Document Detail

The cAMP/PKA pathway rapidly activates SIRT1 to promote fatty acid oxidation independently of changes in NAD(+).
MedLine Citation:
PMID:  22195961     Owner:  NLM     Status:  MEDLINE    
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.
Zachary Gerhart-Hines; John E Dominy; Sharon M Blättler; Mark P Jedrychowski; Alexander S Banks; Ji-Hong Lim; Helen Chim; Steven P Gygi; Pere Puigserver
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.    
Journal Detail:
Title:  Molecular cell     Volume:  44     ISSN:  1097-4164     ISO Abbreviation:  Mol. Cell     Publication Date:  2011 Dec 
Date Detail:
Created Date:  2011-12-26     Completed Date:  2012-02-24     Revised Date:  2014-09-14    
Medline Journal Info:
Nlm Unique ID:  9802571     Medline TA:  Mol Cell     Country:  United States    
Other Details:
Languages:  eng     Pagination:  851-63     Citation Subset:  IM    
Copyright Information:
Copyright © 2011 Elsevier Inc. All rights reserved.
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MeSH Terms
Amino Acid Sequence
Cells, Cultured
Cyclic AMP / metabolism*
Cyclic AMP-Dependent Protein Kinases / metabolism*
Fatty Acids / metabolism*
Mice, Transgenic
Molecular Sequence Data
NAD / metabolism*
Phosphoserine / metabolism
Signal Transduction*
Sirtuin 1 / metabolism*
Trans-Activators / metabolism
Transcription Factors
Grant Support
R01 069966//PHS HHS; R01 DK069966/DK/NIDDK NIH HHS; R01 DK069966-01A1/DK/NIDDK NIH HHS; R01 DK069966-02/DK/NIDDK NIH HHS; R01 DK069966-03/DK/NIDDK NIH HHS; R01 DK069966-04/DK/NIDDK NIH HHS; R01 DK069966-05/DK/NIDDK NIH HHS; R01 DK069966-06/DK/NIDDK NIH HHS; R01 DK069966-07/DK/NIDDK NIH HHS; R01 DK069966-08/DK/NIDDK NIH HHS
Reg. No./Substance:
0/Fatty Acids; 0/Ppargc1a protein, mouse; 0/Trans-Activators; 0/Transcription Factors; 0U46U6E8UK/NAD; 17885-08-4/Phosphoserine; E0399OZS9N/Cyclic AMP; EC AMP-Dependent Protein Kinases; EC 3.5.1.-/Sirt1 protein, mouse; EC 3.5.1.-/Sirtuin 1
Comment In:
Mol Cell. 2012 Jan 13;45(1):9-11   [PMID:  22244328 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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