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

Abstract

Thiazolidinediones (TZDs) are insulin-sensitizing drugs currently used to treat type 2 diabetes. They are activators of peroxisome proliferator-activated receptor (PPAR)-γ, and adipose tissue constitutes a major site for their biological effects. PPAR coactivator (PGC)-1α is a transcriptional coactivator of PPARγ 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-1α gene expression in brown and white adipocytes is a direct target of TZDs via PPARγ activation. Activators of the retinoid X receptor also induce PGC-1α gene expression. This is due to the presence of a PPARγ-responsive element in the distal region of the PGC-1α gene promoter that binds PPARγ/retinoid X receptor heterodimers. Moreover, there is a positive autoregulatory loop of control of the PGC-1α gene through coactivation of PPARγ responsiveness to TZDs by PGC-1α itself. These data indicate that some of the effects of TZDs, especially promotion of mitochondrial biogenesis and oxidative pathways in adipose depots, entail PGC-1α up-regulation via enhanced transcription of the PGC-1α gene. Copyright © 2006 by The Endocrine Society.