Fine-tuned regulation of the PGC-1α gene transcription by different intracellular signaling pathways

Hong T, Ning J, Yang X, Liu H, Han J, Liu Z, Cao W. Fine-tuned regulation of the PGC-1 alpha gene transcription by different intracellular signaling pathways. Am J Physiol Endocrinol Metab 300: E500-E507, 2011. First published December 14, 2010; doi:10.1152/ajpendo.00225.2010.-It has previously been known that transcription of the PGC-1 alpha gene can be either inhibited or stimulated by p38 MAP kinase (p38 MAPK). To determine whether p38 MAPK plays an inhibitory or stimulatory role in PGC-1 alpha gene transcription, we further investigated the role of p38 MAPK in this study. Our results showed that the basal level of p38 MAPK phosphorylation was increased in gastrocnemius of mice under HFD and that p38 MAPK stimulated PGC-1 alpha gene transcription in C2C12 myotubes. Our results also provided new mechanisms in myotubes that the p38 MAPKinduced PGC-1 alpha gene transcription was mediated by CREB. In exploring the role of the Akt-dependent insulin signaling on PGC-1 alpha gene transcription, we found that the basal Akt-dependent signaling was increased in gastrocnemius of mice under HFD. The p38 MAPKinduced PGC-1 alpha gene transcription was prevented by insulin. Insulin suppression of PGC-1 alpha gene transcription was neutralized by overexpression of the constitutively nuclear form of FoxO1. Finally, we located three insulin response elements (IREs) in the PGC-1 alpha promoter, and mutations of these IREs abolish or blunt activity of the PGC-1 alpha promoter. Together, our results show that transcription of the PGC-1 alpha gene is balanced by different intracellular signaling pathways.