Placental mTOR Signaling and Sexual Dimorphism in Metabolic Health across the Lifespan of Offspring

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.

Gene and Protein Expression of Placental Nutrient-Stress Sensor Proteins in Fetal Growth Restriction

“…As a nutrient sensor, mechanistic target of rapamycin (mTOR) has been implicated to be involved in the trajectory of fetal growth [23], and previous studies have demonstrated that mTOR activity is reduced [19,20,[24][25][26][27] or increased [28] in FGR placentae. While our placental staining confirmed the presence of mTOR and pS6 S240 in the human trophoblast cells [25,27,29], we observed no differences in mTOR protein expression, assessed both by IHC and western blotting, between our female AGA and FGR placentae.…”

Maternal Exercise Prior to and during Gestation Induces Sex-Specific Alterations in the Mouse Placenta

“…Exercise during pregnancy has been shown to be beneficial for both mother and child and may reduce the negative consequences of maternal obesity [15]. The placenta, which plays an essential role in nutrient transport and fetal growth, shows sexually dimorphic differences with maternal stressors, such as undernutrition and maternal obesity [38,39]. In this study, we investigated the influence of maternal EX on the placenta and potential mechanisms associated with maternal EX contributing to intrauterine effects, independent of maternal diet and/or weight changes in control-fed mice.…”

RISING STARS: Mechanistic insights into maternal–fetal cross talk and islet beta-cell development

“…mTOR signaling is also shown to regulate the expression and localization of both amino acid ( Roos et al 2007 , 2009 a , b ) and glucose transport systems ( Buller et al 2008 ), likely impacting the flux of nutrients from mother to fetus. As such, evidence suggests that dysregulation of placental mTOR signaling in humans is associated with FGR and poor pregnancy outcomes ( Roos et al 2007 , Sati et al 2016 , Dimasuay et al 2017 , Beetch & Alejandro 2021 , Satterfield et al 2021 ). A recent study revealed a more direct association between placental mTOR and offspring metabolic health.…”