Leptin affects system A amino acid transport activity in the human placenta: evidence for STAT3 dependent mechanisms.
BACKGROUND
Amino acids are important nutrients during fetal development, and the activity of placental amino acid transporters is crucial in the regulation of fetal growth. Leptin, an adipocyte- and placenta-derived hormone, has been proposed to act as a peripheral signal in reproduction in humans. Leptin is elevated during pregnancy and elevated further in pathologic pregnancies such as preeclampsia. However, the role of leptin in placental function has not been fully elucidated. We hypothesize that leptin plays a role in the regulation of placental amino acid transport by activation of the JAK-STAT pathway.


METHODS
Placental amino acid transport, specifically system A transport was studied in placental villous fragments using the amino acid analog, methylaminoisobutyric acid (MeAIB). Specific inhibitors of the JAK-STAT signal transduction pathway were used to further elucidate their role in leptin-mediated effects on amino acid transport activity. Western blotting was performed to identify STAT3 phosphorylation as a measure of leptin receptor activation.


RESULTS
Leptin significantly increased system A amino acid transporter activity by 22-42% after 1h of incubation. Leptin activated JAK-STAT signaling pathway as evidenced by STAT3 phosphorylation, and inhibition of STAT3 or JAK2 resulted in 36-45% reduction in system A amino acid transporter activity. Furthermore, blocking endogenously produced leptin also decreased system A transport by 45% comparable to STAT3 inhibition.


CONCLUSIONS
These data demonstrate that leptin stimulates system A by JAK-STAT dependent pathway in placental villous fragments. Our findings support the autocrine/paracrine role of leptin in regulating amino acid transport in the human placenta.
von Versen-Höynck
F
F
Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, USA.
Rajakumar
A
A
Parrott
M S
MS
Powers
R W
RW
D026924:Amino Acid Transport System A / Q000378:metabolism*; D002824:Chorionic Villi / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D053612:Janus Kinases / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D020738:Leptin / Q000378:metabolism / Q000494:pharmacology*; D010766:Phosphorylation; D010920:Placenta / Q000187:drug effects* / Q000378:metabolism*; D011247:Pregnancy; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
D026924:Amino Acid Transport System A; D020738:Leptin; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D007770:L-Lactate Dehydrogenase; D053612:Janus Kinases