FoxM1 is up-regulated by obesity and stimulates beta-cell proliferation.

beta-Cell mass expansion is one mechanism by which obese animals compensate for insulin resistance and prevent diabetes. FoxM1 is a transcription factor that can regulate the expression of multiple cell cycle genes and is necessary for the maintenance of adult beta-cell mass, beta-cell proliferation, and glucose homeostasis. We hypothesized that FoxM1 is up-regulated by nondiabetic obesity and initiates a transcriptional program leading to beta-cell proliferation. We performed gene expression analysis on islets from the nondiabetic C57BL/6 Leptin(ob/ob) mouse, the diabetic BTBR Leptin(ob/ob) mouse, and an F2 Leptin(ob/ob) population derived from these strains. We identified obesity-driven coordinated up-regulation of islet Foxm1 and its target genes in the nondiabetic strain, correlating with beta-cell mass expansion and proliferation. This up-regulation was absent in the diabetic strain. In the F2 Leptin(ob/ob) population, increased expression of Foxm1 and its target genes segregated with higher insulin and lower glucose levels. We next studied the effects of FOXM1b overexpression on isolated mouse and human islets. We found that FoxM1 stimulated mouse and human beta-cell proliferation by activating many cell cycle phases. We asked whether FOXM1 expression is also responsive to obesity in human islets by collecting RNA from human islet donors (body mass index range: 24-51). We found that the expression of FOXM1 and its target genes is positively correlated with body mass index. Our data suggest that beta-cell proliferation occurs in adult obese humans in an attempt to expand beta-cell mass to compensate for insulin resistance, and that the FoxM1 transcriptional program plays a key role in this process.