The DOI matches its Crossref record; 33 of the 33 references it cites were found in a registry or an index.
AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity
Open accessAbstract
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 ratio. Recent evidence indicated an important role for AMPK in the therapeutic benefits of metformin, thiazolidinediones and exercise, 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 ATP. 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-gamma coactivator 1alpha 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.
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“The synthesis of mitochondria in myocytes is upregulated to meet the demands associated with an increase in capillary density, which in turn leads to increased oxygen extraction and metabolism122 through the induction of calcium and metabolic signalling pathways such as those involving 5’-AMP-activated serine/threonine-protein kinase (AMPK) and sirtuins123.”
From Sarcopenic obesity in older adults: aetiology, epidemiology and treatment strategies (2018) · cites this paper as [123]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“SIRT1 increases mitochondrial activity and biogenesis by deacetylating and activating PGC1α (peroxisome proliferator-activated receptor-γ co-activator 1α) [102].”
From NAD+ Precursors Nicotinamide Mononucleotide (NMN) and Nicotinamide Riboside (NR): Potential Dietary Contribution to Health (2023) · cites this paper as [102]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“The adenosine monophosphate-activated protein kinase (AMPK) is a cellular energy regulator which senses changes in the intracellular AMP/ATP ratio. During energy limitation, low levels of ATP activate AMPK, which acts to maintain cellular energy stores.”
From NAD+ Precursors Nicotinamide Mononucleotide (NMN) and Nicotinamide Riboside (NR): Potential Dietary Contribution to Health (2023) · cites this paper as [102]
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In the citing paper
“Thus, AMPK enhances the SIRT1 activity by increasing cellular NAD+ levels, resulting in the deacetylation and modulation of the activity of energy metabolism-related downstream SIRT1 targets, which include the PGC1α, the forkhead box O1 (FOXO1) and O3 (FOXO3a) transcription factors [102].”
From NAD+ Precursors Nicotinamide Mononucleotide (NMN) and Nicotinamide Riboside (NR): Potential Dietary Contribution to Health (2023) · cites this paper as [102]
In the citing paper
“In support of this hypothesis, it has now been demonstrated in mammalian systems that lifespan-extending metabolic manipulations, such as exercise75–77, caloric restriction78, time-restricted feeding and a ketogenic diet79, as well as healthy circadian rhythms1,11 (including regular sleep patterns80), work in part by increasing NAD+ levels, which leads to the activation of sirtuins.”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [77]
In the citing paper
“SIRT1 is known to be activated in response to metabolic changes, such as low glucose or exercise, that increase cellular NAD+ (62, 354).”
From Redox regulation of mitochondrial function (2012) · cites this paper as [62]
In the citing paper
“Drug-induced activation of AMPK produces gene expression patterns similar to those observed during exercise (104).”
From Diet and physical exercise as key players to tackle MASLD through improvement of insulin resistance and metabolic flexibility (2024) · cites this paper as [104]
In the citing paper
“Deacetylation of FOXO1 and FOXO3a by SIRT1 (19, 20) mediates autophagic signaling in muscle cells, and aging attenuates SIRT1, which reduces autophagy (134).”
From Mitochondria initiate and regulate sarcopenia (2017) · cites this paper as [19]
In the citing paper
“Recent studies show that AMPK also enhances SIRT1 activity by increasing cellular NAD+ levels, resulting in the deacetylation and modulation of the activity of downstream SIRT1 targets 160.”
From Cellular bioenergetics as a target for obesity therapy (2010) · cites this paper as [160]
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Citations
Cites
Role of AMP-Activated Protein Kinase in Mechanism of Metformin Action
Zhou, G., Myers, R., Li, Y., Chen, Y., Shen, X., Fenyk-Melody, J., Wu, M., Ventre, J., Doebber, T., Fujii, N., et al. (2001) · Journal of Clinical Investigation · doi:10.1172/jci13505 · Cited by 5,652
Resveratrol improves health and survival of mice on a high-calorie diet
Baur, J. A., Pearson, K. J., Price, N. L., Jamieson, H. A., Lerin, C., Kalra, A., Prabhu, V. V., Allard, J. S., Lopez-Lluch, G., Lewis, K., et al. (2006) · Nature · doi:10.1038/nature05354 · Cited by 4,290
Self-citationLagouge, M., Argmann, C., Gerhart-Hines, Z., Meziane, H., Lerin, C., Daussin, F., Messadeq, N., Milne, J., Lambert, P., Elliott, P., et al. (2006) · Cell · doi:10.1016/j.cell.2006.11.013 · Cited by 4,057
Self-citationTranscriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase
Imai, S.-I., Armstrong, C. M., Kaeberlein, M., & Guarente, L. (2000) · Nature · doi:10.1038/35001622 · Cited by 3,510
Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase
Brunet, A., Sweeney, L. B., Sturgill, J. F., Chua, K. F., Greer, P. L., Lin, Y., Tran, H., Ross, S. E., Mostoslavsky, R., Cohen, H. Y., et al. (2004) · Science · doi:10.1126/science.1094637 · Cited by 3,239
Nutrient control of glucose homeostasis through a complex of PGC-1α and SIRT1
Rodgers, J. T., Lerin, C., Haas, W., Gygi, S. P., Spiegelman, B. M., & Puigserver, P. (2005) · Nature · doi:10.1038/nature03354 · Cited by 3,160
Self-citationAMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1α
Jäger, S., Handschin, C., St.-Pierre, J., & Spiegelman, B. M. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0705070104 · Cited by 2,491
AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy
Hardie, D. G. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2249 · Cited by 2,261
Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation
Watanabe, M., Houten, S. M., Mataki, C., Christoffolete, M. A., Kim, B. W., Sato, H., Messaddeq, N., Harney, J. W., Ezaki, O., Kodama, T., et al. (2006) · Nature · doi:10.1038/nature04330 · Cited by 2,220
Self-citationThe Kinase LKB1 Mediates Glucose Homeostasis in Liver and Therapeutic Effects of Metformin
Shaw, R. J., Lamia, K. A., Vasquez, D., Koo, S.-H., Bardeesy, N., DePinho, R. A., Montminy, M., & Cantley, L. C. (2005) · Science · doi:10.1126/science.1120781 · Cited by 1,950
Cited by
Sorted by citations
AMPK: guardian of metabolism and mitochondrial homeostasis
Herzig, S., & Shaw, R. J. (2017) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2017.95 · Cited by 4,192
Mitochondria: In Sickness and in Health
Nunnari, J., & Suomalainen, A. (2012) · Cell · doi:10.1016/j.cell.2012.02.035 · Cited by 3,479
The AMPK signalling pathway coordinates cell growth, autophagy and metabolism
Mihaylova, M. M., & Shaw, R. J. (2011) · Nature Cell Biology · doi:10.1038/ncb2329 · Cited by 2,923
Erasers of Histone Acetylation: The Histone Deacetylase EnzymesPreprint
Seto, E., & Yoshida, M. (2014) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a018713 · Cited by 2,105
Mammalian Sirtuins: Biological Insights and Disease Relevance
Haigis, M. C., & Sinclair, D. A. (2010) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev.pathol.4.110807.092250 · Cited by 2,085
Metadata
- Authors
- Cantó, C., Gerhart-Hines, Z., Feige, J. N., Lagouge, M., Noriega, L., Milne, J. C., Elliott, P. J., Puigserver, P., & Auwerx, J.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Harvard University (US)
- Corresponding author
- Auwerx, Johan
- Venue
- Nature
- Published
- 2009-03-04
- Volume
- 458
- Issue
- 7241
- Pages
- 1056-1060
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3616311
- OpenAlex
- W2022267544
- Cited by
- 3,300
- References
- 33
- Citations by year
- 2026: 197 · 2025: 185 · 2024: 185 · 2023: 191 · 2022: 221 · 2021: 221 · 2020: 231 · 2019: 191 · 2018: 195 · 2017: 187 · 2016: 206 · 2015: 175 · 2014: 179 · 2013: 200 · 2012: 183
- FWCI
- 71.47
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-59820, DK069966, R01DK069966, P01DK059820)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Keywords
- AMPK, SIRT1, NAD+ metabolism, energy expenditure, skeletal muscle, PGC-1α, FOXO1, FOXO3, deacetylation, mitochondrial biogenesis, oxidative metabolism, type 2 diabetes, transcriptional regulation
- MeSH terms
- Forkhead Box Protein O1, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Forkhead Box Protein O3, Acetylation, Aminoimidazole Carboxamide, Animals, Cell Line, Energy Metabolism, Enzyme Activation, Gene Expression Regulation, Male, Mutation, NAD, Oxygen Consumption, Phosphorylation, Ribonucleotides, Transcription Factors, Transcription, Genetic, Trans-Activators, Muscle, Skeletal, Sirtuins, Genes, Mitochondrial, Mice, Forkhead Transcription Factors, AMP-Activated Protein Kinases, Sirtuin 1
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