| First Author | Beetch M | Year | 2025 |
| Journal | Diabetologia | Volume | 68 |
| Issue | 12 | Pages | 2823-2839 |
| PubMed ID | 41062808 | Mgi Jnum | J:375981 |
| Mgi Id | MGI:8267115 | Doi | 10.1007/s00125-025-06542-z |
| Citation | Beetch M, et al. (2025) Placental mTOR signalling links mitochondrial dysfunction, nutrient transport and neonatal beta cell perturbations in mice. Diabetologia 68(12):2823-2839 |
| abstractText | AIMS/HYPOTHESIS: Fetal programming of metabolic health is influenced by the in utero environment. The placental nutrient sensor mechanistic target of rapamycin (mTOR) is implicated in regulating fetal growth and programming of offspring metabolic health, but the mechanisms are unknown. METHODS: Using a placental mTOR deficiency model to induce fetal growth restriction (FGR), we investigated mTOR-modulated placental mitochondrial function, nutrient transport and developmental programming of pancreatic beta cells, which are exquisitely sensitive to nutrient levels in utero. RESULTS: We found defects in placental mitochondria function and morphology that were specific to placentas of mTOR knockout (mTORKO) mice. Despite smaller placentas and FGR in both sexes, nutrient transporter expression and leucine flux were paradoxically increased in female mTORKO placentas. Female fetuses exposed to placental mTOR deficiency (mTORKO(pl)) displayed significantly reduced circulating insulin without neonatal perturbations in insulin secretion. However, average beta cell size and proliferation were increased in mTORKO(pl) female fetuses, possibly driven by system A (SNAT) amino acids, suggesting an immature beta cell phenotype. Adult mTORKO(pl) female offspring exhibit increased susceptibility to diet-induced obesity, insulin resistance and inability to mount a beta cell mass response to a hypernutrient environment. CONCLUSIONS/INTERPRETATION: Our novel in vivo model of direct placental mTOR-driven FGR provides strong evidence linking placental dysfunction and amino acid transport to proper programming of beta cells in early life. |
