A Two-Hour Fetal Glucagon Infusion Stimulates Hepatic Catabolism of Amino Acids in Fetal Sheep

Postnatally, glucagon acutely lowers plasma amino acid (AA) concentrations by stimulating hepatic AA catabolism, but its fetal actions remain unclear. This study tested whether a 2 h fetal glucagon infusion would stimulate hepatic AA catabolism and inhibit placental AA transfer. Late-gestation pregnant sheep (0.9 gestation) underwent surgical, vascular catheterization and received fetal glucagon (<i>n</i> = 8) or vehicle infusions (<i>n</i> = 8) in a crossover design with a 48 h washout period. Nutrient uptake and utilization were assessed during each infusion, and fetal liver and placental tissue were collected post-infusion under hyperglucagonemic (<i>n</i> = 4) or vehicle (<i>n</i> = 4) conditions. Glucagon receptor was identified in fetal hepatocyte and trophoblast cells. Glucagon reduced fetal plasma AA concentrations by 20% (<i>p</i> = 0.0103) and increased plasma glucose by 47% (<i>p</i> = 0.0152), leading to a three-fold rise in fetal plasma insulin (<i>p</i> = 0.0459). Hepatic gene expression associated with AA catabolism and gluconeogenesis increased (<i>p</i> < 0.0500) following glucagon infusion, and hepatic metabolomic analysis showed enrichment in AA metabolism pathways. However, placental AA transfer was unaffected by 2 h fetal glucagon infusions. In conclusion, a 2 h glucagon infusion stimulates hepatic glucose production and enhances AA catabolism in the fetal liver, lowering plasma AA concentrations. The primary acute effects of fetal glucagon are hepatic, as placental AA transfer is unchanged.