Down-regulation of growth signaling pathways linked to a reduced cotyledonary vascularity in placentomes of over-nourished, obese pregnant ewes.
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.
Zhu
M J
MJ
Center for the Study of Fetal Programming, Department of Animal Science, University of Wyoming, Laramie, WY 82071, USA.
Du
M
M
Nijland
M J
MJ
Nathanielsz
P W
PW
Hess
B W
BW
Moss
G E
GE
Ford
S P
SP
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000818:Animals; D015536:Down-Regulation; D005260:Female; D007328:Insulin / Q000502:physiology; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D009765:Obesity / Q000503:physiopathology*; D010766:Phosphorylation; D010920:Placenta / Q000098:blood supply / Q000502:physiology*; D011247:Pregnancy; D012756:Sheep; D015398:Signal Transduction / Q000502:physiology*
D007328:Insulin; D007334:Insulin-Like Growth Factor I; D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase