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Thiazolidinediones and Rexinoids Induce Peroxisome Proliferator-Activated Receptor-Coactivator (PGC)-1 Gene Transcription: An Autoregulatory Loop Controls PGC-1 Expression in Adipocytes via Peroxisome Proliferator-Activated Receptor- Coactivation

Department of Biochemistry and Molecular Biology, University of Barcelona, 08028 Barcelona, Spain

Address all correspondence and requests for reprints to: Francesc Villarroya, Ph.D., Department of Biochemistry and Molecular Biology, University of Barcelona, Avda Diagonal 645, 08028 Barcelona, Spain. E-mail: fvillarroya{at}ub.edu.

Thiazolidinediones (TZDs) are insulin-sensitizing drugs currently used to treat type 2 diabetes. They are activators of peroxisome proliferator-activated receptor (PPAR)-, and adipose tissue constitutes a major site for their biological effects. PPAR coactivator (PGC)-1 is a transcriptional coactivator of PPAR 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 gene expression in brown and white adipocytes is a direct target of TZDs via PPAR activation. Activators of the retinoid X receptor also induce PGC-1 gene expression. This is due to the presence of a PPAR-responsive element in the distal region of the PGC-1 gene promoter that binds PPAR/retinoid X receptor heterodimers. Moreover, there is a positive autoregulatory loop of control of the PGC-1 gene through coactivation of PPAR responsiveness to TZDs by PGC-1 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 up-regulation via enhanced transcription of the PGC-1 gene.

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