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

Abstract

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.

Placental contribution to nutritional programming of health and diseases: epigenetics and sexual dimorphism

“…Offspring from obese ewes increased their weight at mid-gestation whereas placentome weight was not altered (Zhu et al, 2009). In a mouse model, a high-fat diet administered before and throughout gestation resulted in fetal overgrowth associated with a normal placental weight (Jones et al, 2009).…”

“…In a sheep model of overnutrition, the placenta demonstrated an impaired vascular development within the fetal cotyledon at an early stage (Redmer et al, 2009), which could explain the reduction of uterine and uteroplacental blood flow at mid-and late gestation (Wallace et al, 2002;Wallace et al, 2008). In another ewe model of obesity, a reduction of vascular density in cotyledonary tissue has been shown at mid-gestation (Zhu et al, 2009). Moreover, at this stage, cotyledonary arteriole diameters were greater in obese ewes, which could increase fetal growth, whereas cotyledonary arterial angiogenic factors from mid-to late gestation decreased in obese ewes, which could limit excessive placental vascular development (Ma et al, 2010).…”

Stress responses at the endometrial–placental interface regulate labyrinthine placental differentiation from trophoblast stem cells

“…In contrast, AMPK is suppressed in placenta during obesogenic diets (Zhu et al 2009). Nutrient restriction and diminished ATP synthesis through serum deprivation in vitro hypersensitizes cells to hypoxic stress by activating as much AMPK in 20 min as is activated overnight when full serum is present (Liu et al 2006, reviewed in Xie et al (2011).…”

Effects of Zinc Deficiency and Supplementation on Leptin and Leptin Receptor Expression in Pregnant Mice

“…Maternal GLUT1-mediated glucose transport is upregulated by AMP-activated protein kinase, the activity of which is regulated by nutrient availability and circulating hormones such as insulin and leptin. [31][32][33] However the regulation of placental GLUT1 expression remains unclear. 34) In accordance with the importance of Zn for fetal development, Zn deficiency was previously associated with congenital malformations, and embryonic and fetal deaths in laboratory animals.…”