The ZEB1 Transcription Factor Links Estrogen Signaling to FGF21 and Reduced Adiposity.

摘要

The estrogen-regulated ZEB1 transcription factor modulates several developmental processes such as bone formation and T-cell maturation, and ZEB1 expression is associated with enhanced aggressiveness in breast, uterine, and prostate cancer. ZEB1 heterozygous female mice fed either a high- or normal-fat diet gain weight at a higher rate than do their wild-type counterparts. This weight gain is due almost exclusively to an increase in fat mass. The gene name of ZEB1 is tcf8. In order to identify potential gene targets for ZEB1 in adipocytes, mouse embryonic fibroblasts (MEFs) were isolated from wild type and tcf8-/- embryos and differentiated into adipocytes. Proteome Array analysis revealed differences in a number of secreted adipose markers. Most notably, FGF21 was secreted at a much lower level from tcf8-/- MEFs.;FGF21 is an important metabolic regulator that protects mice against diet-induced obesity and improves glucose processing. To investigate whether FGF21 is a target for ZEB1, transient transfection reporter assays were done. These functional experiments suggest that ZEB1 activates FGF21 through an E-box located at position -50 relative to the start site of transcription, and this was supported by in vitro protein-DNA binding assays. ZEB1 regulation of FGF21 is one mechanism through which ZEB1 might regulate obesity.