Search

Apelin is an insulin-sensitizing hormone increased in abundance with obesity. Apelin and its receptor, APJ, are expressed in the human placenta, but whether apelin regulates placental function in normal body mass index (BMI) and obese pregnant women remains unknown. We hypothesized that apelin stimulates amino acid transport in cultured primary human trophoblast (PHT) cells and that maternal circulating apelin levels are elevated in obese pregnant women delivering large babies. Treating PHT cells with physiological concentrations of the pyroglutamated form [Pyr 1 ]apelin-13 (0.1-10.0 ng/ml) for 24 h dose-dependently increased System A amino acid transport ( P < 0.05) but did not affect System L transport activity. Mechanistic target of rapamycin (mTOR), extracellular signal-regulated kinase-1/2 (ERK1/2), and AMP-activated protein kinase-α (AMPKα) signaling were unaffected by apelin ( P > 0.05). Plasma apelin was not different in obese women (BMI 35.8 ± 0.7, n = 21) with large babies compared with normal-BMI women (23.1 ± 0.5, n = 16) delivering normal birth weight infants. Apelin was highly expressed in placental villous tissue (20-fold higher vs. adipose), and APJ was present in syncytiotrophoblast microvillous membrane, but neither differed in abundance between normal-BMI and obese women. Phosphorylation (Thr 172 ) of placental AMPKα strongly correlated with microvillous membrane APJ expression ( P < 0.01, R  = 0.63) but negatively correlated with placental apelin abundance ( P < 0.01, R  = -0.62). Neither placental APJ nor apelin abundance correlated with maternal BMI, plasma insulin, birth weight, or mTOR or ERK1/2 signaling ( P > 0.05). Hence, apelin stimulates trophoblast amino acid uptake, establishing a novel mechanism regulating placental function. We found no evidence that apelin constitutes an endocrine link between maternal obesity and fetal overgrowth.

The System L transporter facilitates cellular import of large neutral amino acids (AAs) such as Leu, a potent activator of the intracellular target of rapamycin (TOR) pathway, which signals for cell growth. System L is an AA exchanger, proposed to accumulate certain AAs by coupling to dissipation of concentration gradient(s) of exchange substrates generated by secondary active AA transporters such as System A (SNAT2). We addressed the hypothesis that this type of coupling (termed tertiary active transport) acts as an indirect mechanism to extend the range of AA stimulating TOR to those transported by both Systems A and L (e.g., Gln) through downstream enhancement of Leu accumulation. System A overexpression enabled Xenopus oocytes to accumulate substrate AAs (notably Ser, Gln, Ala, Pro, Met; totaling 2.6 nmol/oocyte) from medium containing a physiological AA mixture at plasma concentrations. Net accumulation of System L (4F2hc-xLAT1) substrates from this medium by System L-overexpressing oocytes was increased by 90% (from 0.7 to 1.35 nmol/oocyte; mainly Leu, Ile) when Systems A and L were coexpressed, coincident with a decline in accumulation of specific System A substrates (Gln, Ser, Met), as expected if the latter were also System L substrates and functional coupling of the transport Systems occurred. AA flux coupling was confirmed as trans-stimulation of Leu influx in System L-expressing oocytes by Gln injection (0.5 nmol/oocyte). The observed changes in Leu accumulation are sufficient to activate the TOR pathway in oocytes, although intracellular AA metabolism limits the potential for AA accumulation by tertiary active transport in this system.