Emerging Perspectives on Essential Amino Acid Metabolism in Obesity and the Insulin-Resistant State

Branched-chain amino acids (BCAAs) are essential amino acids that can be oxidized in skeletal muscle. It is known that BCAA oxidation is promoted by exercise. The mechanism responsible for this phenomenon is attributed to activation of the branched-chain alpha-keto acid dehydrogenase (BCKDH) complex, which catalyzes the second-step reaction of the BCAA catabolic pathway and is the rate-limiting enzyme in the pathway. This enzyme complex is regulated by a phosphorylation-dephosphorylation cycle. The BCKDH kinase is responsible for inactivation of the complex by phosphorylation, and the activity of the kinase is inversely correlated with the activity state of the BCKDH complex, which suggests that the kinase is the primary regulator of the complex. We found recently that administration of ligands for peroxisome proliferator-activated receptor-alpha (PPARalpha) in rats caused activation of the hepatic BCKDH complex in association with a decrease in the kinase activity, which suggests that promotion of fatty acid oxidation upregulates the BCAA catabolism. Long-chain fatty acids are ligands for PPARalpha, and the fatty acid oxidation is promoted by several physiological conditions including exercise. These findings suggest that fatty acids may be one of the regulators of BCAA catabolism and that the BCAA requirement is increased by exercise. Furthermore, BCAA supplementation before and after exercise has beneficial effects for decreasing exercise-induced muscle damage and promoting muscle-protein synthesis; this suggests the possibility that BCAAs are a useful supplement in relation to exercise and sports.

Exercise promotes BCAA catabolism: effects of BCAA supplementation on skeletal muscle during exercise

Leucine kinetic and nitrogen balance (NBAL) methods were used to determine the dietary protein requirements of strength athletes (SA) compared with sedentary subjects (S). Individual subjects were ...

Evaluation of protein requirements for trained strength athletes

Acute administration of leucine and norleucine activates the mammalian target of rapamycin (mTOR) cell-signaling pathway and increases rates of protein synthesis in a number of tissues in fasted rats. Although persistent stimulation of mTOR signaling is thought to increase protein synthetic capacity, little information is available concerning the effects of chronic administration of these agonists on protein synthesis, mTOR signal transduction, or leucine metabolism. Hence, we developed a model of chronic leucine/norleucine supplementation via drinking water and examined the effects of chronic (12 days) supplementation on protein synthesis in adipose tissue, kidney, heart, liver, and skeletal muscle from ad libitum-fed rats. The relative concentration of proteins involved in mTOR signaling and the two initial steps in leucine oxidation were also examined. Leucine or norleucine supplementation was accompanied by increased rates of protein synthesis in adipose tissue, liver, and skeletal muscle, but not in heart or kidney. Supplementation was not associated with increases in the anabolic hormones insulin or insulin-like growth factor I. Chronic supplementation did not cause apparent adaptation in either components of the mTOR cell-signaling pathway that respond to leucine (mTOR, ribosomal protein S6 kinase, and eukaryotic initiation factor 4E-binding protein-1) or the first two steps in leucine metabolism (the mitochondrial isoform of branched-chain amino acid transaminase, branched-chain keto acid dehydrogenase, and branched-chain keto acid dehydrogenase kinase), which may be involved in terminating the signal from leucine. These results suggest that provision of leucine or norleucine supplementation via the drinking water results in stimulation of postprandial protein synthesis in adipose tissue, skeletal muscle, and liver without notable adaptive changes in signaling proteins or metabolic enzymes.

https://www.physiology.org/doi/pdf/10.1152/ajpendo.00085.2002

Tissue-specific effects of chronic dietary leucine and norleucine supplementation on protein synthesis in rats.

Amino acid availability rapidly regulates protein synthesis and degradation. Increasing amino acid concentrations above the levels found in post-absorptive plasma stimulates protein synthesis in a dose-dependent manner at the level of mRNA translation-initiation and inhibits protein degradation by inhibiting lysosomal autophagy. The anabolic effects of insulin on protein synthesis and protein degradation are exerted at the same sites (i.e., peptide chain initiation and lysosomal stabilization) allowing for a rapid synergistic response when both amino acids and insulin increase after a protein-containing meal. In perfused liver preparations, protein anabolic effects are exerted by a group of amino acids acting in concert. The BCAA are among the amino acids required for stimulation of hepatic protein synthesis, but there is no evidence that BCAA or leucine alone are effective. Leucine alone is an important inhibitor of hepatic protein degradation, but maximal inhibition requires in addition several other regulatory amino acids. In heart and skeletal muscle in vitro, increasing the concentration of the three BCAA or of leucine alone reproduces the effects of increasing the supply of all amino acids in stimulating protein synthesis and inhibiting protein degradation. Skeletal muscle is the largest repository of metabolically active protein and a major contributor to total body nitrogen balance. Supplying energy alone (i.e., carbohydrate and lipids) cannot prevent negative nitrogen balance (net protein catabolism) in animals or humans; only provision of amino acids allows the attainment of nitrogen balance. In rats and in humans nourished parenterally, provision of balanced amino acid solutions or of only the three BCAA cause similar improvements in nitrogen balance for several days. There is some evidence that infusions of leucine alone can stimulate muscle protein synthesis in vivo; the effect may be transitory and was not observed by all investigators; provisions of excess leucine alone does not seem to affect total body or muscle protein degradation in vivo. In postabsorptive rats, in vivo, infusion of the three BCAA together stimulates muscle protein synthesis as much as the infusion of a complete amino acid mixture or of a mixture of essential amino acids; the in vivo effect requires coinfusion of glucose or of small (physiological) doses of insulin, suggesting synergism between insulin and amino acids.(ABSTRACT TRUNCATED AT 400 WORDS)

Effects of branched‐chain amino acids on protein turnover

As part of an effort to explain the leucine-induced depressions of plasma isoleucine and valine concentrations, and the concomitant stimulation of valine oxidation in vivo, branched-chain a-keto acid dehydrogenase (BCKAD) activ ity was measured in livers from rats that were fed for only 6 h/d large quantities of individual amino acids in a low protein diet. Preincubation of homogenates with buffer containing Mg2' and Ca2*allowed estimation of fully active complex. Cytosolic and mitochondrial branched-chain-amino-acid aminotransferase (BCAAT)activities were also measured in livers of rats fed an excessof leucine. The percentage of BCKAD in the active form in livers of rats fed the low protein diet containing an excess of leu- cine, isoleucine, valine or phenylalanine for 2 d was double that of rats fed the low protein control diet (control, leucine, isoleucine, valine and phenylalanine groups having, respectively, 45 Â±2, 85 Â±7, 85 Â± 3, 95 Â±5, and 81 Â±4% of hepatic BCKAD in the active form). Consumption of a low protein diet containing an excess of leucine had no significant effect on either cytosolic or mitochondrial BCAATactivi ties of liver. The response of BCKAD in liver can contribute to the leucine-induced stimulation of valine oxidation in vivo but analysis of the results of this study leads to the conclusion that other mechanisms, probably in nonhepatic tissues, must also be involved. J. Nutr. 115: 1550-1561, 1985. INDEXING KEYWORDS branched-chain amino acid antagonism â€¢ branched- chain a-keto acid dehydrogenase â€¢ branched-chain-amino-acid aminotransferase â€¢ amino acid toxicity

Brian W. Heywood

Papers

Activation of Liver Branched-Chain α-Keto Acid Dehydrogenase in Rats by Excesses of Dietary Amino Acids