AMP-activated protein kinase-deficient mice are resistant to the metabolic effects of resveratrol
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OBJECTIVE: Resveratrol, a natural polyphenolic compound that is found in grapes and red wine, increases metabolic rate, insulin sensitivity, mitochondrial biogenesis, and physical endurance and reduces fat accumulation in mice. Although it is thought that resveratrol targets Sirt1, this is controversial because resveratrol also activates 5' AMP-activated protein kinase (AMPK), which also regulates insulin sensitivity and mitochondrial biogenesis. Here, we use mice deficient in AMPKalpha1 or -alpha2 to determine whether the metabolic effects of resveratrol are mediated by AMPK. RESEARCH DESIGN AND METHODS: Mice deficient in the catalytic subunit of AMPK (alpha1 or alpha2) and wild-type mice were fed a high-fat diet or high-fat diet supplemented with resveratrol for 13 weeks. Body weight was recorded biweekly and metabolic parameters were measured. We also used mouse embryonic fibroblasts deficient in AMPK to study the role of AMPK in resveratrol-mediated effects in vitro. RESULTS: Resveratrol increased the metabolic rate and reduced fat mass in wild-type mice but not in AMPKalpha1(-/-) mice. In the absence of either AMPKalpha1 or -alpha2, resveratrol failed to increase insulin sensitivity, glucose tolerance, mitochondrial biogenesis, and physical endurance. Consistent with this, the expression of genes important for mitochondrial biogenesis was not induced by resveratrol in AMPK-deficient mice. In addition, resveratrol increased the NAD-to-NADH ratio in an AMPK-dependent manner, which may explain how resveratrol may activate Sirt1 indirectly. CONCLUSIONS: We conclude that AMPK, which was thought to be an off-target hit of resveratrol, is the central target for the metabolic effects of resveratrol.
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Resveratrol treatment increased physical endurance and protected from high-fat diet-induced muscle accumulation of diacylglyceride and ceramide, and related mitochondrial dysfunction.
“Resveratrol treatment also increased physical endurance and protected from high-fat diet-induced muscle accumulation of diacylglyceride and ceramide, and related mitochondrial dysfunction (248).”
From Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease (2018) · cites this paper as [248]
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- Authors
- Um, J.-H., Park, S.-J., Kang, H., Yang, S., Foretz, M., McBurney, M. W., Kim, M. K., Viollet, B., & Chung, J. H.
- Affiliations
- National Institutes of Health (US)
- Centre National de la Recherche Scientifique (FR)
- Center for Cancer Therapeutics, Ottawa Health Research Institute, Ottawa, Ontario, Canada.
- Institut Cochin, Université Paris Descartes, Centre National de la Recherche Scientifique (UMR 8104), Paris, France;
- Corresponding author
- Chung, Jay H.
- ORCID
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2009-11-23
- Volume
- 59
- Issue
- 3
- Pages
- 554-563
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC2828647
- OpenAlex
- W2156090275
- Cited by
- 647
- References
- 52
- Citations by year
- 2026: 12 · 2025: 12 · 2024: 15 · 2023: 19 · 2022: 19 · 2021: 35 · 2020: 33 · 2019: 33 · 2018: 35 · 2017: 48 · 2016: 48 · 2015: 47 · 2014: 67 · 2013: 55 · 2012: 76
- FWCI
- 40.01
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Diabetes (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- European Commission (LSHMCT-2004-005272)
- National Institutes of Health
- National Heart, Lung, and Blood Institute
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- resveratrol, AMPK, AMPKα1, AMPKα2, SIRT1, insulin sensitivity, glucose tolerance, mitochondrial biogenesis, physical endurance, fat mass, metabolic rate, high-fat diet, polyphenols
- MeSH terms
- Resveratrol, Animals, Cells, Cultured, Drug Resistance, Enzyme Inhibitors, Fibroblasts, Insulin Resistance, Male, Mice, Inbred C57BL, Mice, Mutant Strains, Mitochondria, NAD, Stilbenes, Weight Loss, Glucose Intolerance, Muscle, Skeletal, Mice, AMP-Activated Protein Kinases, Sirtuin 1
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