N-Acetylcysteine Resolves Placental Inflammatory-Vasculopathic Changes in Mice Consuming a High-Fat Diet

The mechanism by which poor maternal nutrition can affect the long-term health of offspring is poorly understood. In mice, we previously found that maternal high-fat diet (HFD) exposure results in reduced fetal growth regardless of maternal genotype. We tested our hypothesis that maternal HFD-induced inflammation contributes to metabolic disease susceptibility of the offspring via alterations in the placenta. The effect of maternal genotype, diet, and treatment with the anti-inflammatory compound N-acetylcysteine (NAC) on placental morphologic features was investigated. Placentas from wild-type dams maintained on a HFD but not those heterozygous (+/-) for Glut4 (Slc2a4) on the same diet had an increase in decidual inflammation and vasculopathy occurring together. NAC administration resulted in amelioration of HFD-induced decidual vasculopathy independent of offspring genotype and sex. Consistent with these morphologic improvements, placentas from HFD dams treated with NAC had decreased mRNA and immunostaining of IL-1β and monocyte chemoattractant protein-1, decreased mRNA of inflammatory genes, and increased mRNA of Vegfa. These results strongly suggest consumption of an HFD results in vascular changes in placenta reflected by alterations in expression of pivotal vascular developmental markers and inflammatory genes all of which are ameliorated by NAC. These placental changes play a key role in the increased programed metabolic disease of HFD-exposed offspring.