Down-regulation of placental mTOR, insulin/IGF-I signaling, and nutrient transporters in response to maternal nutrient restriction in the baboon

Jovita V. Kavitha, Fredrick J. Rosario, Mark J Nijland, Thomas J. McDonald, Guoyao Wu, Yoshikatsu Kanai, Theresa L. Powell, Peter W. Nathanielsz, Thomas Jansson

Research output: Contribution to journalArticle

64 Citations (Scopus)

Abstract

The mechanisms by which maternal nutrient restriction (MNR) causes reduced fetal growth are poorly understood. We hypothesized that MNR inhibits placental mechanistic target of rapamycin (mTOR) and insulin/IGF-I signaling, down-regulates placental nutrient transporters, and decreases fetal amino acid levels. Pregnant baboons were fed control (ad libitum, n=11) or an MNR diet (70% of controls, n=11) from gestational day (GD) 30. Placenta and umbilical blood were collected at GD 165. Western blot was used to determine the phosphorylation of proteins in the mTOR, insulin/IGF-I, ERK1/2, and GSK-3 signaling pathways in placental homogenates and expression of glucose transporter 1 (GLUT-1), taurine transporter (TAUT), sodium-dependent neutral amino acid transporter (SNAT), and large neutral amino acid transporter (LAT) isoforms in syncytiotrophoblast microvillous membranes (MVMs). MNR reduced fetal weights by 13%, lowered fetal plasma concentrations of essential amino acids, and decreased the phosphorylation of placental S6K, S6 ribosomal protein, 4E-BP1, IRS-1, Akt, ERK-1/2, and GSK-3. MVM protein expression of GLUT-1, TAUT, SNAT-2 and LAT-1/2 was reduced in MNR. This is the first study in primates exploring placental responses to maternal undernutrition. Inhibition of placental mTOR and insulin/IGF-I signaling resulting in down-regulation of placental nutrient transporters may link maternal undernutrition to restricted fetal growth.

Original languageEnglish (US)
Pages (from-to)1294-1305
Number of pages12
JournalFASEB Journal
Volume28
Issue number3
DOIs
StatePublished - 2014

Fingerprint

Papio
Sirolimus
Insulin-Like Growth Factor I
Nutrients
Down-Regulation
Mothers
Insulin
Food
Neutral Amino Acid Transport Systems
Glycogen Synthase Kinase 3
Phosphorylation
Facilitative Glucose Transport Proteins
Fetal Development
Malnutrition
Large Neutral Amino Acid-Transporter 1
Amino Acid Transport System L
TOR Serine-Threonine Kinases
Ribosomal Protein S6
Umbilicus
Fetal Weight

Keywords

  • Fetal growth restriction
  • Nonhuman primate
  • Trophoblast

ASJC Scopus subject areas

  • Biochemistry
  • Biotechnology
  • Genetics
  • Molecular Biology
  • Medicine(all)

Cite this

Down-regulation of placental mTOR, insulin/IGF-I signaling, and nutrient transporters in response to maternal nutrient restriction in the baboon. / Kavitha, Jovita V.; Rosario, Fredrick J.; Nijland, Mark J; McDonald, Thomas J.; Wu, Guoyao; Kanai, Yoshikatsu; Powell, Theresa L.; Nathanielsz, Peter W.; Jansson, Thomas.

In: FASEB Journal, Vol. 28, No. 3, 2014, p. 1294-1305.

Research output: Contribution to journalArticle

Kavitha, JV, Rosario, FJ, Nijland, MJ, McDonald, TJ, Wu, G, Kanai, Y, Powell, TL, Nathanielsz, PW & Jansson, T 2014, 'Down-regulation of placental mTOR, insulin/IGF-I signaling, and nutrient transporters in response to maternal nutrient restriction in the baboon', FASEB Journal, vol. 28, no. 3, pp. 1294-1305. https://doi.org/10.1096/fj.13-242271
Kavitha, Jovita V. ; Rosario, Fredrick J. ; Nijland, Mark J ; McDonald, Thomas J. ; Wu, Guoyao ; Kanai, Yoshikatsu ; Powell, Theresa L. ; Nathanielsz, Peter W. ; Jansson, Thomas. / Down-regulation of placental mTOR, insulin/IGF-I signaling, and nutrient transporters in response to maternal nutrient restriction in the baboon. In: FASEB Journal. 2014 ; Vol. 28, No. 3. pp. 1294-1305.
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AU - McDonald, Thomas J.

AU - Wu, Guoyao

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AU - Powell, Theresa L.

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AU - Jansson, Thomas

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