Maternal obesity restricts fetal growth through placental energy failure and iron-associated oxidative stress in mice

Maternal obesity compromises placental development and fetal growth, yet the mechanisms remain unknown. Here, we investigated the impact of high-fat diet (HFD) on placental energy homeostasis in mice. Female C57BL/6 mice were fed a control diet or an HFD, with a subset receiving FerroTerminator-1 (FOT1) to modulate metabolic dysfunction. At embryonic day 18.5, maternal metabolic status, fetal growth, placental morphology, energy metabolism, and oxidative stress were assessed. HFD-fed dams developed dyslipidemia and insulin resistance, and exhibited placental lipid accumulation and impaired labyrinth zone development, resulting in reduced fetal weight and altered fetal liver lipid and glycogen contents. The placenta showed mitochondrial damage, accompanied by reduced ATP content, mitochondrial membrane potential, mitochondrial DNA copy number, and suppressed respiratory chain complex activities. Placental metabolomic profiling showed that HFD was associated with altered levels of metabolites in glycolysis and oxidative phosphorylation pathways. These alterations coincided with placental iron-associated oxidative stress, evidenced by elevated non-heme iron, lipid peroxidation products, upregulation of transferrin receptor (TFRC) and lysophosphatidylcholine acyltransferase 3 (LPCAT3), downregulation of ferritin heavy chain 1 (FTH1) and solute carrier family 40 member 1 (SLC40A1), a reduced glutathione to oxidized glutathione ratio, and impaired glutathione peroxidase 4 (GPX4) expression and activity. Meanwhile, FOT1 administration attenuated placental oxidative stress, partially restored ATP production and mitochondrial function, and improved fetal growth in HFD-fed mice. Collectively, maternal obesity was associated with placental iron-associated oxidative stress and bioenergetic impairment, which may contribute to reduced placental efficiency and FGR.