Fetal growth restriction and placental defects in obese mice are associated with impaired decidualisation: the role of increased leptin signalling modulators SOCS3 and PTPN2.
Published version
Peer-reviewed
Repository URI
Repository DOI
Type
Change log
Authors
Abstract
Decidualisation of the endometrium is a key event in early pregnancy, which enables embryo implantation. Importantly, the molecular processes impairing decidualisation in obese mothers are yet to be characterised. We hypothesise that impaired decidualisation in obese mice is mediated by the upregulation of leptin modulators, the suppressor of cytokine signalling 3 (SOCS3) and the protein tyrosine phosphatase non-receptor type 2 (PTPN2), together with the disruption of progesterone (P4)-signal transducer and activator of transcription (STAT3) signalling. After feeding mice with chow diet (CD) or high-fat diet (HFD) for 16 weeks, we confirmed the downregulation of P4 and oestradiol (E2) steroid receptors in decidua from embryonic day (E) 6.5 and decreased proliferation of stromal cells from HFD. In vitro decidualised mouse endometrial stromal cells (MESCs) and E6.5 deciduas from the HFD showed decreased expression of decidualisation markers, followed by the upregulation of SOCS3 and PTPN2 and decreased phosphorylation of STAT3. In vivo and in vitro leptin treatment of mice and MESCs mimicked the results observed in the obese model. The downregulation of Socs3 and Ptpn2 after siRNA transfection of MESCs from HFD mice restored the expression level of decidualisation markers. Finally, DIO mice placentas from E18.5 showed decreased labyrinth development and vascularisation and fetal growth restricted embryos. The present study revealed major defects in decidualisation in obese mice, characterised by altered uterine response to E2 and P4 steroid signalling. Importantly, altered hormonal response was associated with increased expression of leptin signalling modulators SOCS3 and PTPN2. Elevated levels of SOCS3 and PTPN2 were shown to molecularly affect decidualisation in obese mice, potentially disrupting the STAT3-PR regulatory molecular hub.
Description
Acknowledgements: We would like to thank Dr Karolina Wołodko and Marek Adamowski for the validation of pharmacological hyperleptinemia mouse model; Dr Katarzyna Jankowska for the support with samples preparation for immunostaining.
Keywords
Journal Title
Conference Name
Journal ISSN
1420-9071
Volume Title
Publisher
Publisher DOI
Sponsorship
Narodowa Agencja Wymiany Akademickiej (NAWA Prom, PPI/PRO/2019/1/00042/U/0001)
Biotechnology and Biological Sciences Research Council (BBS/E/B/000C0423)
Medical Research Council (MR/S000437/1)
Ministerio de Ciencia e Innovación (RYC-2019-026956, PID2020-114459RA-I00, PLEC2022-009246)