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Review
. 2021 Oct 26;8(11):970.
doi: 10.3390/children8110970.

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

Megan Beetch  1 , Emilyn U Alejandro  1
Affiliations
Review

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

Megan Beetch et al. Children (Basel). .

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.

Keywords: birth weight; fetal growth restriction; insulin sensitivity; mTOR signaling; obesity; placenta; pregnancy; type II diabetes.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Placental mTOR signaling is altered during pregnancy complications and is associated with birth weight and metabolic health trajectory of the offspring. Various complications during pregnancy lead to decreased mTOR signaling or increased mTOR signaling in the placenta. Upstream regulators and downstream targets of mTOR signaling are depicted, including well-known (solid arrow) and proposed (dashed arrow) players. Decreased placental mTOR signaling and amino acid transport are associated with reduced birth weight and subsequent childhood catch-up growth. Increased placental mTOR signaling and nutrient transport are associated with increased birth weight. There is a positive relationship between both reduced and increased birth weight and childhood obesity, followed by metabolic dysfunction and diabetes in adulthood.
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