Vaughan O R, Fisher H M, Dionelis K N, Jeffreys E C, Higgins J S, Musial B, Sferruzzi-Perri A N, Fowden A L
Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, CB2 3EG, UK.
J Physiol. 2015 Mar 1;593(5):1307-21. doi: 10.1113/jphysiol.2014.287177. Epub 2015 Jan 29.
Glucocorticoids affect glucose metabolism in adults and fetuses, although their effects on materno-fetal glucose partitioning remain unknown. The present study measured maternal hepatic glucose handling and placental glucose transport together with insulin signalling in these tissues in mice drinking corticosterone either from day (D) 11 to D16 or D14 to D19 of pregnancy (term = D21). On the final day of administration, corticosterone-treated mice were hyperinsulinaemic (P < 0.05) but normoglycaemic compared to untreated controls. In maternal liver, there was no change in glycogen content or glucose 6-phosphatase activity but increased Slc2a2 glucose transporter expression in corticosterone-treated mice, on D16 only (P < 0.05). On D19, but not D16, transplacental (3) H-methyl-d-glucose clearance was reduced by 33% in corticosterone-treated dams (P < 0.05). However, when corticosterone-treated animals were pair-fed to control intake, aiming to prevent the corticosterone-induced increase in food consumption, (3) H-methyl-d-glucose clearance was similar to the controls. Depending upon gestational age, corticosterone treatment increased phosphorylation of the insulin-signalling proteins, protein kinase B (Akt) and glycogen synthase-kinase 3β, in maternal liver (P < 0.05) but not placenta (P > 0.05). Insulin receptor and insulin-like growth factor type I receptor abundance did not differ with treatment in either tissue. Corticosterone upregulated the stress-inducible mechanistic target of rapamycin (mTOR) suppressor, Redd1, in liver (D16 and D19) and placenta (D19), in ad libitum fed animals (P < 0.05). Concomitantly, hepatic protein content and placental weight were reduced on D19 (P < 0.05), in association with altered abundance and/or phosphorylation of signalling proteins downstream of mTOR. Taken together, the data indicate that maternal glucocorticoid excess reduces fetal growth partially by altering placental glucose transport and mTOR signalling.
糖皮质激素会影响成年个体和胎儿的葡萄糖代谢，尽管它们对母胎葡萄糖分配的影响尚不清楚。本研究检测了孕期从第11天（D11）至第16天或从第14天至第19天（孕期足月为D21）饮用皮质酮的小鼠母体肝脏葡萄糖处理、胎盘葡萄糖转运以及这些组织中的胰岛素信号传导情况。在给药的最后一天，与未处理的对照组相比，皮质酮处理的小鼠出现高胰岛素血症（P < 0.05）但血糖正常。在母体肝脏中，糖原含量或葡萄糖6 - 磷酸酶活性没有变化，但仅在D16时，皮质酮处理的小鼠中Slc2a2葡萄糖转运蛋白表达增加（P < 0.05）。在D19而非D16时，皮质酮处理的母鼠经胎盘的（3）H - 甲基 - d - 葡萄糖清除率降低了33%（P < 0.05）。然而，当将皮质酮处理的动物按配对方式喂食至与对照组摄入量相同时，旨在防止皮质酮诱导的食物摄入量增加，此时（3）H - 甲基 - d - 葡萄糖清除率与对照组相似。根据胎龄不同，皮质酮处理会增加母体肝脏中胰岛素信号蛋白蛋白激酶B（Akt）和糖原合酶激酶3β的磷酸化水平（P < 0.05），但不会增加胎盘组织中的磷酸化水平（P > 0.05）。胰岛素受体和胰岛素样生长因子I型受体的丰度在两种组织中均不受处理的影响。在自由采食的动物中，皮质酮会上调肝脏（D16和D19）和胎盘（D19）中应激诱导的雷帕霉素作用机制靶点（mTOR）抑制因子Redd1的表达（P < 0.05）。同时，在D19时肝脏蛋白质含量和胎盘重量降低（P < 0.05），这与mTOR下游信号蛋白丰度和/或磷酸化的改变有关。综上所述，数据表明母体糖皮质激素过量部分通过改变胎盘葡萄糖转运和mTOR信号传导来降低胎儿生长。
