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...

SIRT3 is a member of the sirtuin family of protein deacetylases that is preferentially localized to mitochondria. Prominent among the proteins targeted by SIRT3 are enzymes involved in energy metabolism processes, including the respiratory chain, tricarboxylic acid cycle, fatty acid β-oxidation and ketogenesis. Through these actions, SIRT3 controls the flow of mitochondrial oxidative pathways and, consequently, the rate of production of reactive oxygen species. In addition, SIRT3-mediated deacetylation activates enzymes responsible for quenching reactive oxygen species, and thereby exerts a profound protective action against oxidative stress-dependent pathologies, such as cardiac hypertrophy and neural degeneration. SIRT3 also plays a role in multiple additional metabolic processes, from acetate metabolism to brown adipose tissue thermogenesis, often by controlling mitochondrial pathways through the deacetylation of target enzymes. In general, SIRT3 activity and subsequent control of enzymes involved in energy metabolism is consistent with an overall role of protecting against age-related diseases. In fact, experimental and genetic evidence has linked SIRT3 activity with increased lifespan. In the coming years, the identification of drugs and nutrients capable of increasing SIRT3 expression or modulating SIRT3 activity can be expected to provide promising strategies for ameliorating the metabolic syndrome and other oxidative stress-related diseases that appear preferentially with aging, such as cancer, cardiac dysfunction and neural degeneration.