PARP-2 regulates SIRT1 expression and whole-body energy expenditure

Bai, Péter and Cantó, Carles and Brunyánszki, Attila and Huber, Aline and Szántó, Magdolna and Cen, Yana and Yamamoto, Hiroyasu and Houten, S.M. and Kiss, Borbála and Oudart, Hugues and Gergely, Pál and Menissier-de Murcia, Josiane and Schreiber, Valerie and Sauve, Anthony A. and Auwerx, Johan (2011) PARP-2 regulates SIRT1 expression and whole-body energy expenditure. CELL METABOLISM, 13 (4). pp. 450-460. ISSN 1550-4131

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Abstract

SIRT1 is a NAD(+)-dependent enzyme that affects metabolism by deacetylating key transcriptional regulators of energy expenditure. Here, we tested whether deletion of PARP-2, an alternative NAD(+)-consuming enzyme, impacts on NAD(+) bioavailability and SIRT1 activity. Our results indicate that PARP-2 deficiency increases SIRT1 activity in cultured myotubes. However, this increase was not due to changes in NAD(+) levels, but to an increase in SIRT1 expression, as PARP-2 acts as a direct negative regulator of the SIRT1 promoter. PARP-2 deletion in mice increases SIRT1 levels, promotes energy expenditure, and increases mitochondrial content. Furthermore, PARP-2(-/-) mice were protected against diet-induced obesity. Despite being insulin sensitized, PARP-2(-/-) mice were glucose intolerant due to a defective pancreatic function. Hence, while inhibition of PARP activity promotes oxidative metabolism through SIRT1 activation, the use of PARP inhibitors for metabolic purposes will require further understanding of the specific functions of different PARP family members.

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