Cardiac mitochondrial dysfunction contributes to obesity-associated heart disease. Maternal and postnatal diet plays an important role in cardiac function, yet the impacts of a mismatch between prenatal and postweaning diet on cardiometabolic function are not well understood. We tested the hypothesis that switching to a standard chow diet after weaning would attenuate systemic metabolic disorders and cardiac and mitochondrial dysfunction associated with maternal and postnatal high-fat/high-sucrose (HFHS) diet in mice. Six-month-old male CD1 offspring from dams fed a HFHS diet and weaned to the same HFHS diet (HH) or switched to a standard chow diet (HC) were compared to offspring from dams fed a low-fat/low-sucrose diet and maintained on the same diet (LL). HC did not decrease body weight (BW) but normalized glucose tolerance, plasma cholesterol, LDL, and insulin levels compared to the HH. Systolic function indicated by the percent fractional shortening was not altered by diet. In freshly isolated cardiac mitochondria, maximal oxidative phosphorylation-linked respiratory capacity and coupling efficiency were significantly higher in the HC in the presence of fatty acid substrate compared to LL and HH, with modification of genes associated with metabolism and mitochondrial function. Switching to a standard chow diet at weaning can attenuate the deleterious effects of long-term HFHS in adult male mouse offspring.

The prevalence of obesity and type 2 diabetes mellitus (T2DM) among children is alarmingly increasing in the United States, and children born from obese mothers are at greater risk for diabetes and cardiovascular disease. Cardiac mitochondrial dysfunction may contribute to heart disease associated with T2DM and obesity. The purpose of this study was to test hypothesis that a maternal obesogenic diet would alter offspring cardiac mitochondrial function and systemic metabolism. Female CD‐1 mice were fed either a high‐fat, high‐sucrose diet (HFHS) or a refined low‐fat, low‐sucrose diet (LFLS) for eight weeks before initiation of pregnancy, gestation, and during lactation. At 21 days, male mice were randomly divided into 3 groups: offspring of HFHS dams weaned onto a standard chow diet (HC), HFHS diet (HH), or offspring of LFLS dams continue fed to LFLS diet (LL). Glucose and insulin tolerance tests were performed in 6 month‐old male offspring, followed by sacrifice for evaluation of cardiac mitochondrial respiratory function. HFHS diet‐induced maternal obesity impaired glucose tolerance and insulin sensitivity in HH offspring. Switching offspring to the control diet (HC) did not decrease body weight associated with maternal obesity, but significantly decreased subcutaneous fat mass compared to the HH, and preserved glucose tolerance and insulin responsiveness to near LL levels. In freshly isolated cardiac mitochondria, maximal oxidative phosphorylation (OXPHOS)‐linked respiratory capacity and coupling efficiency was significantly higher in the HC in the presence of fatty acid substrate (palmitoylcarnitine) compared to LL. In the absence of fatty acids, OXPHOS‐linked respiratory capacity and OXPHOS coupling control were not altered. These results indicate that both maternal and postnatal diet modulate offspring cardiac mitochondrial metabolism, favoring greater fatty acid oxidation in offspring fed a control diet following maternal obesity. Support or Funding Information This study was funded by the American Physiological Society Research Career Enhancement Award and the University of Texas at San Antonio, Office of the Vice President for Research and the College of Education and Human Developments.

A wealth of studies have shown that an adverse intrauterine and perinatal environment is a strong predictor for cardiometabolic diseases in offspring. Conversely, maternal exercise before and during pregnancy has been shown to diminish the risk of offspring developing metabolic disorders later in life. A few promising human and animal studies demonstrated that adult‐onset exercise in offspring can overcome the detrimental effects on offspring health associated with maternal obesity. However, it is unknown whether exercise initiated by adult offspring can mitigate the negative cardiometabolic health induced by maternal obesity. Female CD‐1 mice were fed either a high‐fat, high‐sucrose diet (HFHS) or a refined low‐fat, low‐sucrose diet (LFLS) for eight weeks before pregnancy and gestation, and during lactation. All dams were sedentary throughout the study. At 21 days, female offspring were weaned onto their maternal diet. At 15 weeks, offspring were randomly divided into exercise and sedentary groups which yielded 4 groups: LLS, LLE, HHS, and HHE (first letter denotes maternal diet, second letter offspring diet, and third letter indicates sedentary (S) and exercised group in offspring(E)). For exercise groups, mice had unrestricted exercise wheel access for 10 weeks. Glucose tolerance test (GTT) was performed at 25 weeks and tissues were collected to evaluate cardiac mitochondrial respiratory function at 26 weeks. Maternal diet did not affect body weight (BW) at weaning. Diet did not affect the daily average distance or hours run. BW was significantly higher in the HHS compared to other groups, but exercise did not alter final body weight. This was also true for fat mass. Exercise induced cardiac hypertrophy in mice fed LL, but not in HH mice. Surprisingly, mice in HHE had impaired glucose tolerance compared to other groups. However, no difference was found between LLE and LLS for GTT. In freshly isolated cardiac mitochondria, HHS significantly lowered the coupling efficiency of carbohydrate (pyruvate) and fatty acid (palmitoylcarnitine) oxidation compared to LLS. Exercise training prevented these effects in the HH mice, but had no exercise effect on OXPHOS coupling with either substrate in LL mice. These results demonstrate that adult‐onset exercise can prevent the deleterious effects of maternal obesity on cardiac mitochondrial function in offspring, but may alter glucose handling by mechanisms that merit further investigation.