Abstract
Maternal and pediatric obesity has risen dramatically over recent years, and is a known predictor of adverse long-term metabolic outcomes in offspring. However, which particular aspects of obese pregnancy promote such outcomes is less clear. While maternal obesity increases both maternal and placental inflammation, it is still unknown whether this is a dominant mechanism in fetal metabolic programming. In this study, we utilized the Fat-1 transgenic mouse to test whether increasing the maternal n-3/n-6 tissue fatty acid ratio could reduce the consequences of maternal obesity-associated inflammation and thereby mitigate downstream developmental programming. Eight-week-old WT or hemizygous Fat-1 C57BL/6J female mice were placed on a high-fat diet (HFD) or control diet (CD) for 8 weeks prior to mating with WT chow-fed males. Only WT offspring from Fat-1 mothers were analyzed. WT-HFD mothers demonstrated increased markers of infiltrating adipose tissue macrophages (P<0.02), and a striking increase in 12 serum pro-inflammatory cytokines (P<0.05), while Fat1-HFD mothers remained similar to WT-CD mothers, despite equal weight gain. E18.5 Fetuses from WT-HFD mothers had larger placentas (P<0.02), as well as increased placenta and fetal liver TG deposition (P<0.01 and P<0.02, respectively) and increased placental LPL TG-hydrolase activity (P<0.02), which correlated with degree of maternal insulin resistance (r = 0.59, P<0.02). The placentas and fetal livers from Fat1-HFD mothers were protected from this excess placental growth and fetal-placental lipid deposition. Importantly, maternal protection from excess inflammation corresponded with improved metabolic outcomes in adult WT offspring. While the offspring from WT-HFD mothers weaned onto CD demonstrated increased weight gain (P<0.05), body and liver fat (P<0.05 and P<0.001, respectively), and whole body insulin resistance (P<0.05), these were prevented in WT offspring from Fat1-HFD mothers. Our results suggest that reducing excess maternal inflammation may be a promising target for preventing adverse fetal metabolic outcomes in pregnancies complicated by maternal obesity.
Highlights
The prevalence of pediatric obesity has increased dramatically over the past two decades and is presenting at a progressively younger age, implicating the importance of early life events in children’s long-term metabolic health
Weight gain was significantly increased in high-fat diet (HFD) mothers, and importantly, Fat-1 and wild type (WT) mice gained similar weight on the HFD prior to mating and during pregnancy relative to control diet (CD) mothers (P,0.05; Figure 1A)
While inflammation and insulin resistance are well-recognized characteristics of both pregnancy and obesity, little is known about the mechanisms linking these maternal changes with fetalplacental health or, perhaps more importantly, the pathogenesis of obesity in offspring
Summary
The prevalence of pediatric obesity has increased dramatically over the past two decades and is presenting at a progressively younger age, implicating the importance of early life events in children’s long-term metabolic health. Numerous studies in animal models demonstrate that maternal obesity and high-fat feeding leads to metabolic impairments in offspring [5,6,7,8,9,10,11,12,13,14], including obesity, fatty liver disease, insulin resistance and diabetes. Such studies suggest that early fetal and neonatal exposure to the altered metabolic environment of maternal obesity can have long-term negative consequences. While maternal systemic and placental inflammation are recognized as prominent features of pregnancies complicated by obesity [25,26,27,28,29,30,31], little is known about the causal role this inflammation may play in altering fetalplacental developmental programming
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