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Abstract
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.
Highlights
Accepted: 24 October 2021Decades of research have revealed that many diseases diagnosed over a lifetime have fetal origins
Sity, nutrient restriction, gestational diabetes mellitus (GDM), preeclampsia (PE), polycysperturbations suggest an important link between placental mechanistic target of rapamycin (mTOR), birth weight, and the tic ovarian syndrome (PCOS)
2016 aimed to delineate whether placental signaling and pregnancy outcomes differ between maternal obesity and/or GDM and they found that obese women with GDM had babies with higher estimated fetal weight; birth weight was not affected by GDM or BMI [33]
Summary
Decades of research have revealed that many diseases diagnosed over a lifetime have fetal origins. Decreased placental mTOR signaling and stream regulators downstream targets of mTOR are depicted, including well-known amino acid transport are associated with reduced birth weight and subsequent childhood catch-up growth. Human studies as well as animal sponse to several environmental and pregnancy-related factors including maternal obemodels recapitulating environmental intrauterine insults and subsequent placental mTOR sity, nutrient restriction, gestational diabetes mellitus (GDM), preeclampsia (PE), polycysperturbations suggest an important link between placental mTOR, birth weight, and the tic ovarian syndrome. Maternal obesity is mTOR perturbations suggest an important link between placental mTOR, weight, linked to several pregnancy complications, such as GDM, PCOS and PE, and increases and the trajectory of offspring metabolic health. Association relationships and direct manipulation of mTOR signaling have delineated a strong link between placental mTOR, birth weight, and programming of offspring metabolic health. Human pathophysiology is reviewed with discussion of important animal studies to better facilitate readers’ understanding
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