The role of adiposity in the association of branched-chain amino acids and metabolic and clinical markers in healthy adults on controlled diets.

Abstract

Branched-chain amino acids (BCAAs) leucine, isoleucine, and valine have been positively associated with adiposity and insulin resistance. Targeted metabolomic data from plasma samples of healthy adults (n=40 men, n=40 women) aged 18-45 years old derived from a randomized crossover feeding trial (Carbohydrates and Related Biomarkers-ClinicalTrials.gov Identifier: NCT00622661) were used to further elucidate why BCAAs are elevated in settings of increased adiposity and insulin resistance. Twelve metabolites were selected from a combination of a literature search and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway review for cross-sectional analysis. Linear mixed models were used to evaluate associations between (1) adiposity and metabolites related to BCAA catabolism, (2) adiposity, HOMA-IR, and CRP, and (3) markers of BCAA catabolism, adipokines (leptin and adiponectin), and markers of inflammation (CRP, IL-6, and SAA). Adiposity was positively associated with leucine (p=0.043), isoleucine (p=0.035), valine (p=0.034), pyruvate (p=0.015), alanine (p=6e-4), glutamic acid (p=8e-7), and isovaleric acid (p= 2e-4). Conversely, malonic acid concentration was found to be inversely associated with body adiposity (p=0.014). These results support the hypothesis that elevated BCAAs are part of a metabolic signature of obesity and reductions in BCAA catabolism at the first two steps of BCAA catabolism likely drive elevations in plasma BCAA concentrations. Serum glucose, insulin, HOMA-IR score, and CRP were all positively associated with adiposity (p=2.3e-3, p=7.88e-6, p=3.65e-6, p=5e-3, respectively). These results were significant even after adjustments for plasma leucine, isoleucine, and valine concentration, and carbohydrate intake. Finally, plasma leptin was positively associated with leucine (p=0.042), isoleucine (p=0.045), valine (p=0.021), and glutamic acid (p= 0.027) and these associations could be related to insulin resistance and regulation of plasma insulin levels. Leptin was inversely associated with malonic acid which may be related to the opposing roles leptin and malonic acid-derived malonyl-CoA play in fatty acid metabolism. These exploratory metabolomic results provide key connections between metabolites related to BCAA catabolism, adiposity, inflammation, and adipokine activity. These results have broad applications towards understanding the complex signaling effects of BCAAs on the human metabolome.