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Specific SIRT1 Activation Mimics Low Energy Levels and Protects against Diet-Induced Metabolic Disorders by Enhancing Fat Oxidation
Open accessAbstract
The NAD(+)-dependent deacetylase SIRT1 controls metabolic processes in response to low nutrient availability. We report the metabolic phenotype of mice treated with SRT1720, a specific and potent synthetic activator of SIRT1 that is devoid of direct action on AMPK. SRT1720 administration robustly enhances endurance running performance and strongly protects from diet-induced obesity and insulin resistance by enhancing oxidative metabolism in skeletal muscle, liver, and brown adipose tissue. These metabolic effects of SRT1720 are mediated by the induction of a genetic network controlling fatty acid oxidation through a multifaceted mechanism that involves the direct deacetylation of PGC-1alpha, FOXO1, and p53 and the indirect stimulation of AMPK signaling through a global metabolic adaptation mimicking low energy levels. Combined with our previous work on resveratrol, the current study further validates SIRT1 as a target for the treatment of metabolic disorders and characterizes the mechanisms underlying the therapeutic potential of SIRT1 activation.
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“In the cases of resveratrol and the sirtuin activator SRT1720, there is convincing evidence that they protect from metabolic damage and improve mitochondrial respiration in a PGC-1α-dependent fashion”
From The Hallmarks of Aging (2013) · cites this paper as Feige et al., 2008
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“However, SRT1720 has been shown in BAT to modify lipid droplet size and gene expression 157,158.”
From Cellular bioenergetics as a target for obesity therapy (2010) · cites this paper as [158]
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SIRT1 Activation by Small Molecules
Dai, H., Kustigian, L. M., Carney, D. P., Case, A. W., Considine, T., Hubbard, B. P., Perni, R. B., Riera, T. V., Szczepankiewicz, B. G., Vlasuk, G. P., et al. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.133892 · Cited by 215
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The coordination of nuclear and mitochondrial communication during aging and calorie restriction
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Henstridge, D. C., Bruce, C. R., Drew, B. G., Tory, K., Kolonics, A., Estevez, E., Chung, J., Watson, N., Gardner, T., Lee-Young, R. S., et al. (2014) · Diabetes · doi:10.2337/db13-0967 · Cited by 201
“Another important fuel-sensing molecule is the NAD-dependent deacetylase SIRT1, an important regulator of oxidative metabolism (12,35).”
Background
Metadata
- Authors
- Feige, J. N., Lagouge, M., Canto, C., Strehle, A., Houten, S. M., Milne, J. C., Lambert, P. D., Mataki, C., Elliott, P. J., & Auwerx, J.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Amsterdam UMC Location University of Amsterdam (NL)
- Corresponding author
- Auwerx, Johan
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2008-11
- Volume
- 8
- Issue
- 5
- Pages
- 347-358
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W2077834313
- Cited by
- 719
- References
- 39
- Citations by year
- 2026: 7 · 2025: 15 · 2024: 19 · 2023: 22 · 2022: 22 · 2021: 30 · 2020: 29 · 2019: 28 · 2018: 42 · 2017: 28 · 2016: 41 · 2015: 51 · 2014: 58 · 2013: 64 · 2012: 63
- FWCI
- 27.44
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- HAL (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- Pure Amsterdam UMC (submittedVersion, other-oa)
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- SIRT1, SRT1720, NAD+-dependent deacetylase, fatty acid oxidation, diet-induced obesity, insulin resistance, AMPK signaling, PGC-1α, FOXO1, p53, brown adipose tissue, skeletal muscle metabolism, hepatic metabolism, endurance running performance, low energy availability, metabolic adaptation, resveratrol, metabolic disorders
- MeSH terms
- Acetylation, Animals, Diet, Dietary Fats, Energy Metabolism, Heterocyclic Compounds, 4 or More Rings, Insulin Resistance, Male, Metabolic Diseases, Mice, Inbred C57BL, Motor Activity, Obesity, Oxidation-Reduction, Physical Conditioning, Animal, Sirtuins, Lipid Metabolism, Mice, Sirtuin 1
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