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Overnutrition and maternal obesity in sheep pregnancy alter the JNK‐IRS‐1 signaling cascades and cardiac function in the fetal heart
Author(s) -
Wang Jingying,
Ma Heng,
Tong Chao,
Zhang Hanying,
Lawlis Gavin B.,
Li Yuanda,
Zang Mengwei,
Ren Jun,
Nijland Mark J.,
Ford Stephen P.,
Nathanielsz Peter W.,
Li Ji
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.09-142315
Subject(s) - medicine , endocrinology , insulin resistance , insulin receptor , fetus , cardiac function curve , protein kinase b , ampk , insulin , signal transduction , phosphorylation , pregnancy , protein kinase a , biology , heart failure , biochemistry , genetics
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 μU/ml, respectively) vs. CON ewes (23.80±1.38 mg/dl and 0.769±0.256 μU/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.—Wang, J., Ma, H., Tong, C., Zhang, H., Lawlis, G. B., Li, Y., Zang, M., Ren, J., Nijland, M. J., Ford, S. P., Nathanielsz, P. W., Li, J. Overnutrition and maternal obesity in sheep pregnancy alter the JNK‐IRS‐1 signaling cascades and cardiac function in the fetal heart. FASEBJ. 24, 2066–2076 (2010). www.fasebj.org