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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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“122 Furthermore, activated AMPK can lead to acetyl-CoA carboxylase (ACC) 1/2 phosphorylation, inhibiting SREBP-1c phosphorylation and de novo lipogenesis.”
BackgroundAutophagy and lysosomal dysfunction in diabetes and its complications
Arden, C., Park, S. H., Yasasilka, X. R., Lee, E. Y., & Lee, M. (2024) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2024.06.010 · Cited by 44
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“[33,34] Moreover, it is reported that metformin inhibits hepatic mTORC1 signaling, which is dependent on the adenosine monophosphate‐activated protein kinase and TSC complex.[35] This prompted us to investigate whether DDX5 had any effect on the TSC1/2 complex in NASH.”
BackgroundTargeting Mitochondrial Network Architecture in Down Syndrome and Aging
Mollo, N., Cicatiello, R., Aurilia, M., Scognamiglio, R., Genesio, R., Charalambous, M., Paladino, S., Conti, A. M. F., Nitsch, L., & Izzo, A. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21093134 · Cited by 41
“In addition to its role as PGC-1α activator, metformin inhibits, both in vitro and in vivo, mTORC1 signaling (Figure 7), either via AMPK-dependent [161] or via AMPK-independent mechanisms [162].”
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Huang, Q., Ren, Y., Yuan, P., Huang, M., Liu, G., Shi, Y., Jia, G., & Chen, M. (2024) · Journal of Inflammation Research · doi:10.2147/jir.s467882 · Cited by 41
“38 Metformin activates AMPK by elevating the cytoplasmic ADP/ATP and AMP/ATP ratios.”
BackgroundZuliani, I., Urbinati, C., Valenti, D., Quattrini, M. C., Medici, V., Cosentino, L., Pietraforte, D., Domenico, F. D., Marzia Perluigi, A., Vacca, R. A., et al. (2020) · Journal of Clinical Medicine · doi:10.3390/jcm9061669 · Cited by 38
“Furthermore, a dose response curve has been previously performed [4] that confirms that the concentration levels of metformin that can be achieved with the 100 mg/kg dose are comparable to those obtained with the standard dose used in humans for the treatment of type-2 diabetes (~20 mg/kg), with both giving plasma con…”
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“AMPK-depend inhibition of mTORC1 also explains the benefit in the context of cancer and cardiovascular diseases as well as the immunomodulatory effect (Howell et al., 2017).”
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“The elevated AMP induces AMPK (affected by AMP/ATP ratio) over-expression, which phosphorylates tuberous sclerosis complex 2 (TSC2, a tumor suppressor protein) [195, 196].”
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“The mitochondrial complex I / mTORC1 connection exemplified by metformin [175,186] may prompt a search for novel complex I inhibitors designed to suppress mTORC1 specifically.”
BackgroundTargeting breast cancer and their stem cell population through AMPK activation: novel insights
Uprety, B., & Abrahamse, H. (2022) · Cells · doi:10.3390/cells11030576 · Cited by 33
“mTORC1 is a nutrition-sensitive protein complex composed of mTOR kinase and the scaffolding protein raptor, catalysing various biosynthetic pathways in the human body [83].”
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“Furthermore, metformin activates SIRT1, AMPK, and Parkin while inhibiting complex 1 and mTOR activities, thereby inducing mitophagy [175].”
Metformin reduces HGF-induced resistance to alectinib via the inhibition of Gab1
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“Our data therefore imply that one of the physiological consequences of metformin-induced inhibition of mTORC1 [36] on systemic metabolism is the release of ketone bodies, here BHBA, in the circulating metabolome of cancer patients.”
BackgroundIdentification of the target protein and molecular mechanism of honokiol in anti-inflammatory action
Cai, X., Jiang, X., Zhao, M., Su, K., Tang, M., Hong, F., Ye, N., Zhang, R., Li, N., Wang, L., et al. (2022) · Phytomedicine · doi:10.1016/j.phymed.2022.154617 · Cited by 35
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“5 mM of metformin, a dose previously used in dermal fibroblast cells and hepatocytes [24, 25], normalized the elevated protein synthesis in FMR1KO neurons (Fig.”
BackgroundAge‐related AMP‐activated protein kinase alterations: From cellular energetics to longevity
Васильевна, М. Г., & Клебанов, А. А. (2019) · Cell Biochemistry and Function · doi:10.1002/cbf.3384 · Cited by 32
“For example, this biguanide in large doses inhibits the mTORC1 independently from AMPK.27 In addition, it was found that the drug can also affect v‐ATPase thereby promoting the translocation of the AXIN/LKB1 complex onto the lysosome surface to form a new v‐ATPase‐Ragulator complex, which leads to AMPK activation.28 I…”
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“IGF-1 = insulin-like growth factor-1; IGF1R = insulin-like growth factor-1 receptor; IRS = insulin receptor substrate; PI3K = phosphoinositide 3-kinase; PIP2 = phosphatidylinositol4,5-bisphosphate; PIP3 = phosphatidylinositol-4,5-triphosphate; PTEN = phosphatase and tensin homolog; PDK1 = phosphoinositide-dependent ki…”
BackgroundInfluentialComprehensive Review on Colorectal Cancer and Transplant
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“Metformin indirectly inhibits the mTOR pathway and has been studied as a potential chemopreventive agent (87).”
BackgroundMetformin Promotes Beclin1-Dependent Autophagy to Inhibit the Progression of Gastric Cancer
Liu, S., Yue, C., Chen, H., Chen, Y., & Li, G. (2020) · OncoTargets and Therapy · doi:10.2147/ott.s242298 · Cited by 32
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Modulating mTOR Signaling as a Promising Therapeutic Strategy for Atherosclerosis
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“Both drugs induced AMPK in clinically significant doses, which additionally suppressed mTORC1 and triggered autophagy [82].”
BackgroundAn investigation into the pleiotropic activity of metformin. A glimpse of haemostasis
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Anti-Aging Effect of Metformin: A Molecular and Therapeutical Perspective
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“Specifically, low-dose metformin inhibits mTORC1 via the AMPK and TSC complex, while higher doses have an AMPK-independent mechanism that inhibits T cell growth and glucose uptake [127].”
BackgroundMitochondrial mechanisms in Alzheimer’s disease: Quest for therapeutics
Kalani, K., Chaturvedi, P., Chaturvedi, P., Verma, V. K., Lal, N., Awasthi, S. K., & Kalani, A. (2023) · Drug Discovery Today · doi:10.1016/j.drudis.2023.103547 · Cited by 28
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“AMPK stimulates the formation of autophagosomes by inhibiting mTOR and has been described to reduce the amount of PrPSc in a neuroblastoma cell line persistently with permanent infection (Heiseke et al., 2009; Howell et al., 2017; Abdelaziz et al., 2020).”
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“Metformin is an indirect agonist of adenosine monophosphate-activated protein kinase (AMPK) [48] and a mammalian target of rapamycin complex 1 (mTORC1) inhibitor [46,49].”
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“The data obtained from mice demonstrated that activation of AMPKα and inhibition of mTOR pathways could significantly induce autophagy and further improve the starvation-induced hepatic metabolism disorder (Zhang et al., 2013; Chauvin et al., 2014; Howell et al., 2017).”
BackgroundCurrent and novel approaches in the pharmacological treatment of hepatocellular carcinoma
Villarruel-Melquiades, F., Mendoza‐Garrido, M. E., García-Cuellar, C. M., Sánchez-Pérez, Y., Pérez‐Carreón, J. I., & Camacho, J. (2023) · World Journal of Gastroenterology · doi:10.3748/wjg.v29.i17.2571 · Cited by 27
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AMPKα loss promotes KRAS-mediated lung tumorigenesis
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“…of metformin on multiple biochemical pathways relevant to aging (Kulkarni et al., 2020), showing that metformin activates AMPK and inhibits mTORC1 (Howell et al., 2017; Kalender et al., 2010; Martin- Montalvo et al., 2013), activates SIRT1 (Cuyàs et al., 2018), decreases IGF- 1 levels (Sarfstein…”
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Regulation of autophagy by perilysosomal calcium: a new player in β-cell lipotoxicity
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The interplay between cell death and senescence in cancer
Shimizu, K., Inuzuka, H., & Tokunaga, F. (2024) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2024.11.001 · Cited by 28
Resveratrol, Rapamycin and Metformin as Modulators of Antiviral Pathways
Benedetti, F., Sorrenti, V., Buriani, A., Fortinguerra, S., Scapagnini, G., & Zella, D. (2020) · Viruses · doi:10.3390/v12121458 · Cited by 26
Inhibition of mTORC1 through ATF4-induced REDD1 and Sestrin2 expression by Metformin
Jang, S., Hong, S.-E., Lee, D.-H., Kim, J.-Y., Kim, J. Y., Ye, S.-K., Hong, J., Park, I., & Jin, H. (2021) · BMC Cancer · doi:10.1186/s12885-021-08346-x · Cited by 29
Overcoming Drug Resistance in Advanced Prostate Cancer by Drug Repurposing
Bahmad, H. F., Demus, T., Moubarak, M. M., Daher, D., Moreno, J. C. A., Polit, F., López, O., Merhe, A., Abou-Kheir, W. G., Nieder, A. M., et al. (2022) · Medical Sciences · doi:10.3390/medsci10010015 · Cited by 27
Efficacy of Metformin as Adjuvant Therapy in Metastatic Breast Cancer Treatment
Essa, N. M., Salem, H. F., Elgendy, M. O., Gabr, A., Omran, M. M., Hassan, N. A., Tashkandi, H., Harakeh, S., & Boshra, M. S. (2022) · Journal of Clinical Medicine · doi:10.3390/jcm11195505 · Cited by 26
“A prior trial revealed that metformin suppressed the signaling of mTOR in a dose-dependent manner, denoting that low-dose metformin significantly suppressed mTOR through the TSC and AMPK pathway, whereas the high-dose metformin might follow a different mechanism of action [30,38].”
BackgroundLong-term exposure of human endothelial cells to metformin modulates miRNAs and isomiRs
Giuliani, A., Londin, E. R., Ferracin, M., Mensa’, E., Prattichizzo, F., Ramini, D., Marcheselli, F., Recchioni, R., Rippo, M. R., Bonafè, M., et al. (2020) · Scientific Reports · doi:10.1038/s41598-020-78871-5 · Cited by 23
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Nguyen, L. V., Nguyen, K. D. A., Ma, C. T., Nguyen, Q., Nguyen, H. T. H., Yang, D.-J., Tran, T. L., Kim, K. W., & Doan, K. V. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22031431 · Cited by 24
“In hepatocytes, metformin was shown to inhibit mTOR/S6 kinase signaling via AMPK activation [29].”
BackgroundXu, L., Wang, X., Chen, Y., Soong, L., Chen, Y., Cai, J., Liang, Y., & Sun, J. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.638575 · Cited by 23
“The TSC1-Dependent mTOR Signaling Pathways Regulated by Metformin It is known that while the mTOR signaling pathway is critical for T cell activation and differentiation (28), mTOR is also a potential target of metformin (29, 30).”
BackgroundCurrent Status of Autophagy Enhancers in Metabolic Disorders and Other Diseases
Park, K., & Lee, M. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.811701 · Cited by 24
“Then, metformin would be able to enhance autophagic activity since AMPK activation can upregulate autophagic activity through direct phosphorylation of ULK1 and Beclin 1, key molecules in the initiation of autophagy, or inhibition of mTORC1 (Egan et al., 2011; Howell et al., 2017; Kim J. et al., 2013; Kim et al., 2011…”
BackgroundAMPK suppresses Th2 cell responses by repressing mTORC2
Pandit, M., Timilshina, M., Gu, Y., Acharya, S., Chung, Y., Seo, S., & Chang, J. (2022) · Experimental & Molecular Medicine · doi:10.1038/s12276-022-00832-x · Cited by 25
Molecular mechanisms underlying the regulation of tumour suppressor genes in lung cancer
Jy, L., Bhandare, R. R., Boddu, S. H. S., SHAIK, A. B., Saktivel, L. P., Gupta, G., Negi, P., Barakat, M. M., Singh, S. K., Dua, K., et al. (2024) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2024.116275 · Cited by 25
Protein Kinases in Obesity, and the Kinase-Targeted Therapy
Engin, A. (2024) · Advances in experimental medicine and biology · doi:10.1007/978-3-031-63657-8_7 · Cited by 25
The Roles of AMPK in Revascularization
Chen, M.-H., & Fu, Q.-M. (2020) · Cardiology Research and Practice · doi:10.1155/2020/4028635 · Cited by 22
“In addition, AMPK suppresses the energy-intensive protein biosynthesis process by phosphorylating tuberous sclerosis complex 2 (TSC2) which regulates activity of mammalian target of rapamycin complex 1(mTORC1) promoting protein synthesis [20, 63].”
BackgroundGranata, S., Mercuri, S., Troise, D. E., Gesualdo, L., Stallone, G., & Zaza, G. (2023) · Frontiers in Medicine · doi:10.3389/fmed.2023.1168967 · Cited by 23
“According to these authors, such beneficial effects of mTOR-Is on the glycemic homeostasis could be explained by the chronic inhibition of mTORC1 (a biological/pharmacological effect such as that observed after metformin administration) (112).”
BackgroundChinnapaka, S., Yang, K. S., Flowers, Q., Faisal, M., Nerone, W. V., Rubin, J. P., & Ejaz, A. (2021) · Biomedicines · doi:10.3390/biomedicines9121782 · Cited by 22
“Various studies have shown that metformin inhibits the mammalian target of rapamycin (mTOR) [24,25].”
BackgroundSong, Y., Liu, Z., Zhu, X., Hao, C., Hao, W., Wu, S., Yang, J., Lu, X., & Jin, C. (2022) · Biochemical Pharmacology · doi:10.1016/j.bcp.2022.115140 · Cited by 21
Lai, H.-T., Naumova, N., Marchais, A., Gaspar, N., Geoerger, B., & Brenner, C. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.948097 · Cited by 23
Effect of metformin on the epigenetic age of peripheral blood in patients with diabetes mellitus
Li, M., Bao, L., Zhu, P., & Wang, S. (2022) · Frontiers in Genetics · doi:10.3389/fgene.2022.955835 · Cited by 21
“Especially for aging, metformin can lead to decreased insulin levels, decreased IGF-1 signaling pathway [29] [30], and mTOR inhibition [31] [32], inhibition of mitochondrial complex 1 in the electron transport chain and reduction of endogenous reactive oxygen species (ROS) production [33] [34], activation of AMPK [32]…”
BackgroundMechanisms and effects of metformin on skeletal muscle disorders
Shang, R., & Miao, J. (2023) · Frontiers in Neurology · doi:10.3389/fneur.2023.1275266 · Cited by 23
Phosphorylation dependent proteostasis of sterol regulatory element binding proteins
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Metformin reduces prion infection in neuronal cells by enhancing autophagy
Abdelaziz, D. H., Thapa, S., Abdulrahman, B., Vankuppeveld, L., & Schätzl, H. M. (2019) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2019.12.074 · Cited by 21
Smaug1 membrane-less organelles respond to AMPK and mTOR and affect mitochondrial function
Fernández-Álvarez, A. J., Thomas, M. G., Pascual, M. L., Habif, M., Pimentel, J., Corbat, A. A., Pessoa, J., Spina, P. E. L., Boscaglia, L., Plessis, A., et al. (2021) · Journal of Cell Science · doi:10.1242/jcs.253591 · Cited by 20
A human-based multi-gene signature enables quantitative drug repurposing for metabolic disease
Timmons, J. A., Anighoro, A., Brogan, R. J., Stahl, J., Wahlestedt, C., Farquhar, D. G., Taylor‐King, J. P., Volmar, C., Kraus, W. E., & Phillips, S. M. (2021) · eLife · doi:10.7554/elife.68832 · Cited by 21
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Verrelli, D., Dallera, L., Stendardo, M., Monzani, S., Pasqualato, S., Giorgio, M., & Pallavi, R. (2022) · Nutrients · doi:10.3390/nu14132669 · Cited by 20
Metformin Disrupts Signaling and Metabolism in Fetal Hepatocytes
Swenson, K. S., Wang, D., Jones, A. K., Nash, M. J., O’Rourke, R., Takahashi, D. L., Kievit, P., Hennebold, J. D., Aagaard, K. M., Friedman, J. E., et al. (2023) · Diabetes · doi:10.2337/db23-0089 · Cited by 22
SREBP-2, a new target of metformin?
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Metformin Prolongs Survival in Type 2 Diabetes Lung Cancer Patients With EGFR-TKIs
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Metformin to treat Huntington disease: A pleiotropic drug against a multi-system disorder
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Human Aging and Age-Related Diseases: From Underlying Mechanisms to Pro-Longevity Interventions
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Effects of metformin on adipose-derived stromal cell (ADSC) – Breast cancer cell lines interaction
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mTOR Signaling in the Inner Ear as Potential Target to Treat Hearing Loss
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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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