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

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-1␣ (peroxisome proliferator-activated receptor-␥ coactivator-1␣) 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␣ failed to fully induce the expression of brown fat-specific thermogenic genes. Pgc-1␣ activates Sirt3 gene transcription through coactivation of the orphan nuclear receptor Err (estrogen-related receptor)-␣, which bound the proximal Sirt3 gene promoter region. Err␣ knockdown assays indicated that Err␣ is required for full induction of Sirt3 gene expression in response to Pgc-1␣. The present results indicate that Pgc-1␣ controls Sirt3 gene expression and this action is an essential component of the overall mechanisms by which Pgc-1␣ induces the full acquisition of a brown adipocyte differentiated phenotype.Brown adipose tissue plays a major role in the control of energy expenditure in mammals. The specific mitochondrial uncoupling that is characteristic of brown adipocytes creates a specialized cell type adapted to promoting energy expenditure in response to cold or overfeeding. In contrast, white adipocytes are specialized in the accumulation of metabolic energy in the form of lipids. Brown adipocytes respond to noradrenergic stimulation through ␤-adrenoreceptors in the cell surface, which bind norepinephrine and signal through adenylate cyclase to increase cAMP and activate protein kinase A. Ultimately, this signaling cascade lead to activation of hormonesensitive lipase, induction of the expression of the gene for uncoupling protein-1 (Ucp1) 2 and other genes involved in thermogenesis, and activation of the Ucp1-dependent uncoupling of mitochondria (1). Acquisition of the cellular machinery typical of brown adipocyte thermogenic function is a highly plastic process. In fact, pre-adipocytes or even white adipocytes may acquire brown adipocyte properties in response to developmental or environment regulators. Several molecular agents have been reported to promote brown adipocyte differentiation, central among them is Pgc-1␣.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). For instance, when white adipocytes are forced to expres...

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“…SIRT3 was shown to protect against mitochondrial fragmentation and neuronal cell death induced by SOD1-G93A overexpression [9]. Moreover, PGC-1α, which has been shown to promote SIRT3 [2], showed the same effect as SIRT3 in this model. Interestingly, SIRT3 was also shown to regulate ketone body production by deacetylating mitochondrial 3-hydroxy-3-methylglutaryl CoA synthase 2 (HMGCS2) [10].…”

“…Mitochondrial sirtuins (SIRT3, 4 and 5) play an important role in cellular ROS defense and mitochondrial energy metabolism. Moreover, SIRT3 has been shown to be regulated by PGC-1α, which can promote mitochondrial biogenesis and is associated with ROS suppression and neuroprotection [2,3].…”

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“…The mitochondrial deacetylase SIRT3, which regulates the activity of numerous mitochondrial enzymes, is portrayed as a mitochondrial fidelity protein (1). A role of SIRT3 in regulating mitochondrial biogenesis via activation of the PGC1␣/ERR␣ complex has been demonstrated (20)(21)(22). However, its role in regulating mitochondrial dynamics has never been explored.…”

Role of Sirtuins in Stem Cell Differentiation

“…Although SIRT3-deficient mice show normal adaptive thermogenesis and are metabolically unremarkable, SIRT3 is apparently necessary for in vitro differentiation of brown adipocytes. 76 Thus, SIRT3 might be a positive regulator of adipogenesis, in contrast to SIRT1 and SIRT2, which are negative regulators. Finally, in the particular case of SIRT7 -/-mice, severe heart hypertrophy has been observed, but this defect was associated with inflammation and apoptosis.…”