Hemmeryckx Bianca, van Bree Rita, Van Hoef Berthe, Vercruysse Lisbeth, Lijnen H Roger, Verhaeghe Johan
Department of Obstetrics and Gynecology, Health Canpus Gasthuisberg, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
Endocrinology. 2008 May;149(5):2176-83. doi: 10.1210/en.2007-1272. Epub 2008 Feb 7.
Pregnancy-induced metabolic changes are regulated by signals from an expanded adipose organ. Placental growth factor (PlGF), acting through vascular endothelial growth factor receptor-1, may be among those signals. There is a steep rise in circulating PlGF during normal pregnancy, which is repressed in gravidas who develop preeclampsia. PlGF-deficiency in mice impairs adipose vascularization and development. Here we studied young-adult PlGF-deficient (PlGF(-/-)) and wild-type mice on a high-fat diet in the nongravid state and at embryonic day (E) 13.5 or E18.5 of gestation. Litter size and weight were normal, but E18.5 placentas were smaller in PlGF(-/-) pregnancies. PlGF(-/-) mice showed altered intraadipose dynamics, with the following: 1) less blood vessels and fewer brown, uncoupling protein (UCP)-1-positive, adipocytes in white sc and perigonadal fat compartments and 2) white adipocyte hypertrophy. The mRNA expression of beta(3)-adrenergic receptors, peroxisome proliferator-activated receptor-gamma coactivator-1alpha, and UCP-1 was decreased accordingly. Moreover, PlGF(-/-) mice showed hyperinsulinemia. Pregnancy-associated changes were largely comparable in PlGF(-/-) and wild-type dams. They included expanded sc fat compartments and adipocyte hypertrophy, whereas adipose expression of key angiogenesis/adipogenesis (vascular endothelial growth factor receptor-1, peroxisome proliferator-activated receptor-gamma(2)) and thermogenesis (beta(3)-adrenergic receptors, peroxisome proliferator-activated receptor-gamma coactivator-1alpha, and UCP-1) genes was down-regulated; circulating insulin levels gradually increased during pregnancy. In conclusion, reduced adipose vascularization in PlGF(-/-) mice impairs adaptive thermogenesis in favor of energy storage, thereby promoting insulin resistance and hyperinsulinemia. Pregnancy adds to these changes by PlGF-independent mechanisms. Disturbed intraadipose dynamics is a novel mechanism to explain metabolic changes in late pregnancy in general and preeclamptic pregnancy in particular.
妊娠诱导的代谢变化受脂肪组织扩张产生的信号调节。胎盘生长因子（PlGF）通过血管内皮生长因子受体 -1发挥作用，可能是这些信号之一。正常妊娠期间循环中的PlGF会急剧上升，而子痫前期孕妇体内的PlGF会受到抑制。小鼠体内PlGF缺乏会损害脂肪组织的血管生成和发育。在此，我们研究了非妊娠状态下以及妊娠第13.5天或18.5天的高脂饮食成年PlGF缺陷（PlGF(-/-)）小鼠和野生型小鼠。产仔数和体重正常，但PlGF(-/-)妊娠中第18.5天的胎盘较小。PlGF(-/-)小鼠的脂肪组织内动态发生改变，表现为：1）白色皮下和性腺周围脂肪组织中血管较少，棕色、解偶联蛋白（UCP）-1阳性脂肪细胞较少；2）白色脂肪细胞肥大。β(3)-肾上腺素能受体、过氧化物酶体增殖物激活受体γ共激活因子-1α和UCP-1的mRNA表达相应降低。此外，PlGF(-/-)小鼠表现出高胰岛素血症。PlGF(-/-)和野生型母鼠的妊娠相关变化在很大程度上相似。这些变化包括皮下脂肪组织扩张和脂肪细胞肥大，而关键的血管生成/脂肪生成（血管内皮生长因子受体-1、过氧化物酶体增殖物激活受体γ(2)）和产热（β(3)-肾上腺素能受体、过氧化物酶体增殖物激活受体γ共激活因子-1α和UCP-1）基因的脂肪组织表达下调；妊娠期间循环胰岛素水平逐渐升高。总之，PlGF(-/-)小鼠脂肪组织血管生成减少损害适应性产热，有利于能量储存从而促进胰岛素抵抗和高胰岛素血症。妊娠通过不依赖PlGF的机制加剧了这些变化。脂肪组织内动态紊乱是解释妊娠晚期尤其是子痫前期妊娠代谢变化的一种新机制。
