Overnutrition and maternal obesity in sheep pregnancy alter the JNK‐IRS‐1 signaling cascades and cardiac function in the fetal heart

Abstract

Maternal obesity in pregnancy predisposes offspring to insulin resistance and associated cardiovascular disease. Here, we used a well-established sheep model to investigate the effects of maternal obesity on cardiac functions. Multiparous ewes were assigned to a control (CON) diet [100% of National Research Council (NRC) recommendations] or an obesogenic (OB) diet (150% of NRC recommendations) from 60 d before conception to necropsy on d 135 of pregnancy. Fetal blood glucose and insulin were increased (P<0.01, n=8) in OB (35.09+/-2.03 mg/dl and 3.40+/-1.43 microU/ml, respectively) vs. CON ewes (23.80+/-1.38 mg/dl and 0.769+/-0.256 microU/ml). Phosphorylation of AMP-activated protein kinase (AMPK), a cardioprotective signaling pathway, was reduced (P<0.05), while the stress signaling pathway, p38 MAPK, was up-regulated (P<0.05) in OB maternal and fetal hearts. Phosphorylation of c-Jun N-terminal kinase (JNK) and insulin receptor substrate-1 (IRS-1) at Ser-307 were increased (P<0.05) in OB fetal heart associated with lower downstream PI3K-Akt activity (P<0.05), indicating impaired cardiac insulin signaling. Although OB fetal hearts exhibited a normal contractile function vs. CON fetal hearts during basal perfusion, they developed an impaired heart-rate-left-ventricular-developed pressure product in response to high workload stress. Taken together, fetuses of OB mothers demonstrate alterations in cardiac PI3K-Akt, AMPK, and JNK-IRS-1 signaling pathways that would predispose them to insulin resistance and cardiac dysfunction.

Identification and comparative analyses of myocardial miRNAs involved in the fetal response to maternal obesity

“…These effects have been confirmed in sheep and rat models of maternal overnutrition (3,47,51,85,98,104,111). The in utero environment can substantially modify how the fetal genome is expressed, thereby exerting stimulatory or inhibitory effects on fetal growth and adiposity.…”

“…The microarray data were converted to fold change to directly compare with RT-PCR values, n ϭ 6 RD and 5 HFD, *P Ͻ 0.05. this early stage of development could lead to progressive increase in ventricular stiffness and impaired cardiac function in offspring. We have previously shown that cardiac function is already impaired by late gestation in a sheep model of maternal obesity (104).…”

“…We and others have studied maternal and fetal baboon physiology in both normal pregnancy and following perturbations that led to developmental programming (65). We have shown that maternal overnutrition in sheep leads to impaired fetal cardiac function and altered insulin signaling (104). Our aim in the present study was to undertake a comprehensive sequencing and profiling analysis of miRNA expression in the hearts of baboon fetuses exposed to maternal overnutrition.…”

Maternal obesity induces fibrosis in fetal myocardium of sheep

“…In our previous studies in sheep pregnancy, we observed that MO induced inflammation in fetal skeletal muscle as demonstrated by the upregulation of nuclear factor light-chain enhancer of activated B cells and Jun NH 2 -terminal kinase (JNK) pathways (32,38), changes that were accompanied by enhanced fibrosis (14). Inflammation was detected in the fetal myocardium of the same cohort of sheep as shown by the enhanced phosphorylation of JNK, which correlated with impaired contractile function of fetal myocardia in response to high workload stress (35). These data prompted us to conduct the current study to assess fibrosis in fetal myocardium and associated changes in TGF-␤ and p38 signaling.…”

Alterations in maternal and fetal heart functions accompany failed spiral arterial remodeling in pregnant mice

“…Cost may be almost nil for the mouse mother, unless the transient gain in heart weight results in subsequent inflammation or scarring. 39 The fetal mouse cost is likely cardiac hypertrophy and elevated risk for later cardiovascular disease. 40 Might our data suggest that development of therapeutic approaches for human pregnancies with impaired SA remodeling that prevent engagement of lymphocytes, promote their early disengagement or scavenging of their products would be beneficial in prolonging gestation and permitting physiological normalization of the maternal and fetal circulations near term?…”