Department of Obstetrics and Gynecology, University of Groningen, University Medical Center Groningen , Groningen , The Netherlands.
Department of Developmental Pathology, Institute of Pathology, Bonn University Medical School , Bonn , Germany.
Am J Physiol Regul Integr Comp Physiol. 2018 Dec 1;315(6):R1107-R1114. doi: 10.1152/ajpregu.00420.2017. Epub 2018 Sep 12.
Intrauterine growth restriction (IUGR) is an accepted risk factor for metabolic disorders in later life, including obesity and type 2 diabetes. The level of metabolic dysregulation can vary between subjects and is dependent on the severity and the type of IUGR insult. Classical IUGR animal models involve nutritional deprivation of the mother or uterine artery ligation. The latter aims to mimic a placental insufficiency, which is the most frequent cause of IUGR. In this study, we investigated whether IUGR attributable to placental insufficiency impacts the glucose and lipid homeostasis at advanced age. Placental insufficiency was achieved by deletion of the transcription factor AP-2y ( Tfap2c), which serves as one of the major trophoblast differentiation regulators. TdelT-IUGR mice were obtained by crossing mice with a floxed Tfap2c allele and mice with Cre recombinase under the control of the Tpbpa promoter. In advanced adulthood (9-12 mo), female and male IUGR mice are respectively 20% and 12% leaner compared with controls. At this age, IUGR mice have unaffected glucose clearance and lipid parameters (cholesterol, triglycerides, and phospholipids) in the liver. However, female IUGR mice have increased plasma free fatty acids (+87%) compared with controls. This is accompanied by increased mRNA levels of fatty acid synthase and endoplasmic reticulum stress markers in white adipose tissue. Taken together, our results suggest that IUGR by placental insufficiency may lead to higher lipogenesis in female mice in advanced adulthood, at least indicated by greater Fasn expression. This effect was sex specific for the aged IUGR females.
宫内生长受限（IUGR）是晚年代谢紊乱的公认危险因素，包括肥胖和 2 型糖尿病。代谢失调的程度在不同个体之间有所差异，取决于 IUGR 损伤的严重程度和类型。经典的 IUGR 动物模型涉及母亲的营养剥夺或子宫动脉结扎。后者旨在模拟胎盘功能不全，这是 IUGR 最常见的原因。在这项研究中，我们研究了由于胎盘功能不全导致的 IUGR 是否会影响高龄时的葡萄糖和脂质稳态。通过删除转录因子 AP-2y（Tfap2c）来实现胎盘功能不全，该因子作为主要的滋养层分化调节剂之一。通过将带有 floxed Tfap2c 等位基因的小鼠与带有 Cre 重组酶的小鼠进行杂交，并在 Tpbpa 启动子的控制下获得 TdelT-IUGR 小鼠。在成年后期（9-12 个月），雌性和雄性 IUGR 小鼠分别比对照组瘦 20%和 12%。在这个年龄，IUGR 小鼠的葡萄糖清除率和肝脏中的脂质参数（胆固醇、甘油三酯和磷脂）不受影响。然而，雌性 IUGR 小鼠的血浆游离脂肪酸增加了 87%（+）与对照组相比。这伴随着白色脂肪组织中脂肪酸合成酶和内质网应激标志物的 mRNA 水平增加。总之，我们的结果表明，由于胎盘功能不全导致的 IUGR 可能导致老年雌性小鼠在成年后期更高的脂肪生成，至少 Fasn 表达增加表明了这一点。这种影响在老年 IUGR 雌性中是性别特异性的。
