Down-Regulation of Growth Signaling Pathways Linked to a Reduced Cotyledonary Vascularity in Placentomes of Over-Nourished, Obese Pregnant Ewes
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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 approximately 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.
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Data from over-nutrition models are conflicting: an obesogenic diet causes activation of mTOR in rat placentas, but the opposite was found following over-nutrition in sheep and mice fed an obesogenic diet.
“Thus, whilst an obesogenic diet has been shown to cause activation of mTOR in rat placentas (205), the opposite was found following over-nutrition in sheep (150% of control diet) and mice fed an obesogenic diet (323, 615).”
From Placental Origins of Chronic Disease (2016) · cites this paper as [615]
Dietary restriction during early to mid-gestation in ewes resulted in increased activation of AMPK in the fetal cotyledonary tissues at d78 but not later on d135, whereas over-nutrition resulted in the reverse.
“Dietary restriction (50% of controls) during early to mid-gestation in ewes resulted in increased activation of AMPK in the fetal cotyledonary tissues at d78 but not later on d135 (353), whereas the reverse was the case with over-nutrition (150% of controls) (615).”
From Placental Origins of Chronic Disease (2016) · cites this paper as [615]
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- Authors
- Zhu, M. J., Du, M., Nijland, M. J., Nathanielsz, P. W., Hess, B. W., Moss, G. E., & Ford, S. P.
- Affiliations
- University of Wyoming (US)
- The University of Texas at San Antonio Health Science Center (US)
- Corresponding author
- Ford, S.P.
- Venue
- Placenta
- Publisher
- Elsevier BV
- Published
- 2009-05
- Volume
- 30
- Issue
- 5
- Pages
- 405-410
- ISSN
- 0143-4004 (ISSN-L)
- PMC
- PMC4575950
- OpenAlex
- W1993591219
- Cited by
- 54
- References
- 48
- Citations by year
- 2024: 3 · 2023: 4 · 2022: 3 · 2021: 1 · 2020: 1 · 2019: 3 · 2018: 4 · 2017: 1 · 2016: 3 · 2015: 5 · 2014: 3 · 2013: 6 · 2012: 5
- FWCI
- 5.04
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Placenta (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (2p20rr016474-09)
- National Center for Research Resources (P20-RR-016474, P20 RR0 16474-04)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R03HD057506, R01HD067449)
- Topics
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
- Life Sciences › Agricultural and Biological Sciences › Agronomy and Crop Science › Reproductive Physiology in Livestock
- Health Sciences › Medicine › Obstetrics and Gynecology › Pregnancy and preeclampsia studies
- Keywords
- AMPK, insulin/IGF-1 signaling, placental arteries, maternal obesity, acetyl-CoA carboxylase, IRS-1 phosphorylation, IGF-1 receptor, placental vascularization, fetal growth, fetal insulin, fetal glucose
- MeSH terms
- Acetyl-CoA Carboxylase, Animals, Female, Insulin, Insulin-Like Growth Factor I, Obesity, Phosphorylation, Placenta, Pregnancy, Sheep, Signal Transduction, Down-Regulation, AMP-Activated Protein Kinases
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