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

Julieta Díaz-Delfín,Roser Iglesias,Francesc Ribas,Elayne Hondares,Albert Giralt,Francesc Villarroya,Marta Giralt,Josep A. Villena

doi:10.1074/jbc.m110.202390

Abstract

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-1α (peroxisome proliferator-activated receptor-γ coactivator-1α) 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-1α failed to fully induce the expression of brown fat-specific thermogenic genes. Pgc-1α activates Sirt3 gene transcription through coactivation of the orphan nuclear receptor Err (estrogen-related receptor)-α, which bound the proximal Sirt3 gene promoter region. Errα knockdown assays indicated that Errα is required for full induction of Sirt3 gene expression in response to Pgc-1α. The present results indicate that Pgc-1α controls Sirt3 gene expression and this action is an essential component of the overall mechanisms by which Pgc-1α induces the full acquisition of a brown adipocyte differentiated phenotype.

Highlights

Pgc-1␣ is a transcriptional coactivator that plays a major role in the acquisition of the specific brown adipocyte phenotype
Pgc-1␣ coactivates nuclear receptors and transcription factors and thereby activates genes involved in thermogenesis (e.g. Ucp1), lipid oxidation, and mitochondrial oxidation, which are associated with the specific thermogenic function of brown adipose tissue [2]
Sirt3 gene expression appeared as a component of the pattern of gene expression associated with brown adipocyte differentiation

Summary

The abbreviations used are

Ucp, uncoupling protein 1; Pgc-1␣, peroxisome proliferator-activated receptor-␥ coactivator-1␣; Sirt, silent mating type information regulation 2, homolog 3; Nrf, nuclear respiratory factor; ERR, estrogen-related receptor; Dio, type II 5Ј-deiodinase; Fabp, fatty acid binding protein-4; MEF, mouse embryonic fibroblast; FABP, fatty acidbinding protein. Sirt is highly expressed in brown adipose tissue, in contrast with its low expression in white fat. Sirt gene expression is impaired in brown fat of rodents under conditions of diminished thermogenic activity such as obesity, and it has been proposed that Sirt is involved in the control of cAMP-mediated gene expression in brown fat [16]. We report that PGC-1␣ is a major controller of the transcription of the Sirt gene. By this means, it contributes to the acquisition of the thermogenic capacity of the brown adipose cell

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION