ABSTRACT
BACKGROUND: Obesity during pregnancy is related to adverse maternal and neonatal outcomes. Factors involved in these outcomes may include increased maternal insulin resistance, inflammation, oxidative stress, and nutrient mishandling. The placenta is the primary determinant of fetal outcomes, and its function can be impacted by maternal obesity. The aim of this study on mice was to determine the effect of obesity on maternal lipid handling, inflammatory and redox state, and placental oxidative stress, inflammatory signaling, and gene expression relative to female and male fetal growth. METHODS: Female mice were fed control or obesogenic high-fat/high-sugar diet (HFHS) from 9 weeks prior to, and during, pregnancy. On day 18.5 of pregnancy, maternal plasma, and liver, placenta, and fetal serum were collected to examine the immune and redox states. The placental labyrinth zone (Lz) was dissected for RNA-sequencing analysis of gene expression changes. RESULTS: the HFHS diet induced, in the dams, hepatic steatosis, oxidative stress (reduced catalase, elevated protein oxidation) and the activation of pro-inflammatory pathways (p38-MAPK), along with imbalanced circulating cytokine concentrations (increased IL-6 and decreased IL-5 and IL-17A). HFHS fetuses were asymmetrically growth-restricted, showing sex-specific changes in circulating cytokines (GM-CSF, TNF-α, IL-6 and IFN-γ). The morphology of the placenta Lz was modified by an HFHS diet, in association with sex-specific alterations in the expression of genes and proteins implicated in oxidative stress, inflammation, and stress signaling. Placental gene expression changes were comparable to that seen in models of intrauterine inflammation and were related to a transcriptional network involving transcription factors, LYL1 and PLAG1. CONCLUSION: This study shows that fetal growth restriction with maternal obesity is related to elevated oxidative stress, inflammatory pathways, and sex-specific placental changes. Our data are important, given the marked consequences and the rising rates of obesity worldwide.
ABSTRACT
AIMS: Diets containing high-fat and high sugar (HFHS) lead to overweight/obesity. Overweight/obesity increases the risk of infertility, and of the pregnant mother and her child for developing metabolic conditions. Overweight/obesity has been recreated in mice, but most studies focus on the effects of chronic, long-term HFHS diet exposure. Here, we exposed mice to HFHS from 3 weeks prior to pregnancy with the aim of determining impacts on fertility, and gestational and neonatal outcomes. METHODS: Time-domain NMR scanning was used to assess adiposity, glucose, and insulin tolerance tests were employed to examine metabolic physiology, and morphological and proteomic analyses conducted to assess structure and nutrient levels of maternal organs and placenta. RESULTS: Fertility measures of HFHS dams were largely the same as controls. HFHS dams had increased adiposity pre-pregnancy, however, exhibited exacerbated lipolysis/hyper-mobilization of adipose stores in late pregnancy. While there were no differences in glucose or insulin tolerance, HFHS dams were hyperglycemic and hyperinsulinemic in pregnancy. HFHS dams had fatty livers and altered pancreatic islet morphology. Although fetuses were hyperglycemic and hyperinsulinemic, there was no change in fetal growth in HFHS dams. There were also reductions in placenta formation. Moreover, there was increased offspring loss during lactation, which was related to aberrant mammary gland development and milk protein composition in HFHS dams. CONCLUSIONS: These findings are relevant given current dietary habits and the development of maternal and offspring alterations in the absence of an increase in maternal weight and adiposity during pregnancy, which are the current clinical markers to determine risk across gestation.
