The effect of chronic of
hyperinsulinemia in the fetal liver is poorly understood. Here, we produced
hyperinsulinemia with euglycemia for ∼8 days in fetal sheep [hyperinsulinemic (INS)] at 0.9 gestation. INS fetuses had increased
insulin and decreased
oxygen and
amino acid (AA) concentrations compared with saline-infused fetuses [control (CON)].
Glucose (whole body) utilization rates were increased, as expected, in INS fetuses. In the liver, however, there were few differences in genes and metabolites related to
glucose and lipid metabolism and no activation of
insulin signaling
proteins (Akt and mTOR). There was increased p-AMPK activation and decreased mitochondrial mass (PGC1A expression,
mitochondrial DNA content) in INS livers. Using an unbiased multivariate analysis with 162 metabolites, we identified effects on AA and one-
carbon metabolism in the INS liver. Expression of the
transaminase BCAT2 and
glutaminase genes GLS1 and GLS2 was decreased, supporting decreased AA utilization. We further evaluated the roles of
hyperinsulinemia and
hypoxemia, both present in INS fetuses, on outcomes in the liver. Expression of PGC1A correlated only with
hyperinsulinemia, p-AMPK correlated only with
hypoxemia, and other genes and metabolites correlated with both
hyperinsulinemia and
hypoxemia. In fetal hepatocytes, acute treatment with
insulin activated p-Akt and decreased PGC1A, whereas
hypoxia activated p-AMPK. Overall, chronic
hyperinsulinemia produced greater effects on
amino acid metabolism compared with
glucose and lipid metabolism and a novel effect on one-
carbon metabolism in the fetal liver. These hepatic metabolic responses may result from the downregulation of
insulin signaling and antagonistic effects of
hypoxemia-induced AMPK activation that develop with chronic
hyperinsulinemia.