{"doi":"10.3390/ijms24032149","title":"Insulin Elevates ID2 Expression in Trophoblasts and Aggravates Preeclampsia in Obese ASB4-Null Mice","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.","journal":"International Journal of Molecular Sciences","year":2023,"id":370607,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9577,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":423153,"name":"W. H. Davin Townley-Tilson","orcid":null,"position":1,"is_corresponding":false},{"id":557101,"name":"Neeta L. Vora","orcid":"0000-0002-2504-9455","position":2,"is_corresponding":false},{"id":349216,"name":"Kim Boggess","orcid":null,"position":3,"is_corresponding":false},{"id":422218,"name":"Jonathon W. Homeister","orcid":"0000-0002-2643-3221","position":4,"is_corresponding":false},{"id":412512,"name":"Nobuyo Maeda-Smithies","orcid":null,"position":5,"is_corresponding":false},{"id":1092469,"name":"Feng Li","orcid":"0000-0002-6779-5077","position":6,"is_corresponding":false},{"id":411206,"name":"Yukako Kayashima","orcid":"0000-0003-3415-9135","position":0,"is_corresponding":true}],"reference_count":50,"raw_metadata":null,"created_at":"2026-07-19T01:15:41.237096Z","pmid":"36768469","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}