixed evidence that over time, the effect of dietary BCAAs on circulating levels may become less extreme.

This suggests that circulating levels do not simply reflect diet, but that dietary BCAAs have a systemic physiological effect on amino-acid metabolism. To evaluate how dietary and circulating BCAAs influenced glucose homeostasis, we gathered data on the area under the curve AUC in a glucose tolerance test Glucose AUC; 57 diets from 10 articles , plasma levels of glucose diets from 32 articles and insulin diets from 30 articles and HOMA 55 diets from 10 articles; Fig.

Meta-analysis of all pairwise diets within an experiment detected a significant positive effect for glucose AUC, but not any other traits related to glucose homeostasis Table 1 , Fig. A Orchard plots showing mean effects of increased dietary BCAAs on indicators of glucose metabolism.

B Surface showing meta-regression estimate of lnRR for glucose AUC as a function of the difference in dietary BCAA and non-BCAA levels between experimental and control diets. C , D Bubble plots for lnRR of plasma insulin and HOMA as a function nutritional moderators. All fitted values come from the AIC-favoured model see Additional File 1 : Table S5 for coefficients.

E Orchard plots showing effects for each outcome stratified by whether animals were fasted or fed prior to sampling the significance of between group contrasts are given in Additional File 1 : Table S3.

For glucose AUC, a model fitting an interaction between differences in dietary levels of BCAAs and non-BCAAs had the best fit based on AIC Additional File 1 : Table S2. Using response surfaces in the GFN to plot predicted effect sizes, we saw that increasing BCAAs and non-BCAAs simultaneously i.

increasing protein content , resulted in the largest effects of dietary BCAAs on glucose AUC Fig. The effects of dietary BCAAs on plasma insulin levels were best predicted by the protein to carbohydrate ratio of the diet, in a U-shaped manner; at both low and high protein to carbohydrate ratios, increasing dietary BCAAs increased plasma insulin levels Fig.

Similarly, dietary protein was estimated to have a U-shaped moderating effect of BCAAs on HOMA Fig. Dietary BCAAs positively influenced HOMA when diets were both low and high in dietary protein. For plasma glucose levels, no nutritional moderator had lower AIC than the null meta-analysis.

Neither fasting status, model species nor duration of the study was a significant moderator of effect size for any glucose metabolism outcomes Fig. Trim and fill analysis applied to the effect sizes for these traits estimated 73 and 57 missing studies for plasma insulin and HOMA respectively, and inclusion of such missing studies is estimated to reduce estimated lnRR slightly.

It is notable that overall meta-analytic means for plasma insulin and HOMA traits are already non-significant, although the respective model estimates shown in Fig.

These results suggest that any effects of increasing BCAAs are dependent on the dietary background upon which the change occurs. While slightly different moderators of effect were favoured for the different traits, a recurring theme is dietary protein.

Given evidence that BCAAs influence food intake and body composition [ 10 ], we gathered data on body mass from groups of rodents on different diets 88 articles and percent fat mass from 58 dietary groups 12 articles.

We also had estimates of food and energy intake from groups 66 articles. There was no overall significant effect size for body mass or percent body fat Fig. However, overall effect sizes for food and energy intake were negative and statistically significant suggesting that, on average, intake is lower on high BCAA diets Table 1 ; Fig.

A Orchard plots showing mean effects of increased dietary BCAAs on indicators of body composition and food intake. B , D , E Bubble plots for lnRR of body mass, food and energy intake as a function of nutritional moderators. C Surface showing meta-regression estimate of lnRR for percentage fat mass as a function of the difference in the ratio of dietary BCAA:non-BCAA between experimental and control diets and the protein to carbohydrate ratio of the control diet.

Where shown, individual effect sizes are scaled by their precision. For the effects of increased BCAAs on body mass, the amount of BCAAs in the reference diet was the moderator favoured by AIC Additional File 1 : Table S2.

Where diets were low in BCAAs, increasing BCAAs resulted in increased body weight. However, for diets already high in BCAAs, further increases in BCAAs did not affect body mass Fig. The AIC-favoured model for percentage fat mass included the magnitude of the increase in BCAAs between diets and the protein to carbohydrate ratio of the reference diet.

On a low protein, high carbohydrate diet, relatively large increases of BCAAs had little effect on fat mass, whereas on high protein to carbohydrate diets, small increases in BCAAs were predicted to result in greater adiposity Fig. Finally, the change in ratio of BCAAs to non-BCAAs was the best nutritional predictor of the effect of dietary BCAAs on both food and energy intake.

Where the experimental diet had a lower ratio of BCAAs to non-BCAAs than the control diet, BCAAs resulted in elevated intake Fig. Body weight was moderated by species, whereby effects sizes were slightly larger for rats than mice Additional File 1 : Table S3.

The duration of exposure did not moderate the effect of dietary BCAAs on the intake or body composition Additional File 1 : Table S3. Together, these findings suggest that the effects of dietary BCAAs on body mass, composition and food intake are complex.

Any effects are dependent on the dietary context in which BCAAs are elevated and any concomitant changes in other amino acids. Here, we use multidimensional nutritional modelling, together with established techniques in meta-analysis and meta-regression, to disentangle the complex relationship between diet, BCAAs and metabolic health.

The first issue we addressed was the relationship between dietary BCAAs and blood levels of BCAAs. Overall, there was a positive association between dietary and blood levels of BCAAs in both the fasting and fed state, supporting the notion that circulating BCAA levels are likely to reflect long-term protein intake [ 1 , 7 , 10 , 17 ].

The relationship, however, is more nuanced. In animals restricted to diets containing different amounts of BCAAs, there was a curvilinear relationship between dietary content of BCAAs and the blood levels of BCAAs, a finding consistent with our previous experimental work.

When the dietary background level of BCAAs was lower than standard mouse chow 0. At higher levels dietary BCAA, however, adding more to the diet had little effect. This relationship reflects the network of mechanisms that influence BCAA levels. Blood levels of BCAAs are primarily regulated by BCKDH, a mitochondrial enzyme complex found in the liver and muscle that catabolizes the ketoacid metabolites of BCAAs.

Because insulin and BCAAs both activate BCKDH which acts to reduce BCAA levels [ 17 ], the mechanism for the plateau in BCAA blood levels when dietary content is high may be explained by a compensatory increase in BCKDH activation.

Another mechanism by which an animal can regulate blood levels of BCAAs is by altering dietary intake. As essential amino acids, BCAAs are primarily acquired through dietary sources. In our meta-analysis, animals only had access to a single diet; therefore, the only option for increasing or decreasing BCAA intake is by changing feeding behaviour to consume more, or less food.

Evidence for this response was apparent in the analysis of the relationship between food intake and dietary BCAAs.

However, the effect of BCAAs food intake that we observe is small, even in these experimental animals where dietary BCAA levels are often dramatically manipulated e.

The impact of BCAAs on food intake is, however, complex. While the general trend showed that BCAAs reduced food intake of animals on diets with high BCAA, low non-BCAA ratios, it is important to note that many studies did not experimentally control for protein content when manipulating BCAA levels.

It remains uncertain whether this reduction in food intake is attributable to the satiating effect of increasing total dietary protein. While high amounts of dietary protein can suppress food intake and protein intake is prioritized over intake of fat and carbohydrates [ 23 ], the role of individual amino acids and their mixtures on protein appetite and food intake is complex and not yet fully understood.

We found an effect of dietary BCAAs on food intake consistent with animals having the capacity to regulate food intake according to BCAA content; however, the effect is small and is likely confounded by the overall total protein content and balance of amino acids.

Imbalance of amino acids is also known to influence feeding behaviour, with the effect of suppressing or increasing food intake dependent on the nature of the manipulation. For example, diets extremely deficient or devoid in one or more essential amino acids result in food aversion [ 24 ].

However, when the deficiency is small enough to be leveraged by compensatory feeding, hyperphagia is observed [ 25 ]. When compared to control groups, reducing dietary levels of single amino acids such as methionine, threonine or isoleucine [ 2 , 26 , 27 ] or groups of amino acids such as essential amino acids or the BCAAs [ 4 , 5 , 27 ] sufficiently increases food intake.

In addition to dietary availability, the interaction between amino acids in circulation can regulate food intake by influencing whether the amino acid precursors necessary for neurotransmitter production are transported across the blood-brain barrier in sufficient quantities.

A recent example showed that a diet high in BCAAs but low in tryptophan reduces uptake of tryptophan into the brain by competing for transport across the blood-brain barrier by the LAT1 amino acid transporter [ 10 ]. As tryptophan is the sole precursor for serotonin synthesis, a neurotransmitter involved in the control of food intake [ 28 ], reduced levels in the brain led to lower brain serotonin levels, greatly increased food intake, obesity and shortened lifespan.

All these effects occurred without activation of canonical ageing pathways such as MTOR and IGF1 [ 10 ]. While this increase in food intake on high BCAA diets appear at odds with the findings of this meta-analysis, this effect may be explained by the interaction between dietary BCAAs and the total protein content of the diet.

Many studies that supplement dietary BCAAs also increase the total protein content of the diet, an effect which will have important implications for promoting satiety. Solon-Biet et al , however, use a unique design where BCAAs levels were doubled compared to the control group, while keeping total protein content constant.

In experiments where this is not controlled, the effect of total dietary protein is likely to dominate any effect on appetite of dietary BCAAs. What are the implications for human studies of the finding of this meta-analysis and the curvilinear relationship between dietary BCAAs and blood levels of BCAAs?

First, it must be emphasized that these animal studies involved restriction to a single diet. Humans, on the other hand, have access to multiple foods with different contents of BCAAs, and other components such as tryptophan which can interact with BCAA to influence appetite.

Second, unlike human studies, animal studies are undertaken with homogeneous genotypes and environments. Humans often have conditions and diseases unrelated to BCAA intake, but which may influence BCAA levels via their impact on various anabolic insulin, IGF-1, GH and catabolic TNFα, cortisol, catecholamines, glucagon, inflammatory cytokines factors that influence BCKDH activity.

Even so, we predict that the curvilinear relationship between dietary BCAA and BCAA blood levels seen in animals will be apparent in human populations because it is a consequence of regulatory networks shared with humans. While a positive correlation might be statistically significant over an entire range of blood levels and intakes, this may misrepresent the underlying curvilinear nature of the relationship.

It must be noted, however, that BCAA levels are tightly regulated in the fasting period, so it is not simply a case of more dietary BCAAs entering the blood and increasing BCAA levels.

If an association was found between dietary BCAAs and blood levels when the dietary BCAAs are high , this may be explained by an indirect or confounding association that impacts on the regulatory network—in particular, BCKDH.

For example, people with obesity may consume a diet with higher amounts of BCAAs but also have insulin resistance which impairs BCAA catabolism [ 19 ]. Here, we studied the relationship between blood levels of BCAAs and dietary BCAAs, but not total dietary protein.

A weak association between dietary protein and blood levels of BCAAs has been reported in humans, and stronger associations in animal studies where protein intake and content can be strictly controlled [ 7 , 29 ]. Although BCAAs are only found in dietary protein, the amount of BCAAs varies substantially depending on the source and type of protein, which makes evaluating any association more uncertain.

The second question we addressed with this meta-analysis was whether there are effects of dietary BCAAs on glucose metabolism, and if so, are these moderated by nutrient background? There were four metabolic outcomes assessed insulin, glucose, glucose AUC and HOMA. Only glucose AUC had a significant overall association with dietary BCAAs, but not any other traits related to glucose homeostasis.

Although ascertaining the direction of causality in epidemiological studies is difficult, the most widely accepted conclusion is that elevated BCAAs are a consequence of insulin-resistant states—rather than elevated BCAAs contributing directly to insulin and glucose dysmetabolism, although there is evidence supporting both hypotheses [ 19 ].

The results of our meta-analysis are consistent with that interpretation. That is, we found in otherwise healthy animals i. Model fitting, however, showed that these results are more nuanced and can be influenced by background nutrition.

For glucose AUC, we found that the largest effects of dietary BCAAs occurred when there was a simultaneous increase in non-BCAA content i. increasing protein content , a finding consistent with studies in humans where it has been shown that people not-subject to protein restriction have higher fasting blood glucose [ 5 ].

Although these results are complicated, the unifying theme is that when increased dietary BCAAs reflect increasing dietary protein, there is an increased association with glucose dysmetabolism. An association between excess dietary protein, particularly from animal sources, and cardiometabolic disorders has been widely reported [ 22 , 30 ].

Thus, any association between BCAA and metabolic disease is more likely to be a result of BCAA being a biomarker for the amount and type of dietary protein, rather than being an independent risk factor. On the first question, it seems unlikely that all outcomes respond similarly quickly to dietary BCAAs, yet our analyses detected few moderating effects of study duration.

However, it is important to point out that our search and analysis did not explicitly target longitudinal experiments on the effects of dietary BCAAs. Regarding reversibility, this question requires examination of the responses to a diet switching experiments, which was also beyond the scope of the current synthesis.

Nonetheless, some such studies have been performed. For example, Cummings et al. However, Hahn et al. The GFN-based meta-regression approach that we present allows the user to identify the key nutritional dimensions of major effect, and thus may help to unify the results of different diet-switch experiments.

Finally, we addressed the issue of body composition and BCAAs. Overall, dietary BCAAs were not associated with body mass or body fat in this meta-analysis. However, there were associations when the underlying diet was considered.

Increased BCAAs were associated with increased bodyweight when the background diet was low in BCAAs. This is likely a result of the relationship we found with food intake, where BCAAs were associated with increased food intake when the background diet was low in BCAAs, reflecting behavioural mechanisms of animals to reach intake targets of limiting nutrients [ 20 ].

It is important to note, however, that the balance of amino acids in the diet, in addition to macronutrient background, may exert different effects on food intake. For example, reducing levels of other specific amino acids such as tryptophan, while simultaneously increasing BCAAs may impair central appetite signalling mechanisms and promote hyperphagia [ 10 ].

Our meta-analysis also found that increased dietary BCAAs were associated with elevated body fat when the diet was high in protein and low in carbohydrates.

This is consistent with amino acid biochemistry whereby excess amino acids above those required for protein synthesis can either be utilized via gluconeogenesis or ketogenesis for energy production or indirectly via acetyl coA converted to fat and glycogen [ 1 , 14 ].

This meta-analysis found that there was a curvilinear relationship between dietary BCAAs and blood levels of BCAAs, a finding consistent in both the fasting and fed state.

It is important to note that these studies were undertaken in animal on restricted diets, and therefore, we must be cautious about extrapolating this finding to human data. We predict, however, that given shared regulatory mechanisms with humans, the curvilinear relationship between dietary BCAA and blood levels will be apparent in human populations.

We also found that the relationship between dietary BCAAs and phenotypic outcomes glucose and insulin, body composition and food intake is complex and dependent on the underlying diet.

This is an important finding for any study of dietary components and phenotypic outcomes because it emphasizes that diet is a complex mixture whereby each nutrient cannot be considered in isolation. The methodology of this systematic review was pre-specified in a protocol and followed the guidelines of the Systematic Review Centre for Laboratory Animal [SYRCLE [ 32 ];].

A literature search was conducted in the databases Web of Science, Scopus, EMBASE and MEDLINE, as well as the specific journal Nature Metabolism, which was not indexed by those databases at the time.

Keywords and search criteria were formulated, and are reported, using the guidelines in the PRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement.

Screening of studies consisted of two phases. The first phase was based on title and abstract screening, and the second phase was based on a full-text screening. To be accepted for analysis the studies had to meet all of following inclusion criteria:.

An experimental mouse or rat study. Studies in which a dietary treatment involving an altered amount of BCAAs compared to a control group was administered. The study must report one or more of the outcome measures that quantifies circulating BCAA levels or cardio-metabolic health, as given in Table 1.

The study must report the mean, sample size and preferably a measure of variability e. standard deviation SD for the outcome of interest missing SDs were handled via multiple imputation. The study must report the composition of the diet, such that we were able to derive the energy density of the diet, and the percentage energy coming from macronutrients and BCAAs.

Studies were excluded at whichever phase they first were deemed to have violated any criteria, typically, though, assessment of criteria e through i required assessment of the full text phase 2. All data extraction was double checked by a second researcher. Data were extracted from text or tables, and from graphs using the software GraphClick.

When the group sizes were reported as a range, the midpoint was used and rounded up if not a whole number. Where outcome measures are reported as median and range, we estimated the mean and SD following Hozo et al. If data were reported over multiple time points, the longest duration for which concurrent data were available were used.

Leading investigators of studies or commercial providers of diets were contacted in cases where there was missing data. If the data were irretrievable the study was not included those contacted needed to reply within two weeks of request via email.

All analyses were performed in the statistical programming environment R V4. Our effect size of use was the log response ratio lnRR sometimes called the ratio of means ROM and corresponds to the natural logarithm of ratio of the two means. We calculated lnRR such that positive values indicate a greater mean in the dietary group with greater energy coming from BCAAs, and negative values the opposite.

We calculated all pairwise comparisons within an experiment, for example in a study with 3 diet groups, there are 3 unique pairwise comparisons A vs B, A vs C and B vs C , and thus, we calculated 3 lnRRs. Any such covariance was estimated following Lajeunesse [ 37 ], and the associated variance-covariance matrix was accounted for in any analyses [ 38 ].

Where authors had chosen to report their results as separate experiments e. dietary interventional applied to different age classes , we treated them as such, and thus, single publications could contain multiple experiments.

However, if authors split their results due to different diet composition e. on different background levels of protein , we treated these as single experiments, with differences in diet composition used to determine the relative BCAA content of the diets.

Potential moderating effects of other dietary factors were then explored using meta-regression see below. In the event that SDs were missing, we employed multiple imputation [ 40 ]. Imputation was performed on the log scale using the log mean as a predictor, with 20 replicate imputations.

The whole set of analyses were applied to each imputed dataset with results pooled following DB Rubin [ 41 ]. Effect sizes for each health-related outcome were analysed separately. For each outcome, we began by fitting a multi-level meta-analysis MLMA which included the lnRR as the outcome and a variance-covariance matrix for the sampling variance.

A random effect for the experimental unit as there can be several effect sizes from a single experiment from which the effect size came was included in all models. As well as total I 2 , we partitioned I 2 in to that explained by experimental ID following Nakagawa and Santos [ 44 ].

To try and understand the cause of heterogeneity i. variation among reported effects , we used multi-level meta-regression MLMR. To explore how nutritional aspects of experiments influenced the observed effect sizes, we fitted a series of MLMRs with different nutritional moderators, and selected among them based on Akaike information criterion AIC [ 45 ];.

Ranked alongside nutritional MLMRs was the equivalent MLMA, which served as a null model allowing for the possibility that none of the nutritional factors explored moderated the effect size.

Models with the lowest AIC were favoured. In the event that models had AIC scores within 2 points of one another the simplest model i. fewest parameters was selected. We implemented a linear and non-linear variant of each nutritional moderator providing that we had at least 10 effect sizes per parameter in the model.

A complete list of the nutritional moderators explored for each outcome and their interpretation is given in the supplementary materials. Where data allowed, we also tested whether the effect size was predicted by the species mouse or rat and the duration of the dietary exposure duration was log transformed to account for likely non-linear effect of exposure duration.

For measures of circulating plasma BCAA levels and glucose metabolism we evaluated whether being fasted prior to sampling affected the effect size. To visualize overall meta-analysis results, we use orchard plots [ 46 ].

To visualize the results of univariate meta-regressions involving numeric predictors, we use bubble plots. The results of multi-dimensional MLMR were visualized in multi-dimensional nutrient space using the surface-based approach common in the geometric framework for nutrition GFN [ 20 ].

Surfaces were coloured such that blue indicates a negative effect size, red positive and green a zero effect size at that point in the nutrient space. there is a statistically significant effect-size at this point in the nutrient space. Where imputation was used to estimate missing SDs, multiple instances of the publication bias tests were implemented with the results averaged.

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YW helped to design the overall study and analyzed the data. HS, MZ, JW, and KL contributed to the manuscript preparation. This work was supported by Ministry of Science and Technology of China BAI02B05 and YQ , National Natural Science Foundation of China NSFC and , the Laubisch Fund UCLA , the Welch Foundation I , and Science and Technology Commission of Shanghai Municipality 13ZR and 16JC The remaining 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.

BCAA, branched-chain amino acid; BCAT, BCAA transaminase; BCKA, branched-chain keto acid; BCKD, branched-chain-α-ketoacid dehydrogenase; BCKDK, branched-chain-α-ketoacid dehydrogenase kinase; GTT, glucose tolerance test; ITT, insulin tolerance test; PP2Cm, mitochondrial protein phosphatase 2C; PPm1k, protein phosphatase 1K PP2C domain containing ; RER, respiratory exchange ratio; ROS, reactive oxygen species; T2DM, type 2 diabetes mellitus; TCA cycle, tricarboxylic acid cycle.

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Citation: Wang J, Liu Y, Lian K, Shentu X, Fang J, Shao J, Chen M, Wang Y, Zhou M and Sun H BCAA Catabolic Defect Alters Glucose Metabolism in Lean Mice. Received: 07 June ; Accepted: 20 August ; Published: 04 September Copyright © Wang, Liu, Lian, Shentu, Fang, Shao, Chen, Wang, Zhou and Sun.

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BCAA Catabolic Defect Alters Glucose Metabolism in Lean Mice. Introduction In the past several years, insulin resistance and diabetes have been linked with disrupted branched-chain amino acids BCAAs homeostasis in obese animals and humans Lynch and Adams, Indirect Calorimetry Measurements Measurements of oxygen consumption VO 2 and carbon dioxide production VCO 2 with indirect calorimetry were performed at ambient temperature using a Comprehensive Laboratory Animal Monitoring System CLAMS, Columbus Instruments, OH, United States according to the instructions of the manufacturer.

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BCAAs in Metabolic Diseases BCAAz trait is metabllism related to BCAAs and metabolism BCAAe breakdown traitmetabolisk your Insights and Metabolismm more focussed on the impact BCAAs and metabolism BCAAs on building muscle. Readers an encouraged to visit the BCAA breakdown Mashed sweet potatoes BCAAs and Insulin metaboilsm articles for BCAAs and metabolism background snd. BCAAs and metabolism stands for branched chain amino acids. It is the collective name for three particular amino acids the building blocks of proteins :. These amino acids play important roles in building new muscle proteins, providing energy for muscles and control of glucose metabolism. Due to these roles, BCAAs are a popular pre-workout supplement, where they are used to stimulate muscle protein synthesis and boost muscle growth, reduce muscle soreness after a workout, and help to prevent fatigue during exercise. As well as being in various supplements and protein powders, BCAAs are also found in various foods, including: red meat, poultry, eggs, dairy products, nuts, lentils and beans. BCAAs and metabolism

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