Branched-Chain Amino Acids in Metabolic Programming from Genetic and Early-Life Perspectives

Branched-chain amino acids (BCAAs) are essential amino acids that play critical roles in protein synthesis, energy production, and metabolic regulation. While BCAAs are vital for maintaining metabolic health, chronic elevations in circulating BCAA levels have been consistently associated with metabolic disorders, including obesity, insulin resistance (IR), and type 2 diabetes mellitus (T2DM). Despite extensive research, it remains unclear whether elevated plasma BCAA concentrations are a cause or consequence of metabolic dysfunction. Moreover, the tissue-specific regulation of BCAA metabolism and the long-term consequences of altered BCAA exposure during early life remain incompletely understood.To address these gaps, we investigated the mechanistic regulation of systemic BCAA levels and their contribution to metabolic disease susceptibility. Utilizing T2DM-associated ankyrin-B mutant mouse models characterized by elevated circulating BCAA levels prior to the onset of obesity and insulin resistance, we demonstrated that impaired BCAA catabolism in white adipose tissue (WAT) leads to systemic BCAA accumulation by disrupting the surface localization of the Alanine, Serine, Cysteine Transporter 2 (ASCT2) in adipocytes, resulting in diminished BCAA uptake. These findings establish WAT as a critical regulator of systemic BCAA homeostasis and metabolic health.In a separate study, we examined the long-term metabolic effects of early-life exposure to elevated BCAA levels through maternal dietary manipulation. Male offspring from dams fed a BCAA-enriched diet during pregnancy and lactation exhibited persistent hyperglycemia in adulthood, an effect exacerbated by subsequent high-fat diet (HFD) feeding. Notably, maternal BCAA overconsumption attenuated HFD-induced adiposity in the offspring, associated with enhanced lipolysis in WAT without a corresponding rise in circulating free fatty acids, alongside increased hepatic gluconeogenesis. These results suggest that altered adipose-liver metabolic crosstalk contributes to the persistent hyperglycemia in the offspring.Collectively, this work provides new mechanistic insight into the regulation of systemic BCAA metabolism, identifies white adipose tissue as a key site of BCAA degradation, and demonstrates that both genetic and dietary disruptions in BCAA homeostasis contribute to the development of metabolic disease.