title: Interaction between maternal and postnatal high fat diet leads to a greater risk of myocardial dysfunction in offspring via enhanced lipotoxicity, IRS-1 serine phosphorylation and mitochondrial defects.
abstract: Maternal overnutrition is associated with heart diseases in adult offspring. However, combined effect of maternal and postnatal fat intake on cardiac function is unknown. This study was designed to examine the impact of maternal and postnatal fat intake on metabolic, myocardial, insulin and mitochondrial responses in adult offspring. Pregnant FVB mice were fed a low fat (LF) or high fat (HF) diet during gestation and lactation. Weaning male offspring were placed on either LF or HF (calorie-restricted HF-fed mice used as weight control) for 4 months prior to assessment of metabolic indices, myocardial histology, cardiac function, insulin signaling, mitochondrial integrity and reactive oxygen species (ROS) generation. Compared with LF- and HF-fed weight-control mice, postnatal HF intake resulted in obesity, adiposity, dyslipidemia, insulin resistance, cardiac hypertrophy, interrupted cardiac contractile, intracellular Ca(2+) and mitochondrial properties, all of which were significantly accentuated by prenatal fat exposure. Despite the preserved cardiac contractile function, LF offspring from HF-fed dams displayed higher body weights, increased adiposity and glucose intolerance. HF-fed mice with prenatal HF exposure displayed upregulated serine phosphorylation of IRS-1, PTP1B, the rate-limiting fatty acid synthesis enzyme stearoyl-CoA desaturase (SCD1) and hypertrophic markers (calcineurin A, GATA4, ANP, β-MHC and skeletal α-actin), while suppressing AMP-dependent protein kinase, glucose uptake and PGC-1α levels. Importantly, myocardial and mitochondrial ultrastructural abnormalities were more pronounced in HF-fed offspring with prenatal fat exposure, shown as loss of mitochondrial density and membrane potential, increased ROS generation and apoptosis. Our data suggest that prenatal dietary fat exposure predisposes offspring to postnatal dietary fat-induced cardiac hypertrophy and contractile defect possibly via lipotoxicity, glucose intolerance and mitochondrial dysfunction. This article is part of a Special Issue entitled "Focus on Cardiac Metabolism".
authors.affiliation: Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA.
authors.forename: Subat
authors.initials: S
authors.lastname: Turdi
authors.forename: Wei
authors.initials: W
authors.lastname: Ge
authors.forename: Nan
authors.initials: N
authors.lastname: Hu
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Bradley
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Wang
authors.forename: Jun
authors.initials: J
authors.lastname: Ren
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D017667:Adipocytes / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000818:Animals; D017209:Apoptosis; D015415:Biomarkers; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D006332:Cardiomegaly / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology; D059305:Diet, High-Fat / Q000009:adverse effects*; D004452:Echocardiography; D005260:Female; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D006321:Heart / Q000503:physiopathology*; D006801:Humans; D006984:Hypertrophy; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism*; D050356:Lipid Metabolism; D008297:Male; D039382:Maternal Nutritional Physiological Phenomena; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism* / Q000648:ultrastructure; D009929:Organ Size; D010766:Phosphorylation; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000378:metabolism; D000099211:Phospholamban
chemical_list: D055372:AMP-Activated Protein Kinases; D015415:Biomarkers; D002118:Calcium; D002135:Calcium-Binding Proteins; D005947:Glucose; D055504:Insulin Receptor Substrate Proteins; D051057:Proto-Oncogene Proteins c-akt; D017382:Reactive Oxygen Species; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D019831:Sodium-Calcium Exchanger; D000099211:Phospholamban