Detrimental effects of branched-chain amino acids in glucose tolerance can be attributed to valine induced glucotoxicity in skeletal muscle

Objective: The roles of branched-chain amino acids (BCAA) in metabolic health are conflicting, with both positive and negative effects reported. Methods: Individual effects of leucine and valine were tested in vivo (C57BL/6JRj mice) using high-fat (HF) diets supplemented with leucine or valine and compared to a high milk protein diet, with detailed phenotyping, and complemented by in vitro studies in C2C12 myocytes. Results: Under HF conditions, leucine reduced adiposity and improved insulin sensitivity, partly by increasing energy expenditure. In contrast, valine worsened HF-induced impairments, specifically reducing glucose tolerance and insulin sensitivity. These detrimental effects were linked to accumulation of the valine-derived metabolite 3-hydroxyisobutyrate (3-HIB), which increased basal skeletal muscle glucose uptake, promoted glucotoxicity, and impaired myocyte insulin signaling. Conclusion: Valine exerts detrimental effects in an HF context, revealing targetable pathways in BCAA-induced obesity and insulin resistance.