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 (INS) at 0.9 gestation. INS fetuses had increased insulin and decreased oxygen and amino acid (AA) concentrations compared to saline infused fetuses (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, were 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, while hypoxia activated P-AMPK. Overall, chronic hyperinsulinemia produced greater effects on amino acid metabolism compared to 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.

中文翻译：

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慢性高胰岛素血症对胎肝代谢途径和胰岛素信号的影响。

对胎儿肝脏慢性高胰岛素血症的影响知之甚少。在这里，我们在 0.9 妊娠期的胎羊 (INS) 中产生了约 8 天的高胰岛素血症和正常血糖。与注射盐水的胎儿 (CON) 相比，INS 胎儿的胰岛素增加，氧和氨基酸 (AA) 浓度降低。正如预期的那样，INS 胎儿的葡萄糖（全身）利用率增加。然而，在肝脏中，与葡萄糖和脂质代谢相关的基因和代谢物几乎没有差异，并且没有激活胰岛素信号蛋白（AKT 和 mTOR）。INS 肝脏中 P-AMPK 活化增加，线粒体质量（PGC1A 表达，线粒体 DNA 含量）减少。使用对 162 种代谢物的无偏多变量分析，我们确定了对 INS 肝脏中 AA 和一碳代谢的影响。转氨酶 BCAT2 和谷氨酰胺酶基因 GLS1 和 GLS2 的表达降低，支持 AA 利用率降低。我们进一步评估了 INS 胎儿中存在的高胰岛素血症和低氧血症对肝脏结果的作用。PGC1A 的表达仅与高胰岛素血症相关，P-AMPK 仅与低氧血症相关，其他基因和代谢物与高胰岛素血症和低氧血症相关。在胎儿肝细胞中，胰岛素急性治疗激活 P-AKT 并降低 PGC1A，而缺氧激活 P-AMPK。总体而言，与葡萄糖和脂质代谢相比，慢性高胰岛素血症对氨基酸代谢产生更大的影响，并对胎肝中的单碳代谢产生新的影响。