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Cell Metab. 2011 Apr 6;13(4):450-460. doi: 10.1016/j.cmet.2011.03.013.

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

Author information

1
Biotechnologie et Signalisation Cellulaire, UMR7242 CNRS, Université de Strasbourg, ESBS, 67412 Illkirch, France; Department of Medical Chemistry, MHSC, University of Debrecen, 4032 Debrecen, Hungary.
2
Laboratory of Integrative and Systems Physiology, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
3
Department of Medical Chemistry, MHSC, University of Debrecen, 4032 Debrecen, Hungary.
4
Biotechnologie et Signalisation Cellulaire, UMR7242 CNRS, Université de Strasbourg, ESBS, 67412 Illkirch, France.
5
Department of Pharmacology, Weill Cornell Medical College, New York, NY 10065, USA.
6
Laboratory Genetic Metabolic Diseases, AMC, 1115 AZ, Amsterdam, The Netherlands.
7
Biotechnologie et Signalisation Cellulaire, UMR7242 CNRS, Université de Strasbourg, ESBS, 67412 Illkirch, France; Department of Dermatology, University of Debrecen, 4032 Debrecen, Hungary.
8
Centre d'Ecologie et Physiologie Energétiques CNRS UPR9010, 67087 Strasbourg, France.
9
Laboratory of Integrative and Systems Physiology, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland. Electronic address: admin.auwerx@epfl.ch.

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.

PMID:
21459329
PMCID:
PMC3108571
DOI:
10.1016/j.cmet.2011.03.013
[Indexed for MEDLINE]
Free PMC Article

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