Maternal high-fat diet impairs cardiac function in offspring of diabetic pregnancy through metabolic stress and mitochondrial dysfunction
- 15 March 2016
- journal article
- research article
- Published by American Physiological Society in American Journal of Physiology-Heart and Circulatory Physiology
- Vol. 310 (6), H681-H692
- https://doi.org/10.1152/ajpheart.00795.2015
Abstract
Offspring of diabetic pregnancies are at risk of cardiovascular disease at birth and throughout life, purportedly through fuel-mediated influences on the developing heart. Preventative measures focus on glycemic control, but the contribution of additional offenders, including lipids, is not understood. Cellular bioenergetics can be influenced by both diabetes and hyperlipidemia and play a pivotal role in the pathophysiology of adult cardiovascular disease. This study investigated whether a maternal high-fat diet, independently or additively with diabetes, could impair fuel metabolism, mitochondrial function, and cardiac physiology in the developing offspring's heart. Sprague-Dawley rats fed a control or high-fat diet were administered placebo or streptozotocin to induce diabetes during pregnancy and then delivered offspring from four groups: control, diabetes exposed, diet exposed, and combination exposed. Cardiac function, cellular bioenergetics (mitochondrial stress test, glycolytic stress test, and palmitate oxidation assay), lipid peroxidation, mitochondrial histology, and copy number were determined. Diabetes-exposed offspring had impaired glycolytic and respiratory capacity and a reduced proton leak. High-fat diet-exposed offspring had increased mitochondrial copy number, increased lipid peroxidation, and evidence of mitochondrial dysfunction. Combination-exposed pups were most severely affected and demonstrated cardiac lipid droplet accumulation and diastolic/systolic cardiac dysfunction that mimics that of adult diabetic cardiomyopathy. This study is the first to demonstrate that a maternal high-fat diet impairs cardiac function in offspring of diabetic pregnancies through metabolic stress and serves as a critical step in understanding the role of cellular bioenergetics in developmentally programmed cardiac disease.Keywords
Funding Information
- NIH-NICHD (K08HD078504, R25HD072596)
- NIH-NIGMS (P20GM103548, P20GM103620-01A1)
- NSF-REU (DBI-1262744)
- NSF-EPSCoR (1355423)
- Sanford School of Medicine - University of South Dakota (Faculty Grant)
- Sanford - South Dakota State University Research Collaborative Grant
This publication has 65 references indexed in Scilit:
- Mitophagy: mechanisms, pathophysiological roles, and analysisBiological Chemistry, 2012
- Lipid Metabolism and Toxicity in the HeartCell Metabolism, 2012
- Frequency of Gestational Diabetes Mellitus at Collaborating Centers Based on IADPSG Consensus Panel–Recommended CriteriaDiabetes Care, 2012
- Differential regulation of metabolism by nitric oxide andS-nitrosothiols in endothelial cellsAmerican Journal of Physiology-Heart and Circulatory Physiology, 2011
- Mitochondrial dysfunction in diabetic cardiomyopathyBiochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2011
- Is it time to revisit the Pedersen hypothesis in the face of the obesity epidemic?American Journal of Obstetrics and Gynecology, 2011
- Bioenergetic Profile Experiment using C2C12 Myoblast CellsJournal of Visualized Experiments, 2010
- The Randle cycle revisited: a new head for an old hatAmerican Journal of Physiology-Endocrinology and Metabolism, 2009
- How mitochondria produce reactive oxygen speciesBiochemical Journal, 2008
- Maternal Lipids as Strong Determinants of Fetal Environment and Growth in Pregnancies With Gestational Diabetes MellitusDiabetes Care, 2008