title: PARP-1 inhibition increases mitochondrial metabolism through SIRT1 activation.
abstract: SIRT1 regulates energy homeostasis by controlling the acetylation status and activity of a number of enzymes and transcriptional regulators. The fact that NAD(+) levels control SIRT1 activity confers a hypothetical basis for the design of new strategies to activate SIRT1 by increasing NAD(+) availability. Here we show that the deletion of the poly(ADP-ribose) polymerase-1 (PARP-1) gene, encoding a major NAD(+)-consuming enzyme, increases NAD(+) content and SIRT1 activity in brown adipose tissue and muscle. PARP-1(-/-) mice phenocopied many aspects of SIRT1 activation, such as a higher mitochondrial content, increased energy expenditure, and protection against metabolic disease. Also, the pharmacologic inhibition of PARP in vitro and in vivo increased NAD(+) content and SIRT1 activity and enhanced oxidative metabolism. These data show how PARP-1 inhibition has strong metabolic implications through the modulation of SIRT1 activity, a property that could be useful in the management not only of metabolic diseases, but also of cancer.
authors: Biotechnologie et Signalisation Cellulaire, UMR7242 CNRS, Université de Strasbourg, ESBS, Illkirch, France; Department of Medical Chemistry, University of Debrecen, Debrecen, Hungary.
authors: Péter
authors: P
authors: Bai
authors: Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, Switzerland.
authors: Carles
authors: C
authors: Cantó
authors: CEPE, CNRS UPR9010, Strasbourg, France.
authors: Hugues
authors: H
authors: Oudart
authors: Department of Medical Chemistry, University of Debrecen, Debrecen, Hungary.
authors: Attila
authors: A
authors: Brunyánszki
authors: Department of Pharmacology, Weill Cornell Medical College, New York, NY 10021, USA.
authors: Yana
authors: Y
authors: Cen
authors: Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, Switzerland.
authors: Charles
authors: C
authors: Thomas
authors: Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, Switzerland.
authors: Hiroyasu
authors: H
authors: Yamamoto
authors: Biotechnologie et Signalisation Cellulaire, UMR7242 CNRS, Université de Strasbourg, ESBS, Illkirch, France.
authors: Aline
authors: A
authors: Huber
authors: Biotechnologie et Signalisation Cellulaire, UMR7242 CNRS, Université de Strasbourg, ESBS, Illkirch, France.
authors: Borbála
authors: B
authors: Kiss
authors: Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, Switzerland.
authors: Riekelt H
authors: RH
authors: Houtkooper
authors: Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, Switzerland.
authors: Kristina
authors: K
authors: Schoonjans
authors: Biotechnologie et Signalisation Cellulaire, UMR7242 CNRS, Université de Strasbourg, ESBS, Illkirch, France.
authors: Valérie
authors: V
authors: Schreiber
authors: Department of Pharmacology, Weill Cornell Medical College, New York, NY 10021, USA.
authors: Anthony A
authors: AA
authors: Sauve
authors: Biotechnologie et Signalisation Cellulaire, UMR7242 CNRS, Université de Strasbourg, ESBS, Illkirch, France.
authors: Josiane
authors: J
authors: Menissier-de Murcia
authors: Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, Switzerland. Electronic address: admin.auwerx@epfl.ch.
authors: Johan
authors: J
authors: Auwerx
mesh_terms: D002001:Adipose Tissue, Brown / Q000201:enzymology / Q000378:metabolism; D000818:Animals; D004734:Energy Metabolism; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000201:enzymology / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D018384:Oxidative Stress; D010641:Phenotype; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D034741:RNA, Small Interfering; D009243:NAD; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1