Abstract 1374: Impairment of JNK-IRS-1 Signaling Cascades and Cardiac Function in Fetal Heart During Overnourished Obese Sheep Pregnancy
Obese pregnant mothers may expose their children to high risk of Type 2 diabetes and myocardial hypertrophy. We hypothesize that alterations in cardiac signaling pathways and cardiac function may occur in embryonic-fetal development during maternal obesity and nutritional excess. Phenotype matched multiparous ewes were assigned to a control (C, 100% National research Council (NRC) recommendations) or obese (OB, 150% NRC) diet from 60 days before conception to necropsy on day 75 of pregnancy. Maternal and fetal blood was collected under anesthesia, and following euthanasia, left ventricular tissue (LVT) was collected from both maternal and fetal hearts for further immunoblotting assays. Glucose and insulin levels in fetal blood were markedly increased (p<0.01, n=5) in OB (35.09±2.03 mg/dL and 3.4±1.433 uU/ml, respectively) vs. C ewes (23.8±1.38 mg/dL and 0.769±0.256 uU/ml, respectively). Total LVT weight of both the OB ewes and fetuses were greater (p<0.05, n=5) than those in the C group. The immunoblotting results revealed that phosphorylation of AMP-activated protein kinase (AMPK), which is associated with cardioprotection, was reduced (p<0.05, n=5) in both maternal and fetal LVT from OB sheep, while the stress signaling, p38 MAPK, was up-regulated (p<0.05, n=5). Phosphorylation of c-Jun N-terminal kinase (JNK) and insulin receptor substrate-1 (IRS-1) at Ser307 site were increased (p<0.05, n=5) in LVT of OB ewes and fetuses, which resulted in markedly decreased downstream Akt phosphorylation (p<0.01, n=5), suggesting an impaired cardiac insulin signaling. The left ventricle developed pressure was decreased in OB fetal hearts (30.2±2.6 vs. 45.2±3.9 mmHg, OB vs. C, p<0.05, n=3) in Langendorff perfusion mode. The level of fatty acid transporter protein FATP1 and FATP4 did not change between OB and C ewes and fetuses. However, the level of CD36 facilitating myocardial fatty acid transport was decreased in OB ewes (p<0.05, n=5), indicating a high risk of hypertrophic cardiomyopathy.
Conclusions: These data suggest that obese pregnant mothers could predispose their offsprings to cardiac malfunction and insulin resistance during fetal development, as demonstrated by blunted Akt and AMPK signaling pathways, and altered JNK-IRS-1 signaling cascades.
This research has received full or partial funding support from the American Heart Association, National Center.