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Maternal high-fat diet impairs cardiac function in offspring of diabetic pregnancy through metabolic stress and
Kennedy S Mdaki1, Tricia D Larsen1, Angela L Wachal1
1Children's Health Research Center, Sanford Research, Sioux Falls, South Dakota;
Insights
Maternal high-fat diet and diabetes during pregnancy impair offspring heart function. Combination exposure leads to severe cardiac dysfunction and lipid accumulation, highlighting metabolic stress in developmental programming.
Area of Science:
- Cardiovascular Biology
- Developmental Biology
- Metabolic Disease
Background:
- Offspring of diabetic pregnancies face lifelong cardiovascular disease risk, linked to fuel-mediated effects on the developing heart.
- Glycemic control is key, but the impact of lipids and cellular bioenergetics in this context remains unclear.
- Maternal hyperlipidemia and diabetes can influence cellular energy production, a critical factor in adult cardiovascular disease.
Purpose of the Study:
- To investigate if maternal high-fat diet, alone or with diabetes, impairs offspring cardiac fuel metabolism and mitochondrial function.
- To assess the combined effects of maternal diabetes and high-fat diet on fetal heart development and physiology.
- To understand the role of cellular bioenergetics in developmental programming of cardiac disease.
Main Methods:
- Rats received control/high-fat diet and placebo/streptozotocin during pregnancy, yielding four offspring groups: control, diabetes-exposed, diet-exposed, and combination-exposed.
- Evaluated offspring cardiac function, cellular bioenergetics (mitochondrial and glycolytic stress tests, palmitate oxidation), lipid peroxidation, and mitochondrial morphology/copy number.
- Utilized Sprague-Dawley rat model to examine fuel metabolism and mitochondrial health in developing hearts.
Main Results:
- Diabetes-exposed offspring showed reduced glycolytic and respiratory capacity, and impaired proton leak.
- High-fat diet-exposed offspring exhibited increased mitochondrial copy number, lipid peroxidation, and signs of mitochondrial dysfunction.
- Combination-exposed offspring had the most severe outcomes, including cardiac lipid droplets and impaired systolic/diastolic function, mirroring adult diabetic cardiomyopathy.
Conclusions:
- Maternal high-fat diet exacerbates cardiac dysfunction in offspring of diabetic pregnancies via metabolic stress.
- This study demonstrates the critical role of cellular bioenergetics in developmental programming of cardiac disease.
- Findings underscore the need to consider lipid profiles alongside glycemic control in preventing offspring cardiovascular risks.
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.
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