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Metformin Inhibits Hepatic mTORC1 Signaling via Dose-Dependent Mechanisms Involving AMPK and the TSC Complex
Open accessAbstract
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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“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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“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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“One of metformin’s major intracellular effects is on the mammalian target of rapamycin (mTOR) pathway, known to be important for nutrient sensing, by both 5 AMP-activated protein kinase (AMPK)-dependent [66] and AMPK-independent [67] mechanisms.”
BackgroundMetformin inhibits IL-6 signaling by decreasing IL-6R expression on multiple myeloma cells
Mishra, A. K., & Dingli, D. (2019) · Leukemia · doi:10.1038/s41375-019-0470-4 · Cited by 72
Salinomycin, as an autophagy modulator-- a new avenue to anticancer: a review
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“the one hand, phosphorylation of TSC2 and raptor by AMPK is known to elevate TSC2/TSC1 activity and reduce mTOR’s kinase function, respectively [87, 88].”
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Couteur, D. G. L., Solon‐Biet, S. M., Parker, B. L., Pulpitel, T., Brandon, A. E., Hunt, N. J., Wali, J. A., Gokarn, R., Senior, A. M., Cooney, G. J., et al. (2021) · Cell Metabolism · doi:10.1016/j.cmet.2021.10.016 · Cited by 71
mTOR Inhibitor Therapy and Metabolic Consequences: Where Do We Stand?
Kezić, A., Popović, L., & Lalic, K. S. (2018) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2018/2640342 · Cited by 68
“At a lower dosage, metformin requires AMPK and the TSC to inhibit mTORC1, whereas at higher dosage, this effect is AMPK and TSC independent [80].”
BackgroundThe Role of AMPK/mTOR Signaling Pathway in Anticancer Activity of Metformin
Chomaničová, N., Gažová, A., Adamičková, A., Valášková, S., & Kyselovič, J. (2021) · Physiological Research · doi:10.33549/physiolres.934618 · Cited by 68
Understanding the action mechanisms of metformin in the gastrointestinal tract
Cheng, M., Ren, L., Jia, X., Wang, J., & Cong, B. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1347047 · Cited by 78
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The role of AMPK in metabolism and its influence on DNA damage repair
Szewczuk, M., Boguszewska, K., Kaźmierczak-Barańska, J., & Karwowski, B. T. (2020) · Molecular Biology Reports · doi:10.1007/s11033-020-05900-x · Cited by 69
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“Notably, activated AMPK can directly phosphorylate and activate tuberous sclerosis complex 2 (TSC2), leading to repression of mTOR signaling pathways.(24,27)”
BackgroundDietary Intervention Impacts Immune Cell Functions and Dynamics by Inducing Metabolic Rewiring
Okawa, T., Nagai, M., & Hase, K. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2020.623989 · Cited by 68
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Metformin prevents the pathological browning of subcutaneous white adipose tissue
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“Metformin’s cellular actions are often attributed to this drug inhibiting complex I of the electron transport chain (ETC), subsequently increasing the AMP:ATP ratio and activating adenosine monophosphate kinase (AMPK) [14].”
BackgroundRepurposing Brigatinib for the Treatment of Colorectal Cancer Based on Inhibition of ER-phagy
Zhang, Z., Gao, W. Q., Zhou, L., Chen, Y., Qin, S., Zhang, L., Liu, J., He, Y., Lei, Y., Chen, H., et al. (2019) · Theranostics · doi:10.7150/thno.36254 · Cited by 61
“For instance, metformin, which was originally used to treat diabetes in an insulin-dependent manner, showed anti-cancer effect in different cancers via an insulin-independent mechanism [43, 44].”
BackgroundThe Metabolic Heterogeneity and Flexibility of Cancer Stem Cells
Tanabe, A., & Sahara, H. (2020) · Cancers · doi:10.3390/cancers12102780 · Cited by 61
“In addition to the ETS, metformin is known to inhibit mTORC1 activity indirectly or directly [176,177].”
BackgroundThe Anti-Aging Mechanism of Metformin: From Molecular Insights to Clinical Applications
Zhang, T., Li-jun, Z., Makarczyk, M. J., Feng, P., & Zhang, J. (2025) · Molecules · doi:10.3390/molecules30040816 · Cited by 64
“By activating AMPK, metformin inhibits the mTOR pathway, a key modulator of cellular anabolic progression, proliferation, autophagy, and aging [35].”
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Counteracting Chemoresistance with Metformin in Breast Cancers: Targeting Cancer Stem Cells
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STAT3/LKB1 controls metastatic prostate cancer by regulating mTORC1/CREB pathway
Pěnčík, J., Philippe, C., Schlederer, M., Atas, E., Pecoraro, M., Grund‐Gröschke, S., Li, W., Tracz, A., Heidegger, I. M., Lagger, S., et al. (2023) · Molecular Cancer · doi:10.1186/s12943-023-01825-8 · Cited by 53
“Metformin, a first-line treatment for patients with t2DM, activates AMP-activated protein kinase (AMPK), which results in inhibition of mTORC1 [21].”
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Biguanides drugs: Past success stories and promising future for drug discovery
Grytsai, O., Myrgorodska, I., Rocchi, S., Ronco, C., & Benhida, R. (2021) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2021.113726 · Cited by 51
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“61,62 The second pathway involves the direct phosphorylation and suppression of RAPTOR, which is a scaffold protein of the mTORC1 complex.”
BackgroundMolecular mechanisms of action of metformin: latest advances and therapeutic implications
Zhu, H., Jia, Z., Li, Y. R., & Danelisen, I. (2023) · Clinical and Experimental Medicine · doi:10.1007/s10238-023-01051-y · Cited by 59
“…downstream target of AMPK signaling is the mammalian target of rapamycin (mTOR), which is inhibited following metformin-mediated activation of AMPK [16]. mTOR is a major nutrient-sensi-tive regulator of growth in animals and plays important roles in diverse biological processes, including glucose…”
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Metadata
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › 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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