Fetal growth restriction (FGR), a major risk factor for stillbirth, and neonatal and adulthood morbidity, is associated with reduced placental size and decreased placental nutrient transport. In mice, a small, normal placenta increases its nutrient transport, thus compensating for its reduced size and maintaining normal fetal growth. Whether this adaptation occurs for glutamine and glutamate, two key amino acids for placental metabolism and fetal growth, is unknown. Additionally, an assessment of placental transport of glutamine and glutamate between FGR and normal pregnancy is currently lacking. We thus tested the hypothesis that the transport of glutamine and glutamate would be increased (per gram of tissue) in a small normal placenta [C57BL6/J (wild-type, WT) mice], but that this adaptation fails in the small dysfunctional placenta in FGR [insulin-like growth factor 2 knockout (P0) mouse model of FGR]. In WT mice, comparing the lightest versus heaviest placenta in a litter, unidirectional maternofetal clearance (K_mf ) of ¹⁴ C-glutamine and ¹⁴ C-glutamate (^glutamine K_mf and ^glutamate K_mf ) was significantly higher at embryonic day (E) 18.5, in line with increased expression of LAT1, a glutamine transporter protein. In P0 mice, ^glutamine K_mf and ^glutamate K_mf were higher (P0 versus wild-type littermates, WTL) at E15.5. At E18.5, ^glutamine K_mf remained elevated whereas ^glutamate K_mf was similar between groups. In summary, we provide evidence that ^glutamine K_mf and ^glutamate K_mf adapt according to placental size in WT mice. The placenta of the growth-restricted P0 fetus also elevates transport capacity to compensate for size at E15.5, but this adaptation is insufficient at E18.5; this may contribute to decreased fetal growth.

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