Leptin distribution and metabolism in the pregnant rat: Transplacental leptin passage increases in late gestation but is reduced by excess glucocorticoids

Leptin is essential for the establishment of pregnancy and appears to promote fetal growth, but the mechanisms regulating fetal leptin exposure remain unclear. In rodents, indirect evidence suggests that fetal leptin is partly derived from the maternal circulation via transplacental passage. Indeed, the placenta expresses mRNA for Ob-Ra, one of the short forms of the leptin receptor (Ob-R-S) important in leptin transport, and this expression increases markedly in late pregnancy. Therefore, we determined the transplacental passage of maternal leptin to the fetus in the rat and whether this transport increases near term in association with a rise in placental expression of Ob-R-S protein. Because of the proposed role of leptin in promoting fetal growth, we also assessed the effect of glucocorticoid-induced fetal growth retardation on placental leptin transport. Anesthetized rats received a constant infusion of I-125-leptin via a jugular cannula before and at d 16 and 22 of pregnancy ( term = d 23); plasma samples were obtained at 10, 20, 40, 60, 80, and 100 min, and fetuses and placentas were collected at the time of the final sample. The metabolic clearance rate of leptin fell ( P < 0.01) from 3.08 +/- 0.23 ml/min per kg in nonpregnant rats to 2.36 +/- 0.13 ml/min per kg by d 22. Transplacental passage of I-125-leptin, estimated from its concentration in the whole fetus relative to maternal plasma, increased 10-fold ( P < 0.005) between d 16 and d 22 of pregnancy. Over this same period, Ob-R-S protein expression in the placental labyrinth zone increased by almost 2-fold. Transplacental leptin passage was reduced ( P < 0.05) by 77% after maternal dexamethasone treatment, whereas suppression of endogenous glucocorticoid synthesis ( by metyrapone) increased ( P < 0.05) the transfer of maternal leptin to the fetus by 55%. These data show that transplacental passage of maternal leptin is a significant source of fetal leptin and increases markedly during late pregnancy. Consistent with the proposed role of leptin as a fetal growth factor, transplacental leptin passage is reduced in association with glucocorticoid-induced fetal growth retardation.