Tanner Amelia R, Cilvik Sarah N, Nguyen Marjorie A, Dobrinskikh Evgenia, Anthony Russell V, Wesolowski Stephanie R, Rozance Paul J
Perinatal Research Center, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, USA.
Department of Pediatrics, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA.
Int J Mol Sci. 2025 Feb 22;26(5):1904. doi: 10.3390/ijms26051904.
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 ( = 8) or vehicle infusions ( = 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 ( = 4) or vehicle ( = 4) conditions. Glucagon receptor was identified in fetal hepatocyte and trophoblast cells. Glucagon reduced fetal plasma AA concentrations by 20% ( = 0.0103) and increased plasma glucose by 47% ( = 0.0152), leading to a three-fold rise in fetal plasma insulin ( = 0.0459). Hepatic gene expression associated with AA catabolism and gluconeogenesis increased ( < 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.
出生后，胰高血糖素通过刺激肝脏氨基酸（AA）分解代谢来急性降低血浆氨基酸浓度，但其在胎儿期的作用仍不清楚。本研究测试了2小时的胎儿胰高血糖素输注是否会刺激肝脏氨基酸分解代谢并抑制胎盘氨基酸转运。妊娠晚期绵羊（妊娠0.9期）接受手术、血管插管，并在交叉设计中接受胎儿胰高血糖素输注（n = 8）或载体输注（n = 8），洗脱期为48小时。在每次输注期间评估营养物质的摄取和利用，并在输注后在高胰高血糖素血症（n = 4）或载体（n = 4）条件下收集胎儿肝脏和胎盘组织。在胎儿肝细胞和滋养层细胞中鉴定出胰高血糖素受体。胰高血糖素使胎儿血浆氨基酸浓度降低20%（P = 0.0103），血浆葡萄糖增加47%（P = 0.0152），导致胎儿血浆胰岛素增加三倍（P = 0.0459）。胰高血糖素输注后，与氨基酸分解代谢和糖异生相关的肝脏基因表达增加（P < 0.0500），肝脏代谢组学分析显示氨基酸代谢途径富集。然而，2小时的胎儿胰高血糖素输注对胎盘氨基酸转运没有影响。总之，2小时的胰高血糖素输注刺激肝脏葡萄糖生成并增强胎儿肝脏中的氨基酸分解代谢，降低血浆氨基酸浓度。胎儿胰高血糖素的主要急性作用是在肝脏，因为胎盘氨基酸转运没有变化。
