title: PARP-2 regulates SIRT1 expression and whole-body energy expenditure.
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.
authors: Biotechnologie et Signalisation Cellulaire, UMR7242 CNRS, Université de Strasbourg, ESBS, 67412 Illkirch, France; Department of Medical Chemistry, MHSC, University of Debrecen, 4032 Debrecen, Hungary.
authors: Péter
authors: P
authors: Bai
authors: Laboratory of Integrative and Systems Physiology, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
authors: Carles
authors: C
authors: Canto
authors: Department of Medical Chemistry, MHSC, University of Debrecen, 4032 Debrecen, Hungary.
authors: Attila
authors: A
authors: Brunyánszki
authors: Biotechnologie et Signalisation Cellulaire, UMR7242 CNRS, Université de Strasbourg, ESBS, 67412 Illkirch, France.
authors: Aline
authors: A
authors: Huber
authors: Department of Medical Chemistry, MHSC, University of Debrecen, 4032 Debrecen, Hungary.
authors: Magdolna
authors: M
authors: Szántó
authors: Department of Pharmacology, Weill Cornell Medical College, New York, NY 10065, USA.
authors: Yana
authors: Y
authors: Cen
authors: Laboratory of Integrative and Systems Physiology, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
authors: Hiroyasu
authors: H
authors: Yamamoto
authors: Laboratory Genetic Metabolic Diseases, AMC, 1115 AZ, Amsterdam, The Netherlands.
authors: Sander M
authors: SM
authors: Houten
authors: Biotechnologie et Signalisation Cellulaire, UMR7242 CNRS, Université de Strasbourg, ESBS, 67412 Illkirch, France; Department of Dermatology, University of Debrecen, 4032 Debrecen, Hungary.
authors: Borbala
authors: B
authors: Kiss
authors: Centre d'Ecologie et Physiologie Energétiques CNRS UPR9010, 67087 Strasbourg, France.
authors: Hugues
authors: H
authors: Oudart
authors: Department of Medical Chemistry, MHSC, University of Debrecen, 4032 Debrecen, Hungary.
authors: Pál
authors: P
authors: Gergely
authors: Biotechnologie et Signalisation Cellulaire, UMR7242 CNRS, Université de Strasbourg, ESBS, 67412 Illkirch, France.
authors: Josiane
authors: J
authors: Menissier-de Murcia
authors: Biotechnologie et Signalisation Cellulaire, UMR7242 CNRS, Université de Strasbourg, ESBS, 67412 Illkirch, France.
authors: Valérie
authors: V
authors: Schreiber
authors: Department of Pharmacology, Weill Cornell Medical College, New York, NY 10065, USA.
authors: Anthony A
authors: AA
authors: Sauve
authors: Laboratory of Integrative and Systems Physiology, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland. Electronic address: admin.auwerx@epfl.ch.
authors: Johan
authors: J
authors: Auwerx
mesh_terms: D000818:Animals; D002460:Cell Line; D004041:Dietary Fats / Q000494:pharmacology; D004734:Energy Metabolism; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D018149:Glucose Intolerance; D006801:Humans; D007333:Insulin Resistance; D051379:Mice; D018345:Mice, Knockout; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D004041:Dietary Fats; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D034741:RNA, Small Interfering; D011065:Poly(ADP-ribose) Polymerases; C459820:Parp2 protein, mouse; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1