FOXM1 cooperates with ERα to regulate functional β-cell mass.

Area of Science:

• Endocrinology
• Molecular Biology
• Metabolic Diseases

Background:

• Forkhead box (FOX)M1 is a transcription factor crucial for beta-cell proliferation and insulin secretion.
• Previous studies showed FOXM1 activation enhances beta-cell function in male mice.
• However, the effect of FOXM1 in female mice and the underlying mechanisms remain unclear.

Purpose of the Study:

• To investigate the sexual dimorphism in FOXM1's regulation of beta-cell function.
• To explore the potential interaction between FOXM1 and estrogen signaling in beta-cells.
• To elucidate the molecular mechanisms contributing to sex-based differences in diabetes susceptibility.

Main Methods:

• Expression of constitutively active FOXM1 (FOXM1*) in beta-cells of male and female mice.
• Assessment of beta-cell proliferation, glucose tolerance, and insulin secretion.
• Analysis of beta-cell-specific ERα deletion models.
• Chromatin immunoprecipitation sequencing (ChIP-seq) to determine FOXM1 and ERα binding sites in beta-cells.

Main Results:

• FOXM1* expression increased beta-cell function, proliferation, and mass in male mice but not female mice.
• FOXM1* enhanced glucose-stimulated insulin secretion in male but not female human islets.
• FOXM1* expression rescued metabolic dysfunction in female mice with beta-cell-specific ERα deletion.
• Significant overlap was observed between FOXM1 and ERα binding sites in beta-cells, particularly in the presence of estrogen.

Conclusions:

• FOXM1 and estrogen receptor alpha (ERα) functionally cooperate in regulating beta-cell function.
• This interaction, mediated by estrogen, explains the sexual dimorphism in FOXM1's effects on beta-cells.
• The findings suggest a mechanism for the lower incidence of diabetes in women and highlight sex-specific therapeutic targets.