Maternal body composition and the placental-fetal unit under maternal high-fat feeding partially improve by metformin treatment or lifestyle interventions during pregnancy in a mouse model

Abstract

Introduction

Studies showed that metabolic imbalances during pregnancy in obesity impair the maternal-fetal axis, resulting in fetal growth disturbances with higher risk later in life. Since research has linked many of maternal and fetal sequelae to placental dysfunction, we tested if treatment with an anti-diabetic drug (metformin) or lifestyle interventions improve maternal body weight, placental status or fetal growth.

Methods

Mice were either fed a control or high-fat diet. After mating, high-fat diet mice were split into 4 subgroups, 1 received no intervention while the other 3 received either metformin treatment, a nutritional intervention (NI) or an exercise intervention (RUN). At gestational day 15.5, mice were sacrificed.

Results

All interventions improved body weight of high-fat diet dams, but only NI and RUN maintained fetal growth compared to HFD. Investigation of the placenta showed that (i) NI reduced lipid accumulation in the labyrinth zone (LZ) but neither NI nor RUN attenuated calcification and oxidative stress. Endothelial gammaH2AX staining was decreased in the LZ by both NI and RUN. (ii) Metformin did not attenuate lipid accumulation in the LZ, placental calcification and oxidative stress, however, protein levels of the endothelial cell marker CD31 were restored in whole placenta lysates. No changes were detected for fetal vessel capillary surface or length of the LZ under any intervention group.

Discussion

Although all tested interventions had beneficial effects on the mother and the placental-fetal unit, NI seems to be most promising. Our findings highlight that preventive strategies for women with obesity should aim for pre-counseling advisory service. In particular, NI and RUN protected from endothelial stress response and metformin was vasculo-protective, offering strategies to preserve the physiological placental-fetal unit and materno-fetal nutrient supply.