Maternal obesity during pregnancy disrupts iron homeostasis and promotes fetal hypoxia in the mouse.

Research in both humans and animals has consistently demonstrated that diverse complications during pregnancy impact on the risk of chronic diseases in the offspring. In many settings, over half of women are either overweight or living with obesity during pregnancy. This has short- and long-term impacts on offspring health. The mechanisms mediating changes in the fetal environment that may trigger developmental origins of future cardiometabolic risk in the offspring are not fully elucidated. In this study, using an established mouse model, we aimed to determine whether obesity during pregnancy causes fetal hypoxia and to explore potential underlying mechanisms. We showed that fetal hypoxia is a key component of the in utero obesogenic environment at E13.5/0.7 of gestation. Concomitantly, obese dams exhibit low iron levels, as well as higher circulating levels of hepcidin and C-reactive protein. We also showed that placental structure and efficiency are not affected by maternal obesity at E13.5, suggesting that the reduction in oxygen delivery to the fetus was not a consequence of placental dysfunction at this stage of gestation. We conclude that maternal obesity-induced iron deficiency and fetal hypoxia are important mechanisms by which obesity during pregnancy impacts offspring health. Furthermore, iron deficiency in mothers with obesity is a tractable therapeutic target for intervention that could prevent transmission of poor cardiometabolic health from mother to child. KEY POINTS: Diet-induced maternal obesity resulted in fetal, but not placental, hypoxia. Pregnant mice with obesity had lower circulating iron levels, along with dysregulation of key molecules involved in iron homeostasis, such as transferrin and the hormone hepcidin. Body weight, fat mass, circulating insulin and hepcidin levels in mothers with obesity were significantly correlated with the degree of fetal hypoxia, suggesting they were interrelated.