Maternal high-fat diet impairs cardiac function in offspring of diabetic pregnancy through metabolic stress and mitochondrial dysfunction

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.

Maternal obesity and increased neonatal adiposity correspond with altered infant mesenchymal stem cell metabolism

“…Similar patterns of upregulation in components of the electron transport chain and a downregulation of biogenesis have been reported in our NHP model in fetal offspring of OB, Western style diet-fed mothers (41). Functional effects on mitochondrial health have also been noted in fetal tissue with maternal obesity and high-fat diet exposure in rats (45). Similar alterations in mitochondrial function and quality control, including affected MFN2 protein expression, have been demonstrated across multiple generations of OB mice with (46).…”

Prenatal Exposure to a Maternal High-Fat Diet Affects Histone Modification of Cardiometabolic Genes in Newborn Rats

“…Similar observations were previously reported with echocardiographic data in larger cohorts of rat pups using the same animal model (Figure 1) [11,24]. Although we did not observe any significant interaction effect on neonatal heart weight due to combined diet and diabetes exposure, diabetes-exposed (CS) pups had significantly higher average heart weight compared to controls (CC) (55.64 ± 1.95 mg vs. 48.94 ± 2.03 mg, p < 0.05).…”

“…Together with others reporting liver-tissue-specific fetal metabolic programming [73,74,75], the results discussed here clearly demonstrate that epigenetic cues for metabolic disease risk are established in utero. These results further corroborate our previous reports on hyperinsulinemia and hyperlipidemia observed in rat offspring born to diabetic and/or HF-fed dams, particularly during pregnancy [11]. However, here we did not observe any synergy between prenatal exposure of a HF-diet and diabetes.…”

“…Gene selection was based on two criteria: those with higher levels of changes and also with functional relevance to our previously reported phenotype [11]. Due to the gains of the H3K4me3 mark in the diet exposed group for all genes and in the diabetes exposed group for one of the five selected genes ( Hsp1a1 ), expression levels of these selected genes were anticipated to be upregulated in a corresponding manner.…”

“…Expression of these genes may further explain the lipotoxic phenotype found in the hearts of HF diet-exposed newborn offspring [11]. In this context, we did not observe higher body weight in the HF-diet exposed newborns, although the hearts were larger and had significant lipid deposition [11].…”