Placental mTOR complex 1 regulates fetal programming of obesity and insulin resistance in mice

Abstract

Fetal growth restriction, or low birthweight is a strong determinant for eventual obesity and Type 2 diabetes. Clinical studies suggest placental mechanistic target of rapamycin (mTOR) signaling regulate fetal birthweight and the metabolic health trajectory of the offspring. In the current study, we used genetic model with loss of placental mTOR function (mTORKO Placenta ) to test the direct role of mTOR signaling on birthweight and the metabolic health in the adult offspring. mTORKO Placenta animals displayed reduced placental area and total weight, as well as fetal bodyweight at embryonic day (e) 17.5. Birthweight and serum insulin levels were reduced; however, β-cell mass was normal in mTORKO Placenta newborns. Adult mTORKO Placenta offspring, under a metabolic high-fat challenge, displayed exacerbated obesity and metabolic dysfunction compared to littermate controls. Subsequently, we tested whether enhancing placental mTOR complex 1 (mTORC1) signaling, via genetic ablation of TSC2, in utero would improve glucose homeostasis in the offspring. Indeed, increased placental mTORC1 conferred protection from a diet-induced obesity in the offspring. In conclusion, placental mTORC1 serves as a mechanistic link between placental function and programming of obesity and insulin resistance in the adult offspring.

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

“…Interestingly, fetal weights did not differ by sex or by diet in this study [30]. Upregulation of mTOR activity by genetically deleting TSC2, a negative regulator of mTOR complex 1 (mTORC1), in the mouse placenta resulted in no differences in male or female placental weights or perinatal body weights compared to littermate controls [18]. In contrast to decreasing mTOR in the mouse placenta discussed above, there were no sexual dimorphic effects of increasing mTORC1 activity.…”

“…In a murine model of direct placental mTOR manipulation, genetic deletion of mTOR in the placenta resulted in reduced placental, embryonic, and newborn body weights in female offspring. However, placental mTOR knockout male offspring displayed no differences in placental or body weights [18]. Sexual dimorphism discrepancies between humans and rodent models highlight the true complexity of placental biology in both mammalian systems.…”

“…Interestingly, placental mTOR protein levels have been correlated with early catch-up growth following FGR [21], which in turn may link mTOR-associated FGR to adverse metabolic outcomes, such as obesity, in childhood and beyond. Direct genetic deletion of mTOR from the placental trophoblasts of mice conferred a significant reduction in newborn body weight that manifested in sexually dimorphic outcomes in insulin resistance and obesity in the adult offspring [18].…”

“…Several findings indicate higher BMI in childhood and adulthood in the offspring of mothers with pregnancy complications. Placental mTOR has been implicated in programming offspring tissues to be more sensitive to a metabolic challenge [18].…”

“…Association relationships and direct manipulation of mTOR signaling have delineated a strong link between placental mTOR, birth weight, and programming of offspring metabolic health. Moreover, there is evidence that sexual dimorphism is present in offspring metabolic outcomes [18].…”