Am J Physiol Endocrinol Metab. 2025 Apr 22.
The transcription factor forkhead box (FOX)M1 regulates β-cell proliferation and insulin secretion. Our previous work demonstrates that expressing a constitutively active form of FOXM1 (FOXM1*) in β cells increases β-cell function, proliferation and mass in male mice. However, in contrast to what is observed in males, we demonstrate here that in female mice, expression of FOXM1* in β cells does not affect β-cell proliferation or glucose tolerance. Similarly, FOXM1* transduction of male but not female human islets enhances insulin secretion in response to elevated glucose. We, therefore, examined the mechanism behind this sexual dimorphism. 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. Moreover, in breast cancer cells, ERα and FOXM1 work together to drive gene expression. We, therefore, examined whether FOXM1 and ERα functionally interact in β cells. FOXM1* rescued elevated fasting glucose, glucose intolerance, and HOMA-B in female mice with a β-cell-specific ERα deletion. Furthermore, in the presence of estrogen, the FOXM1 and ERα cistromes exhibit significant overlap in βTC6 β cells. In addition, FOXM1 and ERα binding sites frequently occur in complex enhancers co-occupied by other islet transcription factors. These data indicate that FOMX1 and nuclear ERα cooperate to regulate β-cell function and suggest a general mechanism contributing to the lower incidence of diabetes observed in women.
Keywords: Beta cells; Estrogen receptor; Foxm1