title: The cAMP/PKA pathway rapidly activates SIRT1 to promote fatty acid oxidation independently of changes in NAD(+).
abstract: The NAD(+)-dependent deacetylase SIRT1 is an evolutionarily conserved metabolic sensor of the Sirtuin family that mediates homeostatic responses to certain physiological stresses such as nutrient restriction. Previous reports have implicated fluctuations in intracellular NAD(+) concentrations as the principal regulator of SIRT1 activity. However, here we have identified a cAMP-induced phosphorylation of a highly conserved serine (S434) located in the SIRT1 catalytic domain that rapidly enhanced intrinsic deacetylase activity independently of changes in NAD(+) levels. Attenuation of SIRT1 expression or the use of a nonphosphorylatable SIRT1 mutant prevented cAMP-mediated stimulation of fatty acid oxidation and gene expression linked to this pathway. Overexpression of SIRT1 in mice significantly potentiated the increases in fatty acid oxidation and energy expenditure caused by either pharmacological β-adrenergic agonism or cold exposure. These studies support a mechanism of Sirtuin enzymatic control through the cAMP/PKA pathway with important implications for stress responses and maintenance of energy homeostasis.
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Gerhart-Hines
authors.forename: John E
authors.initials: JE
authors.lastname: Dominy
authors.forename: Sharon M
authors.initials: SM
authors.lastname: Blättler
authors.forename: Mark P
authors.initials: MP
authors.lastname: Jedrychowski
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Banks
authors.forename: Ji-Hong
authors.initials: JH
authors.lastname: Lim
authors.forename: Helen
authors.initials: H
authors.lastname: Chim
authors.forename: Steven P
authors.initials: SP
authors.lastname: Gygi
authors.forename: Pere
authors.initials: P
authors.lastname: Puigserver
mesh_terms: D000107:Acetylation; D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009243:NAD / Q000378:metabolism*; D010084:Oxidation-Reduction; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors
chemical_list: D005227:Fatty Acids; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D009243:NAD; D010768:Phosphoserine; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1