Abstract 18063: Maternal and Postnatal High-Fat Diet Interaction Leads to Greater Risk of Myocardial Dysfunction in Offspring via Obesity-Induced Lipotoxicity, IRS-1 Serine Phosphorylation and Mitochondrial Defects

Abstract

Introduction: Maternal obesity/overnutrition during gestation and lactation are associated with increased prevalence of obesity and cardiovascular risk in adult offspring. Given the pervasive “obesogenic” environment, long-term consequences of maternal and/or postnatal overnutrition on myocardial function warrant immediate attention. Objective: We examined the impact of maternal and long- term postnatal dietary fat exposure on metabolic, myocardial, intracellular Ca2+, insulin and mitochondrial responses. Methods and Results: Pregnant FVB mice were fed either a low-fat (LF, 10% of calories) or high-fat (HF, 45% of calories) diet during gestation and lactation. Weaning male offspring were randomized and placed on either LF or HF (a food-restricted HF-fed mice served as weight control group) for 4 months prior to assessment of metabolic indexes, myocardial histology, cardiac function, insulin signaling, mitochondrial integrity and ROS generation. Compared with LF-fed and HF-fed weight-control mice, postnatal HF intake resulted in obesity (DIO), exhibited marked dyslipidemia, blunted insulin sensitivity, cardiac hypertrophy, compromised myocardial function, intracellular Ca2+ homeostasis and mitochondrial biogenesis, all of which were significantly accentuated in postnatal HF-fed mice with maternal high fat exposure.Interestingly, LF-fed offspring from HF-fed dams displayed higher body weights, increased adiposity and dampened insulin sensitivity compared to LF-fed controls. Maternal HF exposure upregulated postnatal HF-induced IRS-1 serine phosphorylation, PTP1B, lipogenic enzyme SCD-1 and hypertrophic markers while downregulating cardiac AMPK signaling and PGC-1α. Importantly, myocardial and mitochondrial ultrastructural abnormalities were more pronounced in HF-fed offspring with maternal HF exposure, as shown by loss of mitochondrial density and membrane potential, increased ROS generation and apoptosis. Conclusion: We conclude that prenatal fat exposure may program the offspring at a higher risk for postnatal DIO induced cardiac hypertrophy and dysfunction possibly related to cardiac hypertrophy and lipotoxicity, impaired insulin signaling, mitochondrial dysfunction and oxidative stress.