Maternal Diet-induced Obesity Programs Cardiovascular Dysfunction in Adult Male Mouse Offspring Independent of Current Body Weight

Abstract

Obese pregnancies are not only associated with adverse consequences for the mother but also the long-term health of her child. Human studies have shown that individuals from obese mothers are at increased risk of premature death from cardiovascular disease (CVD), but are unable to define causality. This study aimed to determine causality using a mouse model of maternal diet–induced obesity. Obesity was induced in female C57BL/6 mice by feeding a diet rich in simple sugars and saturated fat 6 weeks prior to pregnancy and throughout pregnancy and lactation. Control females were fed laboratory chow. Male offspring from both groups were weaned onto chow and studied at 3, 5, 8, and 12 weeks of age for gross cardiac morphometry using stereology, cardiomyocyte cell area by histology, and cardiac fetal gene expression using qRT-PCR. Cardiac function was assessed by isolated Langendorff technology at 12 weeks of age and hearts were analyzed at the protein level for the expression of the β1 adrenergic receptor, muscarinic type-2 acetylcholine receptor, and proteins involved in cardiac contraction. Offspring from obese mothers develop pathologic cardiac hypertrophy associated with re-expression of cardiac fetal genes. By young adulthood these offspring developed severe systolic and diastolic dysfunction and cardiac sympathetic dominance. Importantly, cardiac dysfunction occurred in the absence of any change in corresponding body weight and despite the offspring eating a healthy low-fat diet. These findings provide a causal link to explain human observations relating maternal obesity with premature death from CVD in her offspring.

Maternal exposure to Western diet affects adult body composition and voluntary wheel running in a genotype-specific manner in mice

“…Additionally, we found no effect of maternal WD on fat pad masses measured at dissection (Table 1). In general, body fat is a positive predictor of leptin levels in mice, including in previous studies of the lines we studied [42,59]. As expected, we found that leptin levels were positively associated with the masses of both posterior subcutaneous fat pads and abdominal pelvic fat pads (Online Supplemental Table 2).…”

Nutrition has a pervasive impact on cardiac microRNA expression in isogenic mice

“…1B). Relative heart weight, however, tended to be greater in offspring of obese mothers, consistent with previous findings in other models of maternal obesity 8,9 ( Fig. 1C).…”

“…3,4 Animal models have identified the risk of hypertension, 5,6 vascular dysfunction, 7 cardiac hypertrophy, and contractile dysfunction 8,9 all to be influenced by maternal obesity during pregnancy. The molecular mechanisms underlying programmed pathologies are not known, but studies in inbred animal model systems again argue against a simple genetic basis.…”

Maternal obesity regulates gene expression in the hearts of offspring

“…As these receptors are developmentally regulated, it is interesting to compare our findings to a recent study which found an up-regulation of Adrbk1 in the offspring of obese mice mothers at 12 weeks of age [8]. This suggests that the decrease we observed may be transient.…”

“…However there is currently a limited mechanistic understanding of how maternal obesity causes foetal programming of CVD; altered sympathetic nervous activity and adrenoceptor expression, have been reported in offspring of obese dams [7]. Recently, it was shown that male offspring from obese mice dams had increased cardiac sympathetic dominance associated with an up-regulation of β1 adrenergic receptors at 12 weeks of age [8].…”