Peroxisome Proliferator-activated Receptor-γ Coactivator-1α Controls Transcription of the Sirt3 Gene, an Essential Component of the Thermogenic Brown Adipocyte Phenotype

Sirt3 (silent mating type information regulation 2, homolog 3), a member of the sirtuin family of protein deacetylases with multiple actions on metabolism and gene expression is expressed in association with brown adipocyte differentiation. Using Sirt3-null brown adipocytes, we determined that Sirt3 is required for an appropriate responsiveness of cells to noradrenergic, cAMP-mediated activation of the expression of brown adipose tissue thermogenic genes. The transcriptional coactivator Pgc-1 alpha (peroxisome proliferator-activated receptor-gamma coactivator-1 alpha) induced Sirt3 gene expression in white adipocytes and embryonic fibroblasts as part of its overall induction of a brown adipose tissue-specific pattern of gene expression. In cells lacking Sirt3, Pgc-1 alpha failed to fully induce the expression of brown fat-specific thermogenic genes. Pgc-1 alpha activates Sirt3 gene transcription through coactivation of the orphan nuclear receptor Err (estrogen-related receptor)-alpha, which bound the proximal Sirt3 gene promoter region. Err alpha knockdown assays indicated that Err alpha is required for full induction of Sirt3 gene expression in response to Pgc-1 alpha. The present results indicate that Pgc-1 alpha controls Sirt3 gene expression and this action is an essential component of the overall mechanisms by which Pgc-1 alpha induces the full acquisition of a brown adipocyte differentiated phenotype.