Maternal BCAA overnutrition programs persistent dysglycemia in lean adult offspring
Year: 2026
Type: article
Abstract: 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. • Maternal BCAA overnutrition programs persistent, sex-dependent dysglycemia in adult offspring • Male offspring develop hyperglycemia and glucose intolerance despite normal adiposity • Maternal BCAA intake uncouples lipid and glucose metabolism via adipose–liver reprogramming • Hepatic PGC-1α–driven oxidative and gluconeogenic reprogramming likely underlies offspring dysglycemia
Source: Molecular Metabolism
Authors: Joyce Tzeng, Ismael Ferrer, Damaris N. Lorenzo
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,270
Funders: American Diabetes Association, University of Pennsylvania, National Institutes of Health, University of North Carolina at Chapel Hill, Nutrition Obesity Research Center, University of North Carolina, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Penn Center for Musculoskeletal Disorders
Awards: G1060378655, Cytoskeletal pathways of cerebellar dysregulation in neurodevelopmental disorders, Molecular mechanisms of ankyrins in the regulation of glucose homeostasis –metabolic consequences of type 2 diabetes ankyrin risk variants, G9000041240, G9000347941, Overall: Resource-based Center for Musculoskeletal Disorders Research (Overall Application), Nutrition Obesity Research Center (NORC)
OpenAlex ID: W7127978877