title: Maternal protein restriction in the rat inhibits placental insulin, mTOR, and STAT3 signaling and down-regulates placental amino acid transporters.
abstract: The mechanisms underlying reduced fetal growth in response to maternal protein restriction are not well established. Maternal levels of insulin, IGF-I, and leptin are decreased in rats fed a low protein (LP) diet. Because these hormones stimulate placental amino acid transporters in vitro, we hypothesized that maternal protein restriction inhibits placental leptin, insulin/IGF-I, and mammalian target of rapamycin signaling and down-regulates the expression and activity of placental amino acid transporters. Pregnant rats were fed either an isocaloric low protein (LP, 4% protein) or control diet (18% protein) and studied at gestational day (GD)15, GD19, or GD21 (term 23). At GD19 and GD21, placental expression of phosphorylated eukaryotic initiation factor 4E binding protein 1 (Thr-36/46 or Thr-70) and phosphorylated S6 ribosomal protein (Ser-235/236) was decreased in the LP group. In addition, placental expression of phosphorylated S6 kinase 1 (Thr-389), phosphorylated Akt (Thr-308), and phosphorylated signal transducer and activator of transcription 3 (Tyr-705) was reduced at GD21. In microvillous plasma membranes (MVM) isolated from placentas of LP animals, protein expression of the sodium-coupled neutral amino acid transporter (SNAT)2 and the large neutral amino acid transporters 1 and 2 was reduced at GD19 and GD21. MVM SNAT1 protein expression was reduced at GD21 in LP rats. SNAT4 and 4F2 heavy chain expression in MVM was unaltered. System A and L amino acid transporter activity was decreased in MVM from LP animals at GD19 and GD21. In conclusion, maternal protein restriction inhibits placental insulin, mammalian target of rapamycin signaling, and signal transducer and activator of transcription 3 signaling, which is associated with a down-regulation of placental amino acid transporters. We speculate that maternal endocrine and metabolic control of placental nutrient transport reduces fetal growth in response to protein restriction.
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, Texas 78229-3900, USA.
authors.forename: Fredrick J
authors.initials: FJ
authors.lastname: Rosario
authors.forename: Nina
authors.initials: N
authors.lastname: Jansson
authors.forename: Yoshikatsu
authors.initials: Y
authors.lastname: Kanai
authors.forename: Puttur D
authors.initials: PD
authors.lastname: Prasad
authors.forename: Theresa L
authors.initials: TL
authors.lastname: Powell
authors.forename: Thomas
authors.initials: T
authors.lastname: Jansson
mesh_terms: D026905:Amino Acid Transport Systems / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D004032:Diet; D004044:Dietary Proteins / Q000494:pharmacology*; D005260:Female; D020567:Fetal Weight; D005786:Gene Expression Regulation / Q000502:physiology*; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D039382:Maternal Nutritional Physiological Phenomena; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D010920:Placenta / Q000378:metabolism*; D010929:Placentation; D011247:Pregnancy; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D051381:Rats; D019893:Ribosomal Protein S6 Kinases / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015430:Weight Gain
chemical_list: D026905:Amino Acid Transport Systems; D002352:Carrier Proteins; D004044:Dietary Proteins; C499526:Eif4ebp1 protein, rat; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases; C526901:Rps6kb1 protein, rat; D058570:TOR Serine-Threonine Kinases