Lopez-Tello Jorge, Salazar-Petres Esteban, Webb Liam, Fowden Abigail L, Sferruzzi-Perri Amanda N
Department of Physiology, Development and Neuroscience, Centre for Trophoblast Research, University of Cambridge, Cambridge, United Kingdom.
Front Cell Dev Biol. 2022 Jul 1;10:928210. doi: 10.3389/fcell.2022.928210. eCollection 2022.
Pregnancy requires adaptations in maternal metabolism to support fetal growth. The phosphoinositol-3-kinase (PI3K) signalling pathway controls multiple biological processes and defects in this pathway are linked to metabolic disorders including insulin resistance and glucose intolerance in non-pregnant animals. However, relatively little is known about the contribution of PI3K signalling to the maternal metabolic adaptations during pregnancy. Using mice with partial inactivation of the PI3K isoform, p110α (due to a heterozygous dominant negative mutation; -D933A), the effects of impaired PI3K-p110α signalling on glucose and insulin handling were examined in the pregnant and non-pregnant states and related to the morphological, molecular, and mitochondrial changes in key metabolic organs. The results show that non-pregnant mice lacking PI3K-p110α are glucose intolerant but exhibit compensatory increases in pancreatic glucose-stimulated insulin release and adipose tissue mitochondrial respiratory capacity and fatty acid oxidation. However, in pregnancy, mutant mice failed to show the normal increment in glucose intolerance and pancreatic β-cell mass observed in wild-type pregnant dams and exhibited further enhanced adipose tissue mitochondrial respiratory capacity. These maladaptations in pregnant mutant mice were associated with fetal growth restriction. Hence, PI3K-p110α is a key regulator of metabolic adaptations that support fetal growth during normal pregnancy.
怀孕需要母体代谢进行适应性变化以支持胎儿生长。磷酸肌醇-3-激酶（PI3K）信号通路控制多种生物学过程，该通路的缺陷与包括非孕动物胰岛素抵抗和葡萄糖不耐受在内的代谢紊乱有关。然而，关于PI3K信号在孕期母体代谢适应性变化中的作用，人们了解得相对较少。利用PI3K亚型p110α部分失活的小鼠（由于杂合显性负性突变；-D933A），研究了PI3K-p110α信号受损对怀孕和非孕状态下葡萄糖和胰岛素处理的影响，并将其与关键代谢器官的形态、分子和线粒体变化相关联。结果表明，缺乏PI3K-p110α的非孕小鼠存在葡萄糖不耐受，但胰腺葡萄糖刺激的胰岛素释放、脂肪组织线粒体呼吸能力和脂肪酸氧化出现代偿性增加。然而，在孕期，突变小鼠未能表现出野生型怀孕母鼠中观察到的葡萄糖不耐受和胰腺β细胞质量的正常增加，且脂肪组织线粒体呼吸能力进一步增强。怀孕突变小鼠的这些适应不良与胎儿生长受限有关。因此，PI3K-p110α是正常孕期支持胎儿生长的代谢适应性变化的关键调节因子。
