Abstract
Existing studies suggest that decreased branched-chain amino acid (BCAA) catabolism and thus elevated levels in blood are associated with metabolic disturbances. Based on such information, we have developed a hypothesis how BCAA degradation mechanistically connects to tricarboxylic acid cycle, intramyocellular lipid storage, and oxidation, thus allowing more efficient mitochondrial energy production from lipids as well as providing better metabolic health. We analyzed whether data from aged Finnish men are in line with our mechanistic hypothesis linking BCAA catabolism and metabolic disturbances. Older Finnish men enriched with individuals having been athletes in young adulthood (n = 593; mean age 72.6 ± 5.9 years) responded to questionnaires, participated in a clinical examination including assessment of body composition with bioimpedance and gave fasting blood samples for various analytes as well as participated in a 2-h 75 g oral glucose tolerance test. Metabolomics measurements from serum included BCAAs (isoleucine, leucine, and valine). Out of the 593 participants, 59 had previously known type 2 diabetes, further 67 had screen-detected type 2 diabetes, 127 impaired glucose tolerance, and 125 impaired fasting glucose, while 214 had normal glucose regulation and one had missing glucose tolerance information. There were group differences in all of the BCAA concentrations (p ≤ 0.005 for all BCAAs), such that those with normal glucose tolerance had the lowest and those with diabetes mellitus had the highest BCAA concentrations. All BCAA levels correlated positively with body fat percentage (r = 0.29-0.34, p < 0.0001 for all). Expected associations with high BCAA concentrations and unfavorable metabolic profile indicators from metabolomics analysis were found. Except for glucose concentrations, the associations were stronger with isoleucine and leucine than with valine. The findings provided further support for our hypothesis by strengthening the idea that the efficiency of BCAA catabolism may be mechanistically involved in the regulation of fat oxidation, thus affecting the levels of metabolic disease risk factors.
Highlights
High serum branched-chain amino acid (BCAA; isoleucine, leucine, and valine) concentrations have been shown to be predictors or markers of insulin resistance [1], obesity [2, 3], diabetes [4, 5], and atherogenetic dyslipidemia [6, 7] and response to a test meal [8]
We suggested that during increased demand for BCAA catabolism, e.g., during exercise due to increased energy-yielding substrate requirement, transamination of BCAAs is essential for cytosolic oxaloacetate formation
As we studied the association between disturbed metabolism and BCAA values, as age adjustment influenced our results only minimally and as in our material the former endurance athletes were older than other participants and they are known to have better metabolic health than other participants [24] we give our results on our aged study group without age-adjustment
Summary
High serum branched-chain amino acid (BCAA; isoleucine, leucine, and valine) concentrations have been shown to be predictors or markers of insulin resistance [1], obesity [2, 3], diabetes [4, 5], and atherogenetic dyslipidemia [6, 7] and response to a test meal [8]. The metabolomics of twin pairs discordant for leisuretime physical activity for 30 years revealed lower concentrations of serum BCAAs, especially isoleucine, in the active vs inactive co-twin [9]. The transcriptomics of skeletal muscle and adipose tissue yielded upregulated mRNA expression signature of BCAA catabolism and fatty acid metabolism in active compared to inactive co-twins [10]. Skeletal muscle has the highest capacity to catabolize BCAAs in humans and adipose tissue, brain, and liver play important roles [14]
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