Preimplantation factor (PIF) links embryo-derived signaling to maternal pancreatic β-cell adaptation through an ERα-dependent pathway
- 1Unidad de Excelencia Instituto de Biomedicina y Genética Molecular (IBGM), Consejo Superior de Investigaciones Científicas (CSIC) y Universidad de Valladolid (U
Abstract
Pregnancy requires maternal pancreatic {beta}-cells adaptations to increased insulin demand, yet the embryo-derived signals contributing to this response remain poorly defined. Here we identify preimplantation factor (PIF), an embryo-derived peptide present in maternal circulation from early gestation, as a regulator of {beta}-cell adaptation. In a murine model of gestational diabetes mellitus (GDM), circulating PIF levels were reduced during mid-gestation, indicating that this endogenous signal is altered under gestational metabolic dysfunction. Conversely, chronic exposure of non-pregnant female mice to synthetic PIF (sPIF) recapitulated key temporal features of gestational {beta}-cell adaptation, including early {beta}-cell proliferation, increased glucose-stimulated circulating C-peptide, expansion of {beta}-cell mass and sustained enhancement of ex vivo glucose-stimulated insulin secretion (GSIS). Mechanistically, sPIF activated rapid ERK-, AKT- and PKA-dependent signaling that converged on estrogen receptor alpha (ER) phosphorylation and nuclear translocation. Pharmacological inhibition and genetic silencing demonstrated that ER is required for full propagation of the functional and kinase responses. This kinase-ER axis was conserved in human islets, where sPIF enhanced insulin secretion in an ER-dependent manner. These findings identify PIF as an embryo-derived metabolic signal supporting maternal {beta}-cell compensation and suggest that reduced PIF availability may contribute to inadequate {beta}-cell adaptation in GDM.
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BibTeX
@misc{pascuamaestro2026preimplantation,
title = {{Preimplantation factor (PIF) links embryo-derived signaling to maternal pancreatic β-cell adaptation through an ERα-dependent pathway}},
author = {R. Pascua-Maestro and A. M. Sartorius-Yanez and S. Hernandez de la Red and T. Boronat-Belda and M. Arevalo-Martinez and M. Martin-Martin and M. Royo and M. Lopez-Corrales and N. Pascual and M.- P. Marco and M. Daniel-Mozo and C. Broca and G. Perdomo and I. Cozar-Castellano and P. Alonso- Magdalena and B. Merino},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.10.750557},
url = {https://www.biorxiv.org/content/10.64898/2026.09.10.750557v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Preimplantation factor (PIF) links embryo-derived signaling to maternal pancreatic β-cell adaptation through an ERα-dependent pathway
AU - R. Pascua-Maestro
AU - A. M. Sartorius-Yanez
AU - S. Hernandez de la Red
AU - T. Boronat-Belda
AU - M. Arevalo-Martinez
AU - M. Martin-Martin
AU - M. Royo
AU - M. Lopez-Corrales
AU - N. Pascual
AU - M.- P. Marco
AU - M. Daniel-Mozo
AU - C. Broca
AU - G. Perdomo
AU - I. Cozar-Castellano
AU - P. Alonso- Magdalena
AU - B. Merino
PY - 2026
DA - 2026/09/10
PB - bioRxiv
DO - 10.64898/2026.09.10.750557
UR - https://www.biorxiv.org/content/10.64898/2026.09.10.750557v1
AB - Pregnancy requires maternal pancreatic {beta}-cells adaptations to increased insulin demand, yet the embryo-derived signals contributing to this response remain poorly defined. Here we identify preimplantation factor (PIF), an embryo-derived peptide present in maternal circulation from early gestation, as a regulator of {beta}-cell adaptation. In a murine model of gestational diabetes mellitus (GDM), circulating PIF levels were reduced during mid-gestation, indicating that this endogenous signal is altered under gestational metabolic dysfunction. Conversely, chronic exposure of non-pregnant female mice to synthetic PIF (sPIF) recapitulated key temporal features of gestational {beta}-cell adaptation, including early {beta}-cell proliferation, increased glucose-stimulated circulating C-peptide, expansion of {beta}-cell mass and sustained enhancement of ex vivo glucose-stimulated insulin secretion (GSIS). Mechanistically, sPIF activated rapid ERK-, AKT- and PKA-dependent signaling that converged on estrogen receptor alpha (ER) phosphorylation and nuclear translocation. Pharmacological inhibition and genetic silencing demonstrated that ER is required for full propagation of the functional and kinase responses. This kinase-ER axis was conserved in human islets, where sPIF enhanced insulin secretion in an ER-dependent manner. These findings identify PIF as an embryo-derived metabolic signal supporting maternal {beta}-cell compensation and suggest that reduced PIF availability may contribute to inadequate {beta}-cell adaptation in GDM.
ER -