Insulin Elevates ID2 Expression in Trophoblasts and Aggravates Preeclampsia in Obese ASB4-Null Mice

Author:

Kayashima Yukako1,Townley-Tilson W. H. Davin1,Vora Neeta L.2,Boggess Kim2,Homeister Jonathon W.1,Maeda-Smithies Nobuyo1,Li Feng1ORCID

Affiliation:

1. Department of Pathology and Laboratory Medicine, The University of North Carolina, Chapel Hill, NC 27599, USA

2. Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, The University of North Carolina, Chapel Hill, NC 27599, USA

Abstract

Obesity is a risk factor for preeclampsia. We investigated how obesity influences preeclampsia in mice lacking ankyrin-repeat-and-SOCS-box-containing-protein 4 (ASB4), which promotes trophoblast differentiation via degrading the inhibitor of DNA-binding protein 2 (ID2). Asb4−/− mice on normal chow (NC) develop mild preeclampsia-like phenotypes during pregnancy, including hypertension, proteinuria, and reduced litter size. Wild-type (WT) and Asb4−/− females were placed on a high-fat diet (HFD) starting at weaning. At the age of 8–9 weeks, they were mated with WT or Asb4−/− males, and preeclamptic phenotypes were assessed. HFD-WT dams had no obvious adverse outcomes of pregnancy. In contrast, HFD-Asb4−/− dams had significantly more severe preeclampsia-like phenotypes compared to NC-Asb4−/− dams. The HFD increased white fat weights and plasma leptin and insulin levels in Asb4−/− females. In the HFD-Asb4−/− placenta, ID2 amounts doubled without changing the transcript levels, indicating that insulin likely increases ID2 at a level of post-transcription. In human first-trimester trophoblast HTR8/SVneo cells, exposure to insulin, but not to leptin, led to a significant increase in ID2. HFD-induced obesity markedly worsens the preeclampsia-like phenotypes in the absence of ASB4. Our data indicate that hyperinsulinemia perturbs the timely removal of ID2 and interferes with proper trophoblast differentiation, contributing to enhanced preeclampsia.

Funder

National Institutes of Health

UNC Lineberger Comprehensive Cancer Center

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

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