Branched-Chain Amino Acid Metabolism is Regulated by ERRα and is Further Impaired by Glucose Loading in Type 2 Diabetes

Increased levels of branched-chain amino acids (BCAAs) are associated with type 2 diabetes (T2D) pathogenesis. However, most metabolomic studies in T2D are limited to an analysis of plasma metabolites under fasting conditions, rather than the dynamic shift in response to a glucose challenge. Moreover, metabolomic profiles of peripheral tissues involved in glucose homeostasis are scarce and the transcriptomic regulation of genes involved in BCAA catabolism in T2D is partially unknown. Using metabolomic and gene expression approaches, we found that impairments in BCAA catabolism in T2D patients under fasting conditions are exacerbated after a glucose load, concomitant with downregulated expression of BCAA-related genes in skeletal muscle. We identified a key regulatory role for Estrogen-Related Receptor α (ERRα) in PGC-1α-mediated upregulation of BCAA genes and leucine oxidation. Thus, metabolic inflexibility in T2D impacts BCAA homeostasis and the transcriptional regulation of BCAA genes via a PGC-1α/ERRα-dependent mechanism.