Beetch Megan, Alejandro Emilyn U
Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55455, USA.
Children (Basel). 2021 Oct 26;8(11):970. doi: 10.3390/children8110970.
Robust evidence of fetal programming of adult disease has surfaced in the last several decades. Human and preclinical investigations of intrauterine insults report perturbations in placental nutrient sensing by the mechanistic target of rapamycin (mTOR). This review focuses on pregnancy complications associated with placental mTOR regulation, such as fetal growth restriction (FGR), fetal overgrowth, gestational diabetes mellitus (GDM), polycystic ovarian syndrome (PCOS), maternal nutrient restriction (MNR), preeclampsia (PE), maternal smoking, and related effects on offspring birthweight. The link between mTOR-associated birthweight outcomes and offspring metabolic health trajectory with a focus on sexual dimorphism are discussed. Both human physiology and animal models are summarized to facilitate in depth understanding. GDM, PCOS and fetal overgrowth are associated with increased placental mTOR, whereas FGR, MNR and maternal smoking are linked to decreased placental mTOR activity. Generally, birth weight is reduced in complications with decreased mTOR (i.e., FGR, MNR, maternal smoking) and higher with increased mTOR (GDM, PCOS). Offspring display obesity or a higher body mass index in childhood and adulthood, impaired glucose and insulin tolerance in adulthood, and deficiencies in pancreatic beta-cell mass and function compared to offspring from uncomplicated pregnancies. Defining causal players in the fetal programming of offspring metabolic health across the lifespan will aid in stopping the vicious cycle of obesity and type II diabetes.
在过去几十年中，胎儿编程导致成人疾病的有力证据浮出水面。对子宫内损伤的人体和临床前研究报告称，雷帕霉素机制靶点（mTOR）对胎盘营养感知存在干扰。本综述重点关注与胎盘mTOR调节相关的妊娠并发症，如胎儿生长受限（FGR）、胎儿过度生长、妊娠期糖尿病（GDM）、多囊卵巢综合征（PCOS）、母体营养限制（MNR）、先兆子痫（PE）、母体吸烟以及对后代出生体重的相关影响。讨论了mTOR相关出生体重结果与后代代谢健康轨迹之间的联系，重点关注性别差异。总结了人体生理学和动物模型，以促进深入理解。GDM、PCOS和胎儿过度生长与胎盘mTOR增加有关，而FGR、MNR和母体吸烟与胎盘mTOR活性降低有关。一般来说，mTOR降低的并发症（即FGR、MNR、母体吸烟）出生体重降低，mTOR增加的并发症（GDM、PCOS）出生体重更高。与无并发症妊娠的后代相比，后代在儿童期和成年期表现出肥胖或更高的体重指数，成年期葡萄糖和胰岛素耐受性受损，以及胰腺β细胞数量和功能不足。确定一生中后代代谢健康胎儿编程中的因果因素将有助于阻止肥胖和II型糖尿病的恶性循环。
