J Physiol. 2026 Jan 31. doi: 10.1113/JP289970. Online ahead of print.
ABSTRACT
Abnormal fetal growth is linked to perinatal complications and increased risk of metabolic and cardiovascular diseases, yet the underlying mechanisms remain unclear. Placental System L amino acid transport is decreased in human pregnancies complicated by fetal growth restriction and increased in fetal overgrowth. We previously demonstrated that trophoblast-specific overexpression (OX) of Slc7a5/LAT1 enhances transplacental leucine transport and fetal growth. However, the mechanistic link between increased placental transfer of leucine and stimulation of fetal growth remains unclear. We hypothesized that trophoblast-specific Slc7a5 OX in mice increases fetal plasma levels of essential amino acids, which are associated with elevated fetal circulating levels of insulin and IGF-1 and activation of fetal liver insulin/IGF-1 and mTOR signalling. Trophoblast-specific Slc7a5 OX in mice was generated by lentiviral transduction of embryonic day (E) 3.5 mouse blastocysts followed by embryo transfer. Maternal and pooled fetal plasma samples and fetal livers were collected at E18.5. Slc7a5 OX significantly increased fetal weight and fetal plasma levels of essential amino acids, including leucine, phenylalanine, tryptophan, lysine, histidine, valine, methionine and isoleucine. Insulin and IGF-1 concentrations were elevated in fetal plasma, and fetal liver showed an increased phosphorylation of p70S6K1-Threonine-389, S6-Serine-235/236 and Akt-Serine-473, indicating activation of insulin/IGF-1 and mTORC1 and mTORC2 pathways. These results support the hypothesis that placental LAT1 overexpression enhances fetal amino acid supply, driving endocrine responses and anabolic signalling that promote accelerated fetal growth. We speculate that targeting placental LAT1 may represent a novel intervention in cases of pathological fetal growth. KEY POINTS: Placental amino acid transport is critical for fetal growth and serves as a link between maternal nutrition, placental function and fetal development. Trophoblast-specific overexpression of Slc7a5 (LAT1) in mice increases placental transport of essential amino acids, including leucine and lysine. Fetal plasma amino acids, insulin and IGF-1 concentrations were elevated following LAT1 overexpression. Fetal hepatic signalling was activated, with increased mTORC1 (p-S6 Ser235/236) and mTORC2 (p-Akt Ser473) phosphorylation, while Akt Thr308 phosphorylation was unaffected. Fetuses exposed to LAT1 overexpression were larger, with increased fetal and placental weights, consistent with a fetal overgrowth phenotype. These findings demonstrate that placental LAT1 functions as a nutrient-sensing regulator of fetal growth via endocrine and metabolic signalling pathways.
PMID:41618849 | DOI:10.1113/JP289970