PGC-1alpha coactivates PDK4 gene expression via the orphan nuclear receptor ERRalpha: a mechanism for transcriptional control of muscle glucose metabolism

The transcriptional coactivator PGC-1alpha is a key regulator of energy metabolism, yet little is known about its role in control of substrate selection. We found that physiological stimuli known to induce PGC-1alpha expression in skeletal muscle coordinately upregulate the expression of pyruvate de...

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Bibliographic Details
Published in:Molecular and cellular biology 2005-12, Vol.25 (24), p.10684-10694
Main Authors: Wende, Adam R, Huss, Janice M, Schaeffer, Paul J, Giguère, Vincent, Kelly, Daniel P
Format: Article
Language:English
Subjects:
Animals
Base Sequence
Binding Sites
ERRalpha Estrogen-Related Receptor
Gene Expression
Gene Expression Regulation, Enzymologic
Glucose - metabolism
Male
Mice
Mice, Inbred C57BL
Molecular Sequence Data
Muscle Fibers, Skeletal - metabolism
Muscle, Skeletal - enzymology
Muscle, Skeletal - metabolism
Oxidation-Reduction
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
PPAR alpha - metabolism
Promoter Regions, Genetic
Protein Kinases - genetics
Protein Kinases - metabolism
Receptors, Cytoplasmic and Nuclear - metabolism
Receptors, Estrogen - metabolism
Response Elements
Trans-Activators - metabolism
Transcription Factors
Up-Regulation
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Summary:The transcriptional coactivator PGC-1alpha is a key regulator of energy metabolism, yet little is known about its role in control of substrate selection. We found that physiological stimuli known to induce PGC-1alpha expression in skeletal muscle coordinately upregulate the expression of pyruvate dehydrogenase kinase 4 (PDK4), a negative regulator of glucose oxidation. Forced expression of PGC-1alpha in C(2)C(12) myotubes induced PDK4 mRNA and protein expression. PGC-1alpha-mediated activation of PDK4 expression was shown to occur at the transcriptional level and was mapped to a putative nuclear receptor binding site. Gel shift assays demonstrated that the PGC-1alpha-responsive element bound the estrogen-related receptor alpha (ERRalpha), a recently identified component of the PGC-1alpha signaling pathway. In addition, PGC-1alpha was shown to activate ERRalpha expression. Chromatin immunoprecipitation assays confirmed that PGC-1alpha and ERRalpha occupied the mPDK4 promoter in C(2)C(12) myotubes. Additionally, transfection studies using ERRalpha-null primary fibroblasts demonstrated that ERRalpha is required for PGC-1alpha-mediated activation of the mPDK4 promoter. As predicted by the effects of PGC-1alpha on PDK4 gene transcription, overexpression of PGC-1alpha in C(2)C(12) myotubes decreased glucose oxidation rates. These results identify the PDK4 gene as a new PGC-1alpha/ERRalpha target and suggest a mechanism whereby PGC-1alpha exerts reciprocal inhibitory influences on glucose catabolism while increasing alternate mitochondrial oxidative pathways in skeletal muscle.
ISSN:0270-7306