| First Author | Gupta D | Year | 2013 |
| Journal | J Biol Chem | Volume | 288 |
| Issue | 35 | Pages | 25440-9 |
| PubMed ID | 23788637 | Mgi Jnum | J:203472 |
| Mgi Id | MGI:5527061 | Doi | 10.1074/jbc.M113.486852 |
| Citation | Gupta D, et al. (2013) Peroxisome proliferator-activated receptor gamma (PPARgamma) and its target genes are downstream effectors of FoxO1 protein in islet beta-cells: mechanism of beta-cell compensation and failure. J Biol Chem 288(35):25440-9 |
| abstractText | The molecular mechanisms and signaling pathways that drive islet beta-cell compensation and failure are not fully resolved. We have used in vitro and in vivo systems to show that FoxO1, an integrator of metabolic stimuli, inhibits PPARgamma expression in beta-cells, thus transcription of its target genes (Pdx1, glucose-dependent insulinotropic polypeptide (GIP) receptor, and pyruvate carboxylase) that are important regulators of beta-cell function, survival, and compensation. FoxO1 inhibition of target gene transcription is normally relieved when upstream activation induces its translocation from the nucleus to the cytoplasm. Attesting to the central importance of this pathway, islet expression of PPARgamma and its target genes was enhanced in nondiabetic insulin-resistant rats and markedly reduced with diabetes induction. Insight into the impaired PPARgamma signaling with hyperglycemia was obtained with confocal microscopy of pancreas sections that showed an intense nuclear FoxO1 immunostaining pattern in the beta-cells of diabetic rats in contrast to the nuclear and cytoplasmic FoxO1 in nondiabetic rats. These findings suggest a FoxO1/PPARgamma-mediated network acting as a core component of beta-cell adaptation to metabolic stress, with failure of this response from impaired FoxO1 activation causing or exacerbating diabetes. |
