Obesity and High-Fat Diet Induce Distinct Changes in Placental Gene Expression and Pregnancy Outcome

Abstract

Obese women are at high risk of pregnancy complications, including preeclampsia, miscarriage, preterm birth, stillbirth, and neonatal death. In the current study, we aimed to determine the effects of obesity on pregnancy outcome and placental gene expression in preclinical mouse models of genetic and nutritional obesity. The leptin receptor (LepR) null-reactivatable (LepRloxTB), LepR-deficient (Leprdb/+), and high-fat diet (HFD)-fed mice were assessed for fertility, pregnancy outcome, placental morphology, and placental transcriptome using standard quantitative polymerase chain reaction (qPCR) and qPCR arrays. The restoration of fertility of LepRloxTB was performed by stereotaxic delivery of adeno-associated virus-Cre into the hypothalamic ventral premammillary nucleus. Fertile LepRloxTB females were morbidly obese, whereas the wild-type mice-fed HFD showed only a mild increase in body weight. Approximately 80% of the LepRloxTB females had embryo resorptions (∼40% of the embryos). In HFD mice, the number of resorptions was not different from controls fed a regular diet. Placentas of resorbed embryos from obese mice displayed necrosis and inflammatory infiltrate in the labyrinth and changes in the expression of genes associated with angiogenesis and inflammation (e.g., Vegfa, Hif1a, Nfkbia, Tlr3, Tlr4). In contrast, placentas from embryos of females on HFD showed changes in a different set of genes, mostly associated with cellular growth and response to stress (e.g., Plg, Ang, Igf1, Igfbp1, Fgf2, Tgfb2, Serpinf1). Sexual dimorphism in gene expression was only apparent in placentas from obese LepRloxTB mice. Our findings indicate that an obese environment and HFD have distinct effects on pregnancy outcome and the placental transcriptome.

The Placental Transcriptome in Late Gestational Hypoxia Resulting in Murine Intrauterine Growth Restriction Parallels Increased Risk of Adult Cardiometabolic Disease

“…In the context of the signaling cascades induced by vascular injury, we also found a significant enrichment for genes involved in inflammatory response, and in particular, both Cd74 and Ccl8 are transcriptionally regulated in human pre-eclamptic placentas 37 . The consistent down-regulation of the heme oxygenase 1 gene ( Hmox1 ) along with the upregulation of multiple serpin peptidase inhibitors ( Serpin1f and Serpinb5 among others) is in agreement with previous reports on the role of these hypoxia-related genes on placental development, IUGR and preeclampsia in humans and animal models 38,39 .…”

Effect of Maternal Obesity in Mice on IL-6 Levels and Placental Endothelial Cell Homeostasis

“…This new insight could have clinical implications since proper placental vascular development is necessary to prevent placental dysfunction and hypertension. Earlier studies in humans and mice showed that HFD could have a profound impact on the female reproductive function, and studies in mice and rats suggest distinct consequences of HFD on placental function and pregnancy outcome [46][47][48]. Furthermore, it has been shown that HFD has a significant impact on hemodynamics and vascularization in the placenta [8,49] and by the use of stereological means, it is possible to evaluate the developmental state of the vascular system in the murine placenta [29].…”

Interferons and Proinflammatory Cytokines in Pregnancy and Fetal Development

“…While, there is a consistent association between maternal body mass index and expression of the inflammatory marker, CRP, there is still no consensus between studies on the changes in systemic cytokine expression during pregnancies in obese women (Pendeloski et al, 2017). Animal studies using mouse and nonhuman primate models support this correlation between obesity, increased inflammatory markers in the mother or placenta, and poor pregnancy outcomes including stillbirth and fetal resorption (Frias et al, 2011; Mahany et al, 2018). More studies are needed to investigate the causal and mechanistic link between increased inflammation in obesity and associated pregnancy complications.…”