Down-Regulation of Growth Signaling Pathways Linked to a Reduced Cotyledonary Vascularity in Placentomes of Over-Nourished, Obese Pregnant Ewes

M. J. Zhu, M. Du, M. J. Nijland, P. W. Nathanielsz, B. W. Hess, G. E. Moss, S. P. Ford

Research output: Contribution to journalArticlepeer-review

38 Scopus citations


Both protein kinase B (Akt) and extracellular signal-regulated kinase 1/2 (ERK1/2) are down-stream components of the insulin/insulin like growth factor-1 (IGF-1) signaling pathway. AMP-activated protein kinase (AMPK) is known to sensitize cells to insulin/IGF-1 signaling. The objective of this study was to assess the activity of AMPK and its role in the observed down-regulation of insulin/IGF-1 signaling in cotyledonary (COT) arteries supplying the placental component of the ewe placentome. Nonpregnant ewes were randomly assigned to a control (C, 100% of NRC recommendations) or obesogenic (OB, 150% of NRC) diet from 60 days before conception until necropsy on day 75 of gestation (n = 5/group) or until lambing (n = 5/group). At necropsy on day 75 of gestation, the smallest terminal arteries that entered the COT tissues (0.5-1.0 mm in diameter) were collected for analyses. Fetal weights were ∼20% greater (P < 0.05) on OB than C ewes, but birth weights of lambs were similar across dietary groups. Fetal plasma concentrations of glucose, insulin and IGF-1 were higher (P < 0.05) in the blood of fetuses from OB than C ewes. Total AMPK and phosphorylated AMPK at Thr 172 (the active form) were reduced (P < 0.05) by 19.7 ± 8.4% and 25.9 ± 7.7%, respectively in the COT arterial tissues of OB ewes. Total acetyl-CoA carboxylase (ACC), a down-stream target of AMPK, and its phosphorylated form were also reduced (P < 0.05) by 32.9 ± 9.2% and 45.4 ± 14.6%, respectively. The phosphorylation of IRS-1 at Ser 789, a site phosphorylated by AMPK, was 24.5 ± 9.0% lower (P < 0.05) in COT arteries of OB than C ewes. No alteration in total insulin receptor, total IGF-1 receptor or their phosphorylated forms was observed, down-stream insulin signaling was down-regulated in COT arteries of OB ewes, which may have resulted in the observed decrease in COT vascular development in OB ewes.

Original languageEnglish (US)
Pages (from-to)405-410
Number of pages6
Issue number5
StatePublished - May 2009
Externally publishedYes


  • IGF-1
  • Insulin
  • Maternal obesity
  • Placentome
  • Sheep
  • Vascularity

ASJC Scopus subject areas

  • Reproductive Medicine
  • Obstetrics and Gynecology
  • Developmental Biology


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