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FOXM1 acts sexually dimorphically to regulate functional β-cell mass.

Authors :
Peng G
Mosleh E
Yuhas A
Katada K
Cherry C
Golson ML
Source :
BioRxiv : the preprint server for biology [bioRxiv] 2023 Jan 12. Date of Electronic Publication: 2023 Jan 12.
Publication Year :
2023

Abstract

The transcription factor FOXM1 regulates β-cell proliferation and insulin secretion. Our previous work demonstrates that expressing an activated form of FOXM1 (FOXM1*) in β cells increases β-cell proliferation and mass in aged male mice. Additionally, FOXM1* enhances β-cell function even in young mice, in which no β-cell mass elevation occurs. Here, we demonstrate that FOXM1 acts in a sexually dimorphic manner in the β cell. Expression of FOXM1* in female mouse β cells does not affect β-cell proliferation or glucose tolerance. Transduction of male but not female human islets with FOXM1* enhances insulin secretion in response to elevated glucose. Estrogen contributes to diabetes susceptibility differences between males and females, and the estrogen receptor (ER)α is the primary mediator of β-cell estrogen signaling. We show that FOXM1* can rescue impaired glucose tolerance in female mice with a pancreas-wide ERα deletion. Further, FOXM1 and ERα binding sites overlap with each other and with other β-cell-enriched transcription factors, including ISL1, PAX6, MAF, and GATA. These data indicate that FOMX1 and ERα cooperate to regulate β-cell function and suggest a general mechanism contributing to the lower incidence of diabetes observed in women.

Details

Language :
English
Database :
MEDLINE
Journal :
BioRxiv : the preprint server for biology
Accession number :
36711451
Full Text :
https://doi.org/10.1101/2023.01.12.523673