Submitted to: Journal of Biological Chemistry
Publication Type: Peer reviewed journal
Publication Acceptance Date: 1/14/2005
Publication Date: 4/8/2005
Citation: Shi, T., Wang, F., Stieren, E., Tong, Q. 2005. SIRT3, a mitochondrial sirtuin deacetylase, regulates mitochondrial function and thermogenesis in brown adipocytes. Journal of Biological Chemistry. 280(14):13560-13567. Interpretive Summary: Dietary restriction delays aging and age-related diseases, such as diabetes and cancer. Sir2 gene mediates the effect of dietary restriction on life span extension in yeast and worms. In this study, we have discovered that the SIRT3, one of the mammalian Sir2-loke genes, is expressed in key metabolic organs, such as white and brown fat, brain, and liver. SIRT3 expression in brown fat is increased by dietary restriction and cold exposure but decreased by obesity and elevated climate temperature. The expression of SIRT3 in brown fat cells up-regulates the expressions of genes responsible for increased energy expenditure and heat generation. SIRT3 also decreases the production of free radicals. This is one step towards the understanding of the molecular mechanism of dietary restriction on metabolism and aging.
Technical Abstract: SIRT3 is one of the seven mammalian sirtuin homologs of the yeast Sir2 gene, which mediates the effect of caloric restriction on life span extension in yeast and Caenorhabditis elegans. Because adipose tissue is essential in energy homeostasis and also plays a role in life span determination, we decided to investigate the function of sirtuin members in fat. We report here that murine SIRT3 is expressed in brown adipose tissue and is localized on the mitochondria inner membrane. Caloric restriction activates SIRT3 expression in both white and brown adipose. Additionally, cold exposure up-regulates SIRT3 expression in brown fat, whereas elevated climate temperature reduces the expression. Enforced expression of SIRT3 in the HIB1B brown adipocytes enhances the expression of the uncoupling protein PGC-1alpha, UCP1, and a series of mitochondria-related genes. Both ADP-ribosyltransferase and deacetylase activities of SIRT3 are required for this action. Furthermore, the SIRT3 deacetylase mutant exhibits a dominant negative effect by inhibiting UCP1 expression. This inhibitive effect can be abolished by the co-expression of PGC-1alpha, indicating a major role of PGC-1alpha,in the SIRT3 action. In addition, SIRT3 stimulates CREB phosphorylation, which reportedly activates PGC-1alpha promoter directly. Functionally, sustained expression of SIRT3 decreases membrane potential and reactive oxygen species production while increasing cellular respiration. Finally, SIRT3, along with genes related to mitochondrial function, is down-regulated in the brown adipose tissue of several genetically obese mice. In summary, our results demonstrate that SIRT3 activates mitochondria functions and plays an important role in adaptive thermogenesis in brown adipose.