Abstract
Fetal growth restriction, or low birth weight, is a strong determinant for eventual obesity and type 2 diabetes. Clinical studies suggest placental mechanistic target of rapamycin (mTOR) signaling regulates fetal birth weight and the metabolic health trajectory of the offspring. In the current study, we used a genetic model with loss of placental mTOR function (mTOR-KOPlacenta) to test the direct role of mTOR signaling on birth weight and metabolic health in the adult offspring. mTOR-KOPlacenta animals displayed reduced placental area and total weight, as well as fetal body weight at embryonic day (E) 17.5. Birth weight and serum insulin levels were reduced; however, β cell mass was normal in mTOR-KOPlacenta newborns. Adult mTOR-KOPlacenta offspring, under a metabolic high-fat challenge, displayed exacerbated obesity and metabolic dysfunction compared with 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 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.
Highlights
Type 2 diabetes (T2D) affects more than 350 million individuals worldwide [1]
While placental mechanistic target of rapamycin (mTOR) signaling has been associated with changes in fetal growth in clinical studies, the impact of its activity on long-term metabolic health trajectory in the offspring has not been directly interrogated
On the other hand, enhanced placental mTOR complex 1 (mTORC1) in utero conferred protection from adverse metabolic dysfunction induced by high-fat diet (HFD)
Summary
Type 2 diabetes (T2D) affects more than 350 million individuals worldwide [1]. It is a complex disease characterized by pancreatic β cell failure in the setting of obesity and insulin resistance in the peripheral tissues. Adverse maternal influences in pregnancy are linked to alteration in fetal birth weight and the long-term health of the offspring. In the United States, about 8% of infants are born with low birth weight [7], a proxy for poor fetal growth. Placental insufficiency is the primary cause of fetal growth restriction (FGR) or low birth weight, which are strong determinants for eventual development of obesity and T2D [8]
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