Experimental chronic fetal hyperglucagonemia stimulates hepatic pathways for amino acid catabolism and...

Glucagon activates amino acid catabolism and gluconeogenesis in adults. Elevated glucagon concentrations in the fetus occur in pregnancy complications, such as fetal growth restriction (FGR) and hypoxia, yet the impact of chronic fetal hyperglucagonemia is unknown. Using chronically catheterized pregnant sheep, glucose tracers, and liver tissue biopsies, we investigated the effects of nine days of glucagon infusion at 5 or 50 ng/kg/min in late-gestation fetal sheep that increased plasma glucagon concentrations by 800%. Glucagon-infused fetuses were euglycemic and exhibited lower plasma and hepatic amino acid concentrations. They also had increased hepatic mRNA expression of amino acid catabolism genes, including ARG2, GLS2, BCAT1, BCAT2, GLUL, HAL, UROC1, and PPARGC1A. Metabolite profiling in liver tissue revealed enrichment of pathways associated with amino acid degradation, elevated tri- and diphosphate nucleotides, and changes in fatty acid metabolites, supporting enhanced hepatic energy metabolism from amino acid oxidation. Hepatic glycogen content was reduced in glucagon-infused fetuses and the gluconeogenic genes PCK1 and G6PC1 were increased, although fetal glucose production was not detected. These findings demonstrate that in the fetal liver, chronic hyperglucagonemia activates amino acid catabolic pathways, indicating a physiological role for glucagon in regulating fetal amino acid homeostasis. These findings have implications for understanding fetal hepatic adaptations during chronic fetal hyperglucagonemia that can occur in the setting of FGR or hypoxia.