The cAMP/PKA Pathway Rapidly Activates SIRT1 to Promote Fatty Acid Oxidation Independently of Changes in NAD +

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The cAMP/PKA Pathway Rapidly Activates SIRT1 to Promote Fatty Acid Oxidation Independently of Changes in NAD +. / Gerhart-Hines, Zachary; Dominy, John E.; Blättler, Sharon M.; Jedrychowski, Mark P.; Banks, Alexander S.; Lim, Ji Hong; Chim, Helen; Gygi, Steven P.; Puigserver, Pere.

In: Molecular Cell, Vol. 44, No. 6, 23.12.2011, p. 851-863.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Gerhart-Hines, Z, Dominy, JE, Blättler, SM, Jedrychowski, MP, Banks, AS, Lim, JH, Chim, H, Gygi, SP & Puigserver, P 2011, 'The cAMP/PKA Pathway Rapidly Activates SIRT1 to Promote Fatty Acid Oxidation Independently of Changes in NAD +', Molecular Cell, vol. 44, no. 6, pp. 851-863. https://doi.org/10.1016/j.molcel.2011.12.005

APA

Gerhart-Hines, Z., Dominy, J. E., Blättler, S. M., Jedrychowski, M. P., Banks, A. S., Lim, J. H., Chim, H., Gygi, S. P., & Puigserver, P. (2011). The cAMP/PKA Pathway Rapidly Activates SIRT1 to Promote Fatty Acid Oxidation Independently of Changes in NAD +. Molecular Cell, 44(6), 851-863. https://doi.org/10.1016/j.molcel.2011.12.005

Vancouver

Gerhart-Hines Z, Dominy JE, Blättler SM, Jedrychowski MP, Banks AS, Lim JH et al. The cAMP/PKA Pathway Rapidly Activates SIRT1 to Promote Fatty Acid Oxidation Independently of Changes in NAD +. Molecular Cell. 2011 Dec 23;44(6):851-863. https://doi.org/10.1016/j.molcel.2011.12.005

Author

Gerhart-Hines, Zachary ; Dominy, John E. ; Blättler, Sharon M. ; Jedrychowski, Mark P. ; Banks, Alexander S. ; Lim, Ji Hong ; Chim, Helen ; Gygi, Steven P. ; Puigserver, Pere. / The cAMP/PKA Pathway Rapidly Activates SIRT1 to Promote Fatty Acid Oxidation Independently of Changes in NAD +. In: Molecular Cell. 2011 ; Vol. 44, No. 6. pp. 851-863.

Bibtex

@article{177e2960f33243998d840698f0f49a8c,
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.",
author = "Zachary Gerhart-Hines and Dominy, {John E.} and Bl{\"a}ttler, {Sharon M.} and Jedrychowski, {Mark P.} and Banks, {Alexander S.} and Lim, {Ji Hong} and Helen Chim and Gygi, {Steven P.} and Pere Puigserver",
note = "Funding Information: We thank members of the Puigserver lab for important discussions on the project. We particularly thank Dr. Joseph Rodgers and Dr. Timothy Kelly for critical reading of the manuscript and Dr. Wei Gu for providing the SIRT1 transgenic mice. We also thank Dr. Fred Alt and Dr. Raul Mostoslavsky for providing the WT and SIRT1 KO MEFs and Dr. John Denu for providing reagents necessary for the coupled deacetylase assay. The authors were supported in part by fellowships from the American Heart Association (Z.G.-H.), NRSA Kirschstein from the National Institutes of Health (J.E.D.), and Swiss National Science Foundation (S.M.B.). The research was supported from funds from the Dana-Farber Cancer Institute and grants from the American Diabetes Association, Department of Defense and National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (NIH/NIDDK), RO1 069966 (P.P.). Z.G.-H. and P.P. conceived of the project. Z.G.-H. designed and performed cellular deacetylation and phosphorylation experiments, phosphorylation mapping, in vitro kinase and Sirtuin activity assays, and mouse experiments and wrote the manuscript. J.E.D. designed and performed cellular deacetylation and phosphorylation experiments, phosphorylation mapping, in vitro Sirtuin activity assays, and mouse experiments and wrote the manuscript. S.M.B. and A.S.B. designed and performed mouse experiments. M.P.J. and S.P.G. performed and analyzed mass spectrometry experiments. J.-H.L. and H.C. performed cellular phosphorylation experiments. P.P. designed experiments and wrote the manuscript. ",
year = "2011",
month = dec,
day = "23",
doi = "10.1016/j.molcel.2011.12.005",
language = "English",
volume = "44",
pages = "851--863",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "6",

}

RIS

TY - JOUR

T1 - The cAMP/PKA Pathway Rapidly Activates SIRT1 to Promote Fatty Acid Oxidation Independently of Changes in NAD +

AU - Gerhart-Hines, Zachary

AU - Dominy, John E.

AU - Blättler, Sharon M.

AU - Jedrychowski, Mark P.

AU - Banks, Alexander S.

AU - Lim, Ji Hong

AU - Chim, Helen

AU - Gygi, Steven P.

AU - Puigserver, Pere

N1 - Funding Information: We thank members of the Puigserver lab for important discussions on the project. We particularly thank Dr. Joseph Rodgers and Dr. Timothy Kelly for critical reading of the manuscript and Dr. Wei Gu for providing the SIRT1 transgenic mice. We also thank Dr. Fred Alt and Dr. Raul Mostoslavsky for providing the WT and SIRT1 KO MEFs and Dr. John Denu for providing reagents necessary for the coupled deacetylase assay. The authors were supported in part by fellowships from the American Heart Association (Z.G.-H.), NRSA Kirschstein from the National Institutes of Health (J.E.D.), and Swiss National Science Foundation (S.M.B.). The research was supported from funds from the Dana-Farber Cancer Institute and grants from the American Diabetes Association, Department of Defense and National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (NIH/NIDDK), RO1 069966 (P.P.). Z.G.-H. and P.P. conceived of the project. Z.G.-H. designed and performed cellular deacetylation and phosphorylation experiments, phosphorylation mapping, in vitro kinase and Sirtuin activity assays, and mouse experiments and wrote the manuscript. J.E.D. designed and performed cellular deacetylation and phosphorylation experiments, phosphorylation mapping, in vitro Sirtuin activity assays, and mouse experiments and wrote the manuscript. S.M.B. and A.S.B. designed and performed mouse experiments. M.P.J. and S.P.G. performed and analyzed mass spectrometry experiments. J.-H.L. and H.C. performed cellular phosphorylation experiments. P.P. designed experiments and wrote the manuscript.

PY - 2011/12/23

Y1 - 2011/12/23

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84255198350&partnerID=8YFLogxK

U2 - 10.1016/j.molcel.2011.12.005

DO - 10.1016/j.molcel.2011.12.005

M3 - Journal article

C2 - 22195961

AN - SCOPUS:84255198350

VL - 44

SP - 851

EP - 863

JO - Molecular Cell

JF - Molecular Cell

SN - 1097-2765

IS - 6

ER -

ID: 347796081