title: Chronic maternal infusion of full-length adiponectin in pregnant mice down-regulates placental amino acid transporter activity and expression and decreases fetal growth.
abstract: Maternal adiponectin levels are inversely correlated to birth weight, suggesting that maternal adiponectin limits fetal growth. We hypothesized that full-length adiponectin (fADN) infusion in pregnant mice down-regulates placental amino acid transporters and decreases fetal growth. Starting at embryonic day (E) 14.5, fADN (0.62 ± 0.02 μg (g body weight)(−1) day(−1), n = 7) or vehicle (control, n = 9) were infused in pregnant C57/BL6 mice by mini-osmotic pump. At E18.5, dams were killed and placental homogenates and trophoblast plasma membrane (TPM) vesicles were prepared. Infusion of fADN elevated maternal serum fADN by 4-fold and decreased fetal weights by 18%. Adiponectin receptor 2, but not adiponectin receptor 1, was expressed in TPM. fADN infusion decreased TPM System A (–56%, P < 0.001) and System L amino acid transporter activity (–50%, P < 0.03). TPM protein expression of SNAT1, 2 and 4 (System A amino acid transporter isoforms) and LAT1 and LAT2, but not CD98, (System L amino acid transporter isoforms) was down-regulated by fADN infusion. To identify possible mechanisms underlying these changes we determined the phosphorylation of proteins in signalling pathways known to regulate placental amino acid transporters. fADN decreased phosphorylation of insulin receptor substrate-1 (Tyr-608), Akt (Thr-308 and Ser-473), S6 kinase 1 (Thr-389), eukaryotic initiation factor 4E binding protein 1 (Thr-37/46 and Thr-70) and ribosomal protein S6 (Ser-235/236) and increased the phosphorylation of peroxisome proliferator-activated receptor α (PPARα) (Ser-21) in the placenta. These data suggest that maternal adiponectin decreases fetal growth by down-regulation of placental amino acid transporters, which limits fetal nutrient availability. This effect may be mediated by inhibition of insulin/IGF-I and mTOR signalling pathways, which are positive regulators of placental amino acid transporters. We have identified a novel physiological mechanism by which the endocrine functions of maternal adipose tissue influence fetal growth.
authors.affiliation: Center for Pregnancy and Newborn Research, Department of Obstetrics and Gynecology, University of Texas Health Science Center San Antonio, Mail Code 7836, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA. josephf@uthscsa.edu
authors.forename: Fredrick J
authors.initials: FJ
authors.lastname: Rosario
authors.forename: Michael A
authors.initials: MA
authors.lastname: Schumacher
authors.forename: Jean
authors.initials: J
authors.lastname: Jiang
authors.forename: Yoshikatsu
authors.initials: Y
authors.lastname: Kanai
authors.forename: Theresa L
authors.initials: TL
authors.lastname: Powell
authors.forename: Thomas
authors.initials: T
authors.lastname: Jansson
mesh_terms: D052242:Adiponectin / Q000097:blood / Q000494:pharmacology*; D026905:Amino Acid Transport Systems / Q000378:metabolism*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002462:Cell Membrane / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D047109:Fetal Development / Q000187:drug effects*; D007328:Insulin / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D047493:PPAR alpha / Q000378:metabolism; D010920:Placenta / Q000187:drug effects* / Q000378:metabolism; D011247:Pregnancy; D054419:Receptors, Adiponectin / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014327:Trophoblasts / Q000378:metabolism
chemical_list: D052242:Adiponectin; D026905:Amino Acid Transport Systems; D007328:Insulin; D047493:PPAR alpha; D054419:Receptors, Adiponectin; C475419:adiponectin receptor 1, mouse; C475421:adiponectin receptor 2, mouse; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases