Transgenic increase in N-3/n-6 Fatty Acid ratio reduces maternal obesity-associated inflammation and limits adverse
Margaret J R Heerwagen1, Michael S Stewart, Becky A de la Houssaye
1Division of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, United States of America.
Insights
Maternal obesity causes inflammation, impacting fetal development and offspring metabolic health. Enhancing maternal omega-3 fatty acids reduced this inflammation, protecting offspring from adverse metabolic programming.
Area of Science:
- Reproductive biology
- Metabolic health
- Developmental programming
Background:
- Maternal obesity is a growing concern, linked to adverse metabolic outcomes in children.
- The specific mechanisms by which maternal obesity affects fetal metabolic programming remain unclear.
- Maternal obesity is associated with increased inflammation in both mother and placenta.
Purpose of the Study:
- To investigate if increasing the maternal n-3/n-6 fatty acid ratio can mitigate inflammation and improve fetal metabolic programming in offspring of obese mothers.
- To determine the role of maternal inflammation in mediating the effects of obesity on fetal development.
Main Methods:
- Utilized the Fat-1 transgenic mouse model to manipulate maternal fatty acid ratios.
- Mice were fed a high-fat diet (HFD) or control diet (CD) before and during pregnancy.
- Analyzed maternal inflammatory markers, placental and fetal liver lipid deposition, and offspring metabolic parameters.
Main Results:
- Mothers on HFD exhibited increased adipose tissue macrophages and pro-inflammatory cytokines compared to controls.
- Fat-1 mice on HFD showed protection against maternal inflammation, similar to control diet groups.
- Fetuses from HFD mothers had larger placentas and increased lipid deposition, which was prevented in offspring of Fat-1 mothers.
- Offspring from HFD mothers displayed increased weight gain, body/liver fat, and insulin resistance, which were mitigated by the Fat-1 modification.
Conclusions:
- Reducing maternal inflammation through enhanced omega-3 fatty acid levels can protect against adverse fetal metabolic programming.
- Targeting maternal inflammation presents a potential strategy to prevent metabolic disorders in offspring of obese mothers.
- The n-3/n-6 fatty acid ratio plays a crucial role in mediating the developmental effects of maternal obesity.
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.
