Transgenic Increase in N-3/N-6 Fatty Acid Ratio Reduces Maternal Obesity-Associated Inflammation and Limits Adverse Developmental Programming in Mice

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.

Developmental origins of NAFLD: a womb with a clue

“…Our laboratory has used a Fat1 transgenic mouse model (which can endogenously convert ω6 fatty acids to ω3 fatty acids) to test the effect of increasing the maternal ω3 to ω6 tissue fatty acid ratio during highfat diet consumption. Wildtype offspring of Fat1 dams had decreased hepatic lipid accumulation and were protected from highfatdietinduced inflammation 27 . Thus, increasing the maternal ω3 to ω6 fatty acid ratio and reducing placental inflammation might be a promising target for improving outcomes in the fetus of a mother with obesity consuming a highfat diet.…”

Supplementation With 2:1 Ratio of N-6:n-3 Polyunsaturated Fatty Acid Improves Liver Steatosis and Serum Cytokine Levels in Young Obese Balinese Women: A Randomized Clinical Trial

“…In that study, wild-type mice fed with a high-fat diet exhibited a high serum concentration of 12 pro-inflammatory cytokines (p<0.05), but no such increase was observed in the transgenic mice [23]. Depner et al reported that among n-3 LC-PUFAs, DHA was more effective than…”

“…The release of GGT typically increases oxidative stress [39]; however, serum GGT levels were relatively decreased in this study, indicating that oxidative stress was reduced. Furthermore, GGT has been strongly associated with body lipids, particularly visceral fat, which contribute to the progression of NAFLD [23,24,40].…”

A maternal mouse diet with moderately high-fat levels does not lead to maternal obesity but causes mesenteric adipose tissue dysfunction in male offspring

“…Kasbi-Chadli et al have recently reported that n-3 PUFA maternal supplementation, which caused the n-6/n-3 PUFA ratio in the maternal diet to decrease from 49.4 to 3.0, reduced the n-6/n-3 PUFA ratio in the plasma of dams and alleviated the metabolic disorders in the adult offspring with diet-induced obesity [44]. Heerwagen et al demonstrated that transgenic mice that decrease in the n-6/n-3 tissue PUFA ratio from 20-50 to 1 reduced maternal obesity-associated inflammation and prevented metabolic impairments in adult offspring [45]. The n-6/n-3 PUFA ratio in these three studies was much more modulated than that in our study, and these three studies basically examined the effects of the n-6/n-3 PUFA ratio on obesity-related disorders in mother and offspring.…”