PARP-2 Regulates SIRT1 Expression and Whole-Body Energy Expenditure

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 defic...

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Bibliographic Details
Published in:Cell metabolism 2011-04, Vol.13 (4), p.450-460
Main Authors: Bai, Péter, Canto, Carles, Brunyánszki, Attila, Huber, Aline, Szántó, Magdolna, Cen, Yana, Yamamoto, Hiroyasu, Houten, Sander M., Kiss, Borbala, Oudart, Hugues, Gergely, Pál, Menissier-de Murcia, Josiane, Schreiber, Valérie, Sauve, Anthony A., Auwerx, Johan
Format: Article
Language:English
Subjects:
Animals
Cell Line
Dietary Fats - pharmacology
Energy Metabolism
Forkhead Box Protein O1
Forkhead Transcription Factors - metabolism
Glucose Intolerance
Humans
Insulin Resistance
Mice
Mice, Knockout
Poly(ADP-ribose) Polymerase Inhibitors
Poly(ADP-ribose) Polymerases - genetics
Poly(ADP-ribose) Polymerases - metabolism
Promoter Regions, Genetic
RNA Interference
RNA, Small Interfering
Sirtuin 1 - genetics
Sirtuin 1 - metabolism
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Summary: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. ▴ PARP-2 negatively regulates SIRT1 expression and protein content ▴ PARP-2−/− mice are leaner and show a better metabolic profile ▴ PARP-2−/− mice are protected against diet-induced obesity ▴ PARP-2 deletion impairs β cell function, rendering mice glucose intolerant
ISSN:1550-4131
1932-7420
DOI:10.1016/j.cmet.2011.03.013