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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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				M. Sano, S. Tokudome, N. Shimizu, N. Yoshikawa, C. Ogawa, K. Shirakawa, J. Endo, T. Katayama, S. Yuasa, M. Ieda, et al. Intramolecular Control of Protein Stability, Subnuclear Compartmentalization, and Coactivator Function of Peroxisome Proliferator-activated Receptor {gamma} Coactivator 1{alpha} J. Biol. Chem., August 31, 2007; 282(35): 25970 - 25980. [Abstract] [Full Text] [PDF]

				G. Karamanlidis, A. Karamitri, K. Docherty, D. G. Hazlerigg, and M. A. Lomax C/EBPbeta Reprograms White 3T3-L1 Preadipocytes to a Brown Adipocyte Pattern of Gene Expression J. Biol. Chem., August 24, 2007; 282(34): 24660 - 24669. [Abstract] [Full Text] [PDF]

				S. Schiaffino, M. Sandri, and M. Murgia Activity-Dependent Signaling Pathways Controlling Muscle Diversity and Plasticity Physiology, August 1, 2007; 22(4): 269 - 278. [Abstract] [Full Text] [PDF]

				A. H. Remels, P. Schrauwen, R. Broekhuizen, J. Willems, S. Kersten, H. R. Gosker, and A. M. Schols Peroxisome proliferator-activated receptor expression is reduced in skeletal muscle in COPD Eur. Respir. J., August 1, 2007; 30(2): 245 - 252. [Abstract] [Full Text] [PDF]

				J. Yan, Z. Gao, G. Yu, Q. He, J. Weng, and J. Ye Nuclear Corepressor Is Required for Inhibition of Phosphoenolpyruvate Carboxykinase Expression by Tumor Necrosis Factor-{alpha} Mol. Endocrinol., July 1, 2007; 21(7): 1630 - 1641. [Abstract] [Full Text] [PDF]

				D. Debevec, M. Christian, D. Morganstein, A. Seth, B. Herzog, M. Parker, and R. White Receptor Interacting Protein 140 Regulates Expression of Uncoupling Protein 1 in Adipocytes through Specific Peroxisome Proliferator Activated Receptor Isoforms and Estrogen-Related Receptor {alpha} Mol. Endocrinol., July 1, 2007; 21(7): 1581 - 1592. [Abstract] [Full Text] [PDF]

				E. Pirinen, T. Kuulasmaa, M. Pietila, S. Heikkinen, M. Tusa, P. Itkonen, S. Boman, J. Skommer, A. Virkamaki, E. Hohtola, et al. Enhanced Polyamine Catabolism Alters Homeostatic Control of White Adipose Tissue Mass, Energy Expenditure, and Glucose Metabolism Mol. Cell. Biol., July 1, 2007; 27(13): 4953 - 4967. [Abstract] [Full Text] [PDF]

				I. A. Barash, M.-L. Bang, L. Mathew, M. L. Greaser, J. Chen, and R. L. Lieber Structural and regulatory roles of muscle ankyrin repeat protein family in skeletal muscle Am J Physiol Cell Physiol, July 1, 2007; 293(1): C218 - C227. [Abstract] [Full Text] [PDF]

				D. C. Wright, P. C. Geiger, D.-H. Han, T. E. Jones, and J. O. Holloszy Calcium Induces Increases in Peroxisome Proliferator-activated Receptor {gamma} Coactivator-1{alpha} and Mitochondrial Biogenesis by a Pathway Leading to p38 Mitogen-activated Protein Kinase Activation J. Biol. Chem., June 29, 2007; 282(26): 18793 - 18799. [Abstract] [Full Text] [PDF]

				N. Dali-Youcef, C. Mataki, A. Coste, N. Messaddeq, S. Giroud, S. Blanc, C. Koehl, M.-F. Champy, P. Chambon, L. Fajas, et al. Adipose tissue-specific inactivation of the retinoblastoma protein protects against diabesity because of increased energy expenditure PNAS, June 19, 2007; 104(25): 10703 - 10708. [Abstract] [Full Text] [PDF]

				S. Crunkhorn, F. Dearie, C. Mantzoros, H. Gami, W. S. da Silva, D. Espinoza, R. Faucette, K. Barry, A. C. Bianco, and M. E. Patti Peroxisome Proliferator Activator Receptor {gamma} Coactivator-1 Expression Is Reduced in Obesity: POTENTIAL PATHOGENIC ROLE OF SATURATED FATTY ACIDS AND p38 MITOGEN-ACTIVATED PROTEIN KINASE ACTIVATION J. Biol. Chem., May 25, 2007; 282(21): 15439 - 15450. [Abstract] [Full Text] [PDF]

				I. Bogacka, T. W. Gettys, L. de Jonge, T. Nguyen, J. M. Smith, H. Xie, F. Greenway, and S. R. Smith The Effect of {beta}-Adrenergic and Peroxisome Proliferator-Activated Receptor-{gamma} Stimulation on Target Genes Related to Lipid Metabolism in Human Subcutaneous Adipose Tissue Diabetes Care, May 1, 2007; 30(5): 1179 - 1186. [Abstract] [Full Text] [PDF]

				J. Jell, S. Merali, M. L. Hensen, R. Mazurchuk, J. A. Spernyak, P. Diegelman, N. D. Kisiel, C. Barrero, K. K. Deeb, L. Alhonen, et al. Genetically Altered Expression of Spermidine/Spermine N1-Acetyltransferase Affects Fat Metabolism in Mice via Acetyl-CoA J. Biol. Chem., March 16, 2007; 282(11): 8404 - 8413. [Abstract] [Full Text] [PDF]

				B. Gershman, O. Puig, L. Hang, R. M. Peitzsch, M. Tatar, and R. S. Garofalo High-resolution dynamics of the transcriptional response to nutrition in Drosophila: a key role for dFOXO Physiol Genomics, March 14, 2007; 29(1): 24 - 34. [Abstract] [Full Text] [PDF]

				C. J Bailey Treating insulin resistance: future prospects Diabetes and Vascular Disease Research, March 1, 2007; 4(1): 20 - 31. [Abstract] [PDF]

				A. Sriwijitkamol, D. K. Coletta, E. Wajcberg, G. B. Balbontin, S. M. Reyna, J. Barrientes, P. A. Eagan, C. P. Jenkinson, E. Cersosimo, R. A. DeFronzo, et al. Effect of Acute Exercise on AMPK Signaling in Skeletal Muscle of Subjects With Type 2 Diabetes: A Time-Course and Dose-Response Study Diabetes, March 1, 2007; 56(3): 836 - 848. [Abstract] [Full Text] [PDF]

				L. S. Chow, L. J. Greenlund, Y. W. Asmann, K. R. Short, S. K. McCrady, J. A. Levine, and K. S. Nair Impact of endurance training on murine spontaneous activity, muscle mitochondrial DNA abundance, gene transcripts, and function J Appl Physiol, March 1, 2007; 102(3): 1078 - 1089. [Abstract] [Full Text] [PDF]

				E. Bonnelye, R. A. Zirngibl, P. Jurdic, and J. E. Aubin The Orphan Nuclear Estrogen Receptor-Related Receptor-{alpha} Regulates Cartilage Formation in Vitro: Implication of Sox9 Endocrinology, March 1, 2007; 148(3): 1195 - 1205. [Abstract] [Full Text] [PDF]

				E. Olmsted-Davis, F. H. Gannon, M. Ozen, M. M. Ittmann, Z. Gugala, J. A. Hipp, K. M. Moran, C. M. Fouletier-Dilling, S. Schumara-Martin, R. W. Lindsey, et al. Hypoxic Adipocytes Pattern Early Heterotopic Bone Formation Am. J. Pathol., February 1, 2007; 170(2): 620 - 632. [Abstract] [Full Text] [PDF]

				F. Backhed, J. K. Manchester, C. F. Semenkovich, and J. I. Gordon From the Cover: Mechanisms underlying the resistance to diet-induced obesity in germ-free mice PNAS, January 16, 2007; 104(3): 979 - 984. [Abstract] [Full Text] [PDF]

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				D. C. Wright, D.-H. Han, P. M. Garcia-Roves, P. C. Geiger, T. E. Jones, and J. O. Holloszy Exercise-induced Mitochondrial Biogenesis Begins before the Increase in Muscle PGC-1{alpha} Expression J. Biol. Chem., January 5, 2007; 282(1): 194 - 199. [Abstract] [Full Text] [PDF]