Department of Integrative Biology and Physiology, University of Minnesota Medical School, University of Minnesota, Minneapolis, MN 55455, USA.
Department of Surgery, University of Minnesota Medical School, University of Minnesota, Minneapolis, MN 55455, USA.
Int J Mol Sci. 2021 Jun 28;22(13):6918. doi: 10.3390/ijms22136918.
Placental dysfunction can lead to fetal growth restriction which is associated with perinatal morbidity and mortality. Fetal growth restriction increases the risk of obesity and diabetes later in life. Placental O-GlcNAc transferase (OGT) has been identified as a marker and a mediator of placental insufficiency in the setting of prenatal stress, however, its role in the fetal programming of metabolism and glucose homeostasis remains unknown. We aim to determine the long-term metabolic outcomes of offspring with a reduction in placental OGT. Mice with a partial reduction and a full knockout of placenta-specific OGT were generated utilizing the Cre-Lox system. Glucose homeostasis and metabolic parameters were assessed on a normal chow and a high-fat diet in both male and female adult offspring. A reduction in placental OGT did not demonstrate differences in the metabolic parameters or glucose homeostasis compared to the controls on a standard chow. The high-fat diet provided a metabolic challenge that revealed a decrease in body weight gain ( = 0.02) and an improved insulin tolerance ( = 0.03) for offspring with a partially reduced placental OGT but not when OGT was fully knocked out. Changes in body weight were not associated with changes in energy homeostasis. Offspring with a partial reduction in placental OGT demonstrated increased hepatic Akt phosphorylation in response to insulin treatment ( = 0.02). A partial reduction in placental OGT was protective from weight gain and insulin intolerance when faced with the metabolic challenge of a high-fat diet. This appears to be, in part, due to increased hepatic insulin signaling. The findings of this study contribute to the greater understanding of fetal metabolic programming and the effect of placental OGT on peripheral insulin sensitivity and provides a target for future investigation and clinical applications.
胎盘功能障碍可导致胎儿生长受限，这与围产期发病率和死亡率有关。胎儿生长受限增加了肥胖和糖尿病的风险。胎盘 O-GlcNAc 转移酶（OGT）已被确定为产前应激情况下胎盘功能不全的标志物和介质，但其在代谢和葡萄糖稳态的胎儿编程中的作用尚不清楚。我们旨在确定胎盘 OGT 减少的后代的长期代谢结果。利用 Cre-Lox 系统生成了胎盘特异性 OGT 部分减少和完全敲除的小鼠。在正常饲料和高脂肪饮食中评估雄性和雌性成年后代的葡萄糖稳态和代谢参数。与对照组相比，胎盘 OGT 减少不会导致代谢参数或葡萄糖稳态的差异。高脂肪饮食提供了代谢挑战，发现部分减少胎盘 OGT 的后代体重增加减少（= 0.02），胰岛素耐量提高（= 0.03），而当 OGT 完全敲除时则没有。体重变化与能量稳态变化无关。部分减少胎盘 OGT 的后代在胰岛素治疗时表现出肝 Akt 磷酸化增加（= 0.02）。当面临高脂肪饮食的代谢挑战时，胎盘 OGT 的部分减少对体重增加和胰岛素耐受具有保护作用。这在一定程度上是由于肝胰岛素信号的增加。本研究的结果有助于更好地理解胎儿代谢编程以及胎盘 OGT 对周围胰岛素敏感性的影响，并为未来的研究和临床应用提供了一个目标。
