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Peroxisome Proliferator-Activated Receptor- Coactivator 1 (PGC-1): Transcriptional Coactivator and Metabolic Regulator

Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115

Correspondence: Address all correspondence and requests for reprints to: Dr. Bruce M. Spiegelman, Dana-Farber Cancer Institute, One Jimmy Fund Way, Smith Building, Room 958, Boston, Massachusetts 02115. E-mail: bruce_spiegelman{at}dfci.harvard.edu

Investigations of biological programs that are controlled by gene transcription have mainly studied the regulation of transcription factors. However, there are examples in which the primary focus of biological regulation is at the level of a transcriptional coactivator. We have reviewed here the molecular mechanisms and biological programs controlled by the transcriptional coactivator peroxisome proliferator-activated receptor- coactivator 1 (PGC-1). Key cellular signals that control energy and nutrient homeostasis, such as cAMP and cytokine pathways, strongly activate PGC-1. Once PGC-1 is activated, it powerfully induces and coordinates gene expression that stimulates mitochondrial oxidative metabolism in brown fat, fiber-type switching in skeletal muscle, and multiple aspects of the fasted response in liver. The regulation of these metabolic and cell fate decisions by PGC-1 is achieved through specific interaction with a variety of transcription factors such as nuclear hormone receptors, nuclear respiratory factors, and muscle-specific transcription factors. PGC-1 therefore constitutes one of the first and clearest examples in which biological programs are chiefly regulated by a transcriptional coactivator in response to environmental stimuli. Finally, PGC-1’s control of energy homeostasis suggests that it could be a target for antiobesity or diabetes drugs.

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