Zinc Finger Protein 407 (ZFP407) Regulates Insulin-Stimulated Glucose Uptake and Glucose Transporter 4 (Glut4) mRNA.

The glucose transporter GLUT4 facilitates insulin-stimulated glucose uptake in peripheral tissues including adipose, muscle, and heart. GLUT4 function is impaired in obesity and type 2 diabetes leading to hyperglycemia and an increased risk of cardiovascular disease and neuropathy. To understand better the regulation of GLUT4 function, a targeted siRNA screen was performed and led to the discovery that ZFP407 regulates insulin-stimulated glucose uptake in adipocytes. The decrease in insulin-stimulated glucose uptake due to ZFP407 deficiency was attributed to a reduction in GLUT4 mRNA and protein levels. The decrease in GLUT4 was due to both decreased transcription of Glut4 mRNA and decreased efficiency of Glut4 pre-mRNA splicing. Interestingly, ZFP407 coordinately regulated this decrease in transcription with an increase in the stability of Glut4 mRNA, resulting in opposing effects on steady-state Glut4 mRNA levels. More broadly, transcriptome analysis revealed that ZFP407 regulates many PPARgamma target genes beyond Glut4. ZFP407 was required for the PPARgamma agonist Rosiglitazone to increase Glut4 expression, but was not sufficient to increase expression of a PPARgamma target gene reporter construct. However, ZFP407 and PPARgamma co-overexpression synergistically activated a PPARgamma reporter construct beyond the level of PPARgamma alone. Thus, ZFP407 may represent a new modulator of the PPARgamma signaling pathway.

Link to Full Text of Paper