AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity


AMP-activated protein kinase (AMPK) is a metabolic fuel gauge conserved along the evolutionary scale in eukaryotes that senses changes in the intracellular AMP/ATP ratio1. Recent evidence indicated an important role for AMPK in the therapeutic benefits of metformin2,3, thiazolidinediones4 and exercise5, which form the cornerstones of the clinical management of type 2 diabetes and associated metabolic disorders. In general, activation of AMPK acts to maintain cellular energy stores, switching on catabolic pathways that produce ATP, mostly by enhancing oxidative metabolism and mitochondrial biogenesis, while switching off anabolic pathways that consume ATP1. This regulation can take place acutely, through the regulation of fast post-translational events, but also by transcriptionally reprogramming the cell to meet energetic needs. Here we demonstrate that AMPK controls the expression of genes involved in energy metabolism in mouse skeletal muscle by acting in coordination with another metabolic sensor, the NAD+-dependent type III deacetylase SIRT1. AMPK enhances SIRT1 activity by increasing cellular NAD+ levels, resulting in the deacetylation and modulation of the activity of downstream SIRT1 targets that include the peroxisome proliferator-activated receptor-γ coactivator 1α and the forkhead box O1 (FOXO1) and O3 (FOXO3a) transcription factors. The AMPK-induced SIRT1-mediated deacetylation of these targets explains many of the convergent biological effects of AMPK and SIRT1 on energy metabolism.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Activation of AMPK triggers PGC-1α deacetylation in C2C12 myotubes and skeletal muscle.
Figure 2: SIRT1 mediates AMPK-induced PGC-1α deacetylation.
Figure 3: AICAR modulates PGC-1α-dependent transcriptional activity, mitochondrial gene expression and oxygen consumption through SIRT1 and NAD + metabolism.
Figure 4: The PGC-1α phosphorylation mutant is resistant to deacetylation.


  1. 1

    Hardie, D. G. AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nature Rev. Mol. Cell Biol. 8, 774–785 (2007)

    CAS  Article  Google Scholar 

  2. 2

    Shaw, R. J. et al. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 310, 1642–1646 (2005)

    ADS  CAS  Article  Google Scholar 

  3. 3

    Zhou, G. et al. Role of AMP-activated protein kinase in mechanism of metformin action. J. Clin. Invest. 108, 1167–1174 (2001)

    CAS  Article  Google Scholar 

  4. 4

    Fryer, L. G., Parbu-Patel, A. & Carling, D. The Anti-diabetic drugs rosiglitazone and metformin stimulate AMP-activated protein kinase through distinct signaling pathways. J. Biol. Chem. 277, 25226–25232 (2002)

    CAS  Article  Google Scholar 

  5. 5

    Barnes, B. R. et al. Changes in exercise-induced gene expression in 5′-AMP-activated protein kinase γ3-null and γ3 R225Q transgenic mice. Diabetes 54, 3484–3489 (2005)

    CAS  Article  Google Scholar 

  6. 6

    Zong, H. et al. AMP kinase is required for mitochondrial biogenesis in skeletal muscle in response to chronic energy deprivation. Proc. Natl Acad. Sci. USA 99, 15983–15987 (2002)

    ADS  CAS  Article  Google Scholar 

  7. 7

    Suwa, M., Nakano, H. & Kumagai, S. Effects of chronic AICAR treatment on fiber composition, enzyme activity, UCP3, and PGC-1 in rat muscles. J. Appl. Physiol. 95, 960–968 (2003)

    CAS  Article  Google Scholar 

  8. 8

    Jager, S., Handschin, C., St-Pierre, J. & Spiegelman, B. M. AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1α. Proc. Natl Acad. Sci. USA 104, 12017–12022 (2007)

    ADS  Article  Google Scholar 

  9. 9

    Rodgers, J. T. et al. Nutrient control of glucose homeostasis through a complex of PGC-1α and SIRT1. Nature 434, 113–118 (2005)

    ADS  CAS  Article  Google Scholar 

  10. 10

    Gerhart-Hines, Z. et al. Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC-1α. EMBO J. 26, 1913–1923 (2007)

    CAS  Article  Google Scholar 

  11. 11

    Nemoto, S., Fergusson, M. M. & Finkel, T. SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1α. J. Biol. Chem. 280, 16456–16460 (2005)

    CAS  Article  Google Scholar 

  12. 12

    Lagouge, M. et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α. Cell 127, 1109–1122 (2006)

    CAS  Article  Google Scholar 

  13. 13

    Dasgupta, B. & Milbrandt, J. Resveratrol stimulates AMP kinase activity in neurons. Proc. Natl Acad. Sci. USA 104, 7217–7222 (2007)

    ADS  CAS  Article  Google Scholar 

  14. 14

    Baur, J. A. et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444, 337–342 (2006)

    ADS  CAS  Article  Google Scholar 

  15. 15

    Hayashi, T. et al. Metabolic stress and altered glucose transport: activation of AMP-activated protein kinase as a unifying coupling mechanism. Diabetes 49, 527–531 (2000)

    CAS  Article  Google Scholar 

  16. 16

    Cool, B. et al. Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome. Cell Metab. 3, 403–416 (2006)

    CAS  Article  Google Scholar 

  17. 17

    Bitterman, K. J., Anderson, R. M., Cohen, H. Y., Latorre-Esteves, M. & Sinclair, D. A. Inhibition of silencing and accelerated aging by nicotinamide, a putative negative regulator of yeast sir2 and human SIRT1. J. Biol. Chem. 277, 45099–45107 (2002)

    CAS  Article  Google Scholar 

  18. 18

    Chua, K. F. et al. Mammalian SIRT1 limits replicative life span in response to chronic genotoxic stress. Cell Metab. 2, 67–76 (2005)

    CAS  Article  Google Scholar 

  19. 19

    Handschin, C., Rhee, J., Lin, J., Tarr, P. T. & Spiegelman, B. M. An autoregulatory loop controls peroxisome proliferator-activated receptor γ coactivator 1α expression in muscle. Proc. Natl Acad. Sci. USA 100, 7111–7116 (2003)

    ADS  CAS  Article  Google Scholar 

  20. 20

    Wende, A. R., Huss, J. M., Schaeffer, P. J., Giguere, V. & Kelly, D. P. PGC-1α coactivates PDK4 gene expression via the orphan nuclear receptor ERRα: a mechanism for transcriptional control of muscle glucose metabolism. Mol. Cell. Biol. 25, 10684–10694 (2005)

    CAS  Article  Google Scholar 

  21. 21

    Huss, J. M., Kopp, R. P. & Kelly, D. P. Peroxisome proliferator-activated receptor coactivator-1α (PGC-1α) coactivates the cardiac-enriched nuclear receptors estrogen-related receptor-α and -γ. Identification of novel leucine-rich interaction motif within PGC-1α. J. Biol. Chem. 277, 40265–40274 (2002)

    CAS  Article  Google Scholar 

  22. 22

    Imai, S., Armstrong, C. M., Kaeberlein, M. & Guarente, L. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 403, 795–800 (2000)

    ADS  CAS  Article  Google Scholar 

  23. 23

    Revollo, J. R., Grimm, A. A. & Imai, S. The NAD biosynthesis pathway mediated by nicotinamide phosphoribosyltransferase regulates Sir2 activity in mammalian cells. J. Biol. Chem. 279, 50754–50763 (2004)

    CAS  Article  Google Scholar 

  24. 24

    Hasmann, M. & Schemainda, I. FK866, a highly specific noncompetitive inhibitor of nicotinamide phosphoribosyltransferase, represents a novel mechanism for induction of tumor cell apoptosis. Cancer Res. 63, 7436–7442 (2003)

    CAS  PubMed  Google Scholar 

  25. 25

    Fulco, M. et al. Glucose restriction inhibits skeletal myoblast differentiation by activating SIRT1 through AMPK-mediated regulation of Nampt. Dev. Cell 14, 661–673 (2008)

    CAS  Article  Google Scholar 

  26. 26

    Brunet, A. et al. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 303, 2011–2015 (2004)

    ADS  CAS  Article  Google Scholar 

  27. 27

    Greer, E. L. et al. The energy sensor AMP-activated protein kinase directly regulates the mammalian FOXO3 transcription factor. J. Biol. Chem. 282, 30107–30119 (2007)

    CAS  Article  Google Scholar 

  28. 28

    Milne, J. C. et al. Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature 450, 712–716 (2007)

    ADS  CAS  Article  Google Scholar 

  29. 29

    Feige, J. N. et al. Specific SIRT1 activation mimics low energy levels and protects against diet-induced metabolic disorders by enhancing fat oxidation. Cell Metab. 8, 347–358 (2008)

    CAS  Article  Google Scholar 

  30. 30

    Woods, A. et al. Characterization of the role of AMP-activated protein kinase in the regulation of glucose-activated gene expression using constitutively active and dominant negative forms of the kinase. Mol. Cell. Biol. 20, 6704–6711 (2000)

    CAS  Article  Google Scholar 

  31. 31

    Watanabe, M. et al. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature 439, 484–489 (2006)

    ADS  CAS  Article  Google Scholar 

  32. 32

    Pich, S. et al. The Charcot-Marie-Tooth type 2A gene product, Mfn2, up-regulates fuel oxidation through expression of OXPHOS system. Hum. Mol. Genet. 14, 1405–1415 (2005)

    CAS  Article  Google Scholar 

  33. 33

    Lin, S. S., Manchester, J. K. & Gordon, J. I. Enhanced gluconeogenesis and increased energy storage as hallmarks of aging in Saccharomyces cerevisiae . J. Biol. Chem. 276, 36000–36007 (2001)

    CAS  Article  Google Scholar 

Download references


This work was supported by grants of CNRS, Ecole Polytechnique Fédérale de Lausanne, INSERM, ULP, NIH (DK59820 and DK069966), EU FP6 (EUGENE2; LSHM-CT-2004-512013) and EU Ideas programme (sirtuins; ERC-2008-AdG-23118). C.C. has been supported by grants of Fondation de la Recherche Medicale (FRM) and EMBO. J.N.F. was supported by a FEBS grant. The authors thank F. Foufelle and P. Ferre, B. Spiegelman, D. P. Kelly, S.-i. Imai, G. Hardie, C. Ammann (Topotarget) and F. Alt for providing materials, and members of the Auwerx and Puigserver laboratories for discussion.

Author Contributions C.C. designed and executed experiments, interpreted data and wrote the manuscript. Z.G.-H., J.C.M., J.N.F., M.L. and L.N. performed experiments and J.N.F. helped with writing. P.J.E. and P.P. provided crucial reagents and helped with data interpretation. J.A. supervised the design and interpretation of the experiments and participated in the writing of the manuscript.

Author information



Corresponding author

Correspondence to Johan Auwerx.

Ethics declarations

Competing interests

[Competing Interests: P.P. consults for and J.C.M. and P.J.E. are employed by Sirtris, a subsidiary of GSK that develops drugs targeting sirtuins.]

Supplementary information

Supplementary Figures

This file contains Supplementary Figures 1-18 with Legends (PDF 2115 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Cantó, C., Gerhart-Hines, Z., Feige, J. et al. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature 458, 1056–1060 (2009).

Download citation

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.