PGC-1α gene expression is down-regulated by Akt- mediated phosphorylation and nuclear exclusion of FoxO1 in insulin-stimulated skeletal muscle

SPECIFIC AIMSThere are multiple binding domains on the promoter region of the peroxisome proliferator activator receptor γ coactivator-1 α (PGC-1α) gene, including a trio of insulin-responsive elements that are activated by the forkhead box class-O (FoxO1) winged helix transcription factor, which is regulated by acute transforming retrovirus thymoma (Akt). In healthy skeletal muscle, insulin phosphorylates Akt, a process that can be impaired in the skeletal muscle of patients with type 2 diabetes. Surprisingly, no studies have examined Akt-mediated regulation FoxO1 and PGC-1α by insulin in skeletal muscle, but this is warranted given the limited but conflicting data with respect to insulin regulation of PGC-1α in skeletal muscle. In the present study we examined the effect of insulin on Akt and FoxO1 phosphorylation and PGC-1α mRNA expression in skeletal muscle from healthy (CON) and insulin-resistant (TYPE 2) humans. To confirm our in vivo data, we next performed experiments in vitro in human primary mus...