Placental mTOR signalling links mitochondrial dysfunction, nutrient transport and neonatal beta cell perturbations in mice
Year: 2025
Type: article
Abstract: 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. Graphical Abstract
Source: Diabetologia
Authors: Megan Beetch, Eunice Oribamise, Seokwon Jo, Briana Clifton, Sarah Larson, Alex Hausmann, Alicia Wong, Brian Akhaphong, Elizabeth Morgan, Emilyn U. Alejandro
Institutions: University of Minnesota, UConn Health
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,490
Funders: American Heart Association, University of Minnesota, National Institutes of Health, Clinical and Translational Science Institute, University of Minnesota, National Heart, Lung, and Blood Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases
Awards: G1202545142, Regulation of Autophagy-driven Pancreatic Beta Cell Function by Nutrient Sensor Proteins, G1869994888, G20074444, G3282987737, G445699482, Minnesota Obesity Prevention Training (MnOPT), The role of O-linked N-Acetylglucosamine Homeostasis in Pancreatic Beta-cell Development and Function, Training Grant in Diabetes and Endocrinology to Enhance Metabolic Healthspan, Inclusive Excellence Training Program in the Systems Biology of Cardiovascular Inflammation, An Interdisciplinary Training Program to Transform Graduate Education In Genetics and Genomics
OpenAlex ID: W4414969065