Metformin Inhibits Hepatic Mtorc1 Signaling via Dose-Dependent Mechanisms Involving AMPK and the TSC Complex
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Metformin is the most widely prescribed drug for the treatment of type 2 diabetes. However, knowledge of the full effects of metformin on biochemical pathways and processes in its primary target tissue, the liver, is limited. One established effect of metformin is to decrease cellular energy levels. The AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) are key regulators of metabolism that are respectively activated and inhibited in acute response to cellular energy depletion. Here we show that metformin robustly inhibits mTORC1 in mouse liver tissue and primary hepatocytes. Using mouse genetics, we find that at the lowest concentrations of metformin that inhibit hepatic mTORC1 signaling, this inhibition is dependent on AMPK and the tuberous sclerosis complex (TSC) protein complex (TSC complex). Finally, we show that metformin profoundly inhibits hepatocyte protein synthesis in a manner that is largely dependent on its ability to suppress mTORC1 signaling.
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Metformin, like rapamycin, is known to inhibit mTOR signaling.
“Of significance is that metformin, like rapamycin, is known to inhibit mTOR signaling, and the inhibition of the mTOR signaling pathway with rapamycin has been shown to extend lifespan in C. elegans, S. cerevisiae, and Drosophila melanogaster (fruit fly) (221–225).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [225]
Inhibition of the mTOR signaling pathway with rapamycin has been shown to extend lifespan in C. elegans, S. cerevisiae, and Drosophila melanogaster.
“Of significance is that metformin, like rapamycin, is known to inhibit mTOR signaling, and the inhibition of the mTOR signaling pathway with rapamycin has been shown to extend lifespan in C. elegans, S. cerevisiae, and Drosophila melanogaster (fruit fly) (221–225).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [225]
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- Authors
- Howell, J. J., Hellberg, K., Turner, M., Talbott, G., Kolar, M. J., Ross, D. S., Hoxhaj, G., Saghatelian, A., Shaw, R. J., & Manning, B. D.
- Affiliations
- Harvard University (US)
- Salk Institute for Biological Studies (US)
- Corresponding author
- Shaw, Reuben J.
- Manning, Brendan D.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2017-02
- Volume
- 25
- Issue
- 2
- Pages
- 463-471
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC5299044
- OpenAlex
- W2572741715
- Cited by
- 408
- References
- 48
- Citations by year
- 2026: 24 · 2025: 40 · 2024: 61 · 2023: 42 · 2022: 47 · 2021: 49 · 2020: 62 · 2019: 42 · 2018: 25 · 2017: 16
- FWCI
- 16.20
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Ellison Medical Foundation
- NIH (F32-DK095508, F30-DK112604, R01-DK080425, P01-CA120964)
- George E. Hewitt Foundation for Medical Research
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- metformin, mTORC1 signaling, AMPK, tuberous sclerosis complex, liver, hepatocytes, protein synthesis, type 2 diabetes, dose-dependent effects
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Animals, Dose-Response Relationship, Drug, Humans, Liver, Metformin, Mice, Inbred C57BL, Organ Specificity, Protein Biosynthesis, Tuberous Sclerosis, Signal Transduction, Mice, Knockout, Hepatocytes, Multiprotein Complexes, AMP-Activated Protein Kinases, TOR Serine-Threonine Kinases
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