Branched-chain amino acids alter neurobehavioral function in rats

Recently, we have described a strong association of branched-chain amino acids (BCAA) and aromatic amino acids (AAA) with obesity and insulin resistance. In the current study, we have investigated the potential impact of BCAA on behavioral functions. We demonstrate that supplementation of either a high-sucrose or a high-fat diet with BCAA induces anxiety-like behavior in rats compared with control groups fed on unsupplemented diets. These behavioral changes are associated with a significant decrease in the concentration of tryptophan (Trp) in brain tissues and a consequent decrease in serotonin but no difference in indices of serotonin synaptic function. The anxiety-like behaviors and decreased levels of Trp in the brain of BCAA-fed rats were reversed by supplementation of Trp in the drinking water but not by administration of fluoxetine, a selective serotonin reuptake inhibitor, suggesting that the behavioral changes are independent of the serotonergic pathway of Trp metabolism. Instead, BCAA supplementation lowers the brain levels of another Trp-derived metabolite, kynurenic acid, and these levels are normalized by Trp supplementation. We conclude that supplementation of high-energy diets with BCAA causes neurobehavioral impairment. Since BCAA are elevated spontaneously in human obesity, our studies suggest a potential mechanism for explaining the strong association of obesity and mood disorders.

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Brain Branched-Chain Amino Acids in Maple Syrup Urine Disease: Implications for Neurological Disorders

International Journal of Molecular Sciences ◽

10.3390/ijms21207490 ◽

2020 ◽

Vol 21 (20) ◽

pp. 7490

Author(s):

Jing Xu ◽

Youseff Jakher ◽

Rebecca C. Ahrens-Nicklas

Keyword(s):

Amino Acids ◽

Maple Syrup Urine Disease ◽

Attention Deficit Disorder ◽

Neurological Disorders ◽

Survival Rates ◽

Branched Chain Amino Acids ◽

Maple Syrup ◽

Urine Disease ◽

Branched Chain ◽

The Brain

Maple syrup urine disease (MSUD) is an autosomal recessive disorder caused by decreased activity of the branched-chain α-ketoacid dehydrogenase complex (BCKDC), which catalyzes the irreversible catabolism of branched-chain amino acids (BCAAs). Current management of this BCAA dyshomeostasis consists of dietary restriction of BCAAs and liver transplantation, which aims to partially restore functional BCKDC activity in the periphery. These treatments improve the circulating levels of BCAAs and significantly increase survival rates in MSUD patients. However, significant cognitive and psychiatric morbidities remain. Specifically, patients are at a higher lifetime risk for cognitive impairments, mood and anxiety disorders (depression, anxiety, and panic disorder), and attention deficit disorder. Recent literature suggests that the neurological sequelae may be due to the brain-specific roles of BCAAs. This review will focus on the derangements of BCAAs observed in the brain of MSUD patients and will explore the potential mechanisms driving neurologic dysfunction. Finally, we will discuss recent evidence that implicates the relevance of BCAA metabolism in other neurological disorders. An understanding of the role of BCAAs in the central nervous system may facilitate future identification of novel therapeutic approaches in MSUD and a broad range of neurological disorders.

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BCAA intake affects protein metabolism in muscle after but not during exercise in humans

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.2001.281.2.e365 ◽

2001 ◽

Vol 281 (2) ◽

pp. E365-E374 ◽

Cited By ~ 48

Author(s):

Eva Blomstrand ◽

Bengt Saltin

Keyword(s):

Amino Acids ◽

Recovery Period ◽

Aromatic Amino Acids ◽

Branched Chain Amino Acids ◽

Cycle Exercise ◽

Placebo Condition ◽

Muscle Concentration ◽

Branched Chain ◽

Sparing Effect ◽

Exercise In Humans

Branched-chain amino acids (BCAA) or a placebo was given to seven subjects during 1 h of ergometer cycle exercise and a 2-h recovery period. Intake of BCAA did not influence the rate of exchange of the aromatic amino acids, tyrosine and phenylalanine, in the legs during exercise or the increase in their concentration in muscle. The increase was ∼30% in both conditions. On the other hand, in the recovery period after exercise, a faster decrease in the muscle concentration of aromatic amino acids was found in the BCAA experiment (46% compared with 25% in the placebo condition). There was also a tendency to a smaller release (an average of 32%) of these amino acids from the legs during the 2-h recovery. The results suggest that BCAA have a protein-sparing effect during the recovery after exercise, either that protein synthesis has been stimulated and/or protein degradation has decreased, but the data during exercise are too variable to make any conclusions about the effects during exercise. The effect in the recovery period does not seem to be mediated by insulin.

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Hyperammonaemia does not impair brain function in the absence of net glutamine synthesis

Biochemical Journal ◽

10.1042/bj2770697 ◽

1991 ◽

Vol 277 (3) ◽

pp. 697-703 ◽

Cited By ~ 67

Author(s):

R A Hawkins ◽

J Jessy

Keyword(s):

Amino Acids ◽

Brain Function ◽

Aromatic Amino Acids ◽

Preceding Paper ◽

Glucose Consumption ◽

High Energy ◽

High Energy Phosphates ◽

Intermediary Metabolites ◽

Glutamine Synthesis ◽

The Brain

1. It has been established that chronic hyperammonaemia, whether caused by portacaval shunting or other means, leads to a variety of metabolic changes, including a depression in the cerebral metabolic rate of glucose (CMRGlc) increased permeability of the blood-brain barrier to neutral amino acids, and an increase in the brain content of aromatic amino acids. The preceding paper [Jessy, DeJoseph & Hawkins (1991) Biochem. J. 277, 693-696] showed that the depression in CMRGlc caused by hyperammonaemia correlated more closely with glutamine, a metabolite of ammonia, than with ammonia itself. This suggested that ammonia (NH3 and NH4+) was without effect. The present experiments address the question whether ammonia, in the absence of net glutamine synthesis, induces any of the metabolic symptoms of cerebral dysfunction associated with hyperammonaemia. 2. Small doses of methionine sulphoximine, an inhibitor of glutamine synthetase, were used to raise the plasma ammonia levels of normal rats without increasing the brain glutamine content. These hyperammonaemic rats, with plasma and brain ammonia levels equivalent to those known to depress brain function, behaved normally over 48 h. There was no depression of cerebral energy metabolism (i.e. the rate of glucose consumption). Contents of key intermediary metabolites and high-energy phosphates were normal. Neutral amino acid transport (tryptophan and leucine) and the brain contents of aromatic amino acids were unchanged. 3. The data suggest that ammonia is without effect at concentrations less than 1 mumol/ml if it is not converted into glutamine. The deleterious effect of chronic hyperammonaemia seems to begin with the synthesis of glutamine.

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Plasma Branched-Chain and Aromatic Amino Acids in Relation to Hypertension

Nutrients ◽

10.3390/nu12123791 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3791

Author(s):

M. H. Mahbub ◽

Natsu Yamaguchi ◽

Ryosuke Hase ◽

Hidekazu Takahashi ◽

Yasutaka Ishimaru ◽

...

Keyword(s):

Amino Acids ◽

Aromatic Amino Acids ◽

Positive Association ◽

Branched Chain Amino Acids ◽

Healthy Controls ◽

Regression Analyses ◽

Current Analysis ◽

Hypertensive Patients ◽

Confounding Variables ◽

Branched Chain

Findings of the available studies regarding the roles of branched-chain amino acids (BCAAs) and aromatic amino acids (AAAs) in hypertension are inconsistent, conflicting and inconclusive. The purpose of this study was to explore and clarify the existence of any relationships of individual BCAAs and AAAs with hypertension with adjustments for potential relevant confounders. A total of 2805 healthy controls and 2736 hypertensive patients were included in the current analysis. The associations between individual amino acids and hypertension were explored by logistic regression analyses adjusted for potential confounding variables. Among the investigated amino acids, only the BCAAs showed consistently significant positive associations with hypertension in the adjusted models (p-trend < 0.05 to 0.001). However, compared with the corresponding lowest quartile of individual BCAAs, the positive association with hypertension remained significant only in the highest quartile (p < 0.01 to 0.001). We confirmed in a relatively large cohort of subjects that BCAAs, not AAAs, demonstrated consistent positive associations with hypertension. The results display the promising potential for the use of BCAAs as relevant and accessible biomarkers, and provide perspectives on interventions directed towards the reduction in plasma BCAA levels in the prevention and management of hypertension.

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Effects of branched chain amino acids and ketoanalogues on brain branched chain and aromatic amino acids in experimental liver disease

Amino Acids ◽

10.1007/978-94-011-2262-7_105 ◽

1990 ◽

pp. 861-866

Author(s):

Santiago Munoz ◽

Marshall Stafford ◽

Sharon Westerberg ◽

Mackenzie Walser ◽

Willis Maddrey

Keyword(s):

Amino Acids ◽

Liver Disease ◽

Aromatic Amino Acids ◽

Branched Chain Amino Acids ◽

Branched Chain ◽

Experimental Liver

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Changes in plasma concentration of kynurenine following intake of branched-chain amino acids are not caused by alterations in muscle kynurenine metabolism

AJP Cell Physiology ◽

10.1152/ajpcell.00285.2021 ◽

2021 ◽

Author(s):

William O Jonsson ◽

Jonathan Ponette ◽

Oscar Horwath ◽

Tomas Rydenstam ◽

Karin Söderlund ◽

...

Keyword(s):

Amino Acids ◽

Plasma Concentration ◽

Kynurenic Acid ◽

Aromatic Amino Acids ◽

Random Order ◽

Fold Increase ◽

Branched Chain Amino Acids ◽

Kynurenine Metabolism ◽

Branched Chain ◽

Exercise Induced

Administration of branched-chain amino acids (BCAA) has been suggested to enhance mitochondrial biogenesis, including levels of PGC-1α, which may, in turn, alter kynurenine metabolism. Ten healthy subjects performed 60 min of dynamic one-leg exercise at ~70% of Wmax on two occasions. They were in random order supplied either a mixture of BCAA or flavored water (placebo) during the experiment. Blood samples were collected during exercise and recovery, and muscle biopsies were taken from both legs before, after and 90 and 180 min following exercise. Ingestion of BCAA doubled their concentration in both plasma and muscle while causing a 30-40% reduction (P<0.05 vs. placebo) in levels of aromatic amino acids in both resting and exercising muscle during 3-h recovery. The muscle concentration of kynurenine decreased by 25% (P<0.05) during recovery, similar in both resting and exercising leg and with both supplements, although plasma concentration of kynurenine during recovery was 10% lower (P<0.05) when BCAA were ingested. Ingestion of BCAA reduced the plasma concentration of kynurenic acid by 60% (P<0.01) during exercise and recovery, while the level remained unchanged with placebo. Exercise induced a 3-4-fold increase (P<0.05) in muscle content of PGC-1a1 mRNA after 90 min of recovery under both conditions, whereas levels of KAT4 mRNA and protein were unaffected by exercise or supplement. In conclusion, the reduction of plasma levels of kynurenine and kynurenic acid caused by BCAA were not associated with any changes in the level of muscle kynurenine, suggesting that kynurenine metabolism was altered in tissues other than muscle.

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The role of branched-chain amino acids and aromatic amino acids of various tissues and the degenerations of skeletal muscle fiber in liver cirrhosis model rat

Gastroenterology ◽

10.1016/s0016-5085(00)85232-4 ◽

2000 ◽

Vol 118 (4) ◽

pp. A773

Author(s):

Yasushi Matsuzaki ◽

Teruo Miyazaki ◽

Masaaki Karube ◽

Norio Ogoshi ◽

Syunpei Miyakawa ◽

...

Keyword(s):

Skeletal Muscle ◽

Amino Acids ◽

Liver Cirrhosis ◽

Muscle Fiber ◽

Aromatic Amino Acids ◽

Branched Chain Amino Acids ◽

Skeletal Muscle Fiber ◽

Branched Chain

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A Comparison of the Effects of Intravenous Infusion of Individual Branched-Chain Amino Acids on Blood Amino Acid Levels in Man

Clinical Science ◽

10.1042/cs0600095 ◽

1981 ◽

Vol 60 (1) ◽

pp. 95-100 ◽

Cited By ~ 51

Author(s):

S. Eriksson ◽

L. Hagenfeldt ◽

J. Wahren

Keyword(s):

Amino Acids ◽

Amino Acid ◽

Intravenous Infusion ◽

Serum Insulin ◽

Aromatic Amino Acids ◽

Branched Chain Amino Acids ◽

Blood Concentrations ◽

Branched Chain Amino Acid ◽

Amino Acid Levels ◽

Branched Chain

1., Intravenous infusions of l-valine (600 μmol/min), l-isoleucine (150 μmol/min), l-leucine (300 μmol/min) and a mixture of the three branched-chain amino acids (70% l-leucine, 20% l-valine, 10% l-isoleucine; 270 μmol/min) were given to four groups of healthy volunteer subjects. Whole-blood concentrations of amino acids and glucose and serum insulin were measured before and during the infusions. 2. Valine and isoleucine infusions resulted in twelve- and six-fold increases in the respective amino acid. During valine infusion, tyrosine was the only amino acid for which a decrease in concentration was seen (25%, P < 0.05). With isoleucine administration, no significant changes were found. In contrast, leucine infusion (during which the leucine concentration rose about sixfold) was accompanied by significant decreases in tyrosine (35%), phenylalanine (35%), methionine (50%), valine (40%) and isoleucine (55%). The arterial glucose concentration fell slightly (5%) and the insulin concentration increased 20% during leucine infusion. 3. Infusion of the mixture of the three branched-chain amino acids resulted in marked decreases in tyrosine (50%), phenylalanine (50%) and methionine (35%). The decreased amino acid levels remained low for 2 h after the end of the infusion. 4. The present findings demonstrate that intravenous infusion of leucine (not infusion of valine or isoleucine) results in marked reductions in the concentrations of the aromatic amino acids and methionine. Infusion of a mixture of the three branched-chain amino acids gives results similar to those obtained with leucine infusion alone. Thus a mixed branched-chain amino acid solution with leucine as its main constituent seems to be the best alternative in the treatment of patients with hepatic cirrhosis and encephalopathy.

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