title: Dysregulation of In Vitro Decidualization of Human Endometrial Stromal Cells by Insulin via Transcriptional Inhibition of Forkhead Box Protein O1.
abstract: Insulin resistance and compensatory hyperinsulinemia are characteristic features of obesity and polycystic ovary syndrome, and both are associated with reduced fertility and implantation. There is little knowledge about the effect of insulin on the decidualization process and previous findings are contradictory. We investigated the effect of insulin on the regulation of forkhead box protein O1 (FOXO1), one of the most important transcription factors during decidualization. Endometrial stromal cells were isolated from six healthy, regularly menstruating women and decidualized in vitro. Gene expression levels of six putative FOXO1 target genes (including insulin-like growth factor binding protein-1 (IGFBP1) and prolactin (PRL)) were measured with Real-Time PCR following FOXO1 inhibition or insulin treatment. PI3K inhibition was used to identify the possible mechanism behind regulation. Subcellular localization of FOXO1 was analyzed with immunofluorescence. All the genes (IGFBP1, CTGF, INSR, DCN, LEFTY2), except prolactin, were evaluated as FOXO1 target genes in decidualizing stromal cells. Insulin caused a significant dose-dependent inhibition of the verified FOXO1 target genes. It was also demonstrated that insulin regulated FOXO1 target genes by transcriptional inactivation and nuclear export of FOXO1 via PI3K pathway. However, insulin did not inhibit the morphological transformation of endometrial stromal cells via transcriptional inactivation of FOXO1. This study provides new insights on the action of insulin on the endometrium via regulation of FOXO1. It is suggested that hyperinsulinemia results in dysregulation of a high number of FOXO1 controlled genes that may contribute to endometrial dysfunction and reproductive failure. Our findings may illuminate possible reasons for unexplained infertility.
authors.affiliation: Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Dorina
authors.initials: D
authors.lastname: Ujvari
authors.affiliation: Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.|Department of Obstetrics and Gynecology, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Ivika
authors.initials: I
authors.lastname: Jakson
authors.affiliation: Department of Obstetrics and Gynecology II, Azerbaijan Medical University, Baku, Azerbaijan.
authors.forename: Shabnam
authors.initials: S
authors.lastname: Babayeva
authors.affiliation: Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.|Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Daniel
authors.initials: D
authors.lastname: Salamon
authors.affiliation: Department of Medicine, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Bence
authors.initials: B
authors.lastname: Rethi
authors.affiliation: Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.|Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Gidlöf
authors.affiliation: Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.|Department of Obstetrics and Gynecology, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Angelica Lindén
authors.initials: AL
authors.lastname: Hirschberg
mesh_terms: D000293:Adolescent; D000328:Adult; D003994:Bucladesine / Q000494:pharmacology; D003656:Decidua / Q000187:drug effects / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004717:Endometrium / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D000071161:Forkhead Box Protein O1 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D055815:Young Adult
chemical_list: C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D007328:Insulin; D003994:Bucladesine; D017258:Medroxyprogesterone Acetate