Maternal BCAA overnutrition programs persistent dysglycemia in lean adult offspring.

Maternal nutrition exerts profound, lasting effects on offspring metabolic health, yet the impact of maternal overconsumption of key nutrients such as branched-chain amino acid (BCAAs) remains poorly understood. Here, we show that intake of a BCAA-enriched isocaloric, protein content-matched diet throughout pregnancy and lactation induces hyperglycemia and altered circulating amino acid profiles in mouse dams, and programs lasting changes in offspring glucose homeostasis. Adult offspring of both sexes on a chow diet exhibited glucose intolerance. Male offspring showed fasting hyperglycemia despite normal adiposity, whereas females maintained normoglycemia via compensatory hyperinsulinemia. Under a postweaning high-fat diet challenge, offspring of BCAA-fed dams were protected from adiposity and hepatic steatosis, yet developed exacerbated hyperglycemia and glucose intolerance. Mechanistically, maternal BCAA overnutrition reprogrammed offspring energy substrate handling through enhanced white adipose tissue lipolysis and fatty acid oxidation, reduced hepatic fatty acid uptake, and increased hepatic oxidative and gluconeogenic capacity. Elevated hepatic PGC-1α served as a central integrator of oxidative and gluconeogenic pathways, uncoupling lipid and glucose metabolism. These findings identify excess maternal BCAA intake as a nutrient-specific driver of developmental programming that uncouples adiposity from glycemic control, highlighting amino acid-driven metabolic plasticity as a critical axis in intergenerational metabolic dysfunction.