Impaired Skeletal Muscle Branched-Chain Amino Acids Catabolism Contributes to Their Increased Circulating Levels in a Non-Obese Insulin-Resistant Fructose-Fed Rat Model

Abstract

Elevated plasma branched-chain amino acids (BCAA) levels are often observed in obese insulin-resistant (IR) subjects and laboratory animals. A reduced capacity of the adipose tissues (AT) to catabolize BCAA has been proposed as an explanation, but it seems restricted to obesity models of genetically modified or high fat–fed rodents. We aimed to determine if plasma BCAA levels were increased in a model of IR without obesity and to explore the underlying mechanisms. Rats were fed with a standard diet, containing either starch or fructose. BCAA levels, body weight and composition were recorded before and after 5, 12, 30, or 45 days of feeding. Elevated blood BCAA levels were observed in our IR model with unaltered body weight and composition. No changes were observed in the liver or the AT, but instead an impaired capacity of the skeletal muscle to catabolize BCAA was observed, including reduced capacity for transamination and oxidative deamination. Although the elevated blood BCAA levels in the fructose-fed rat seem to be a common feature of the IR phenotype observed in obese subjects and high fat–fed animals, the mechanisms involved in such a metabolic phenomenon are different, likely involving the skeletal muscle BCAA metabolism.

Why Are Branched-Chain Amino Acids Increased in Starvation and Diabetes?

“…Recent studies in obesity and IR have demonstrated downregulation of the expression of BCAA catabolizing enzymes in adipose tissue and suggest their role in the pathogenesis of increased BCAA levels [ 65 , 66 , 67 , 68 ]. However, considering that BCAAT activity in adipose tissue is much lower than in muscles and BCKAD activity is also very low [ 12 , 69 ], decreased BCAA oxidation in adipose tissue could have a minor role in the pathogenesis of increased BCAA levels in starvation and diabetes. The shortcomings of the hypothesis are also increased fat mass in obese people, which compensates for decreased activities of BCAA catabolic enzymes in adipocytes, and succinyl-CoA, the end-product of valine catabolism, which is not ketogenic.…”

“…Results indicate impaired flux of BCKA through BCKAD. Decreased BCAAT activity in muscles, but not in liver and adipose tissue, of rats with IR induced by high fructose diet [ 69 ]. Decreased expression of genes encoding BCAAT and BCKAD in the muscles of patients with T2DM [ 100 ].…”

“…Decreased BCAAT activity in muscles, but not in liver and adipose tissue, of rats with IR induced by high fructose diet [ 69 ].…”

Adverse Outcomes in Obese Cardiac Surgery Patients Correlates With Altered Branched-Chain Amino Acid Catabolism in Adipose Tissue and Heart

“…Tissue specific regulation of BCAA catabolic fate are reported in murine models of IR ( 41 , 54 , 55 ). Reduction in systemic BCKA levels in our obese patient cohort prompted us to investigate BCAA metabolism in the heart.…”

Branched chain amino acids: A factor for zone 3 steatosis in non‐alcoholic fatty liver disease

“…A causal relationship between high BCAA level and NAFLD remains unclear; however, BCAAs are metabolized in extrahepatic tissues. The skeletal muscle is a major site of BCAA catabolism, and an impaired BCAA catabolism in the skeletal muscle might cause an elevation of BCAA levels, which leads to an increase in insulin resistance, a characteristic feature of NAFLD . Adipose tissue is also a site of BCAA catabolism, and alterations in mRNA levels of BCAA‐catabolizing genes in adipose tissue are associated with circulating BCAA levels .…”