Thiazolidinediones and rexinoids induce peroxisome proliferator-activated receptor-coactivator (PGC)-1α gene transcription:: An autoregulatory loop controls PGC-1α expression in adipocytes via peroxisome proliferator-activated receptor-γ coactivation

Thiazolidinediones (TZDs) are insulin-sensitizing drugs currently used to treat type 2 diabetes. They are activators of peroxisome proliferator-activated receptor (PPAR)-gamma, and adipose tissue constitutes a major site for their biological effects. PPAR coactivator (PGC)-1 alpha is a transcriptional coactivator of PPAR gamma and other transcription factors. It is involved in the control of mitochondrial biogenesis, and its activity has been linked to insulin sensitization. Here we report that PGC-1 alpha gene expression in brown and white adipocytes is a direct target of TZDs via PPAR gamma activation. Activators of the retinoid X receptor also induce PGC-1 alpha gene expression. This is due to the presence of a PPAR gamma-responsive element in the distal region of the PGC-1 alpha gene promoter that binds PPAR gamma/retinoid X receptor heterodimers. Moreover, there is a positive autoregulatory loop of control of the PGC-1 alpha gene through coactivation of PPAR gamma responsiveness to TZDs by PGC-1 alpha itself. These data indicate that some of the effects of TZDs, especially promotion of mitochondrial biogenesis and oxidative pathways in adipose depots, entail PGC-1 alpha up-regulation via enhanced transcription of the PGC-1 alpha gene.