Cited by 408Metabolism, Diabetes, and CancerPI3K/AKT/mTOR signaling in cancerAutophagy in Disease and Therapy

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Metformin Inhibits Hepatic mTORC1 Signaling via Dose-Dependent Mechanisms Involving AMPK and the TSC Complex

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Howell, Jessica J., Hellberg, Kristina, Turner, Marc, Talbott, George, Kolar, Matthew J., Ross, Debbie S., Hoxhaj, Gerta, Saghatelian, Alan, Shaw, Reuben J., Manning, Brendan D.·2017·Cell Metabolism

DOI 10.1016/j.cmet.2016.12.009PMC PMC5299044

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Abstract

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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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: Howell, Jessica J.
Turner, Marc
Kolar, Matthew J.
Hoxhaj, Gerta
Saghatelian, Alan
Shaw, Reuben J.
Manning, Brendan D.
Venue: Cell Metabolism
Publisher: Elsevier BV
Published: 2017-02
Volume: 25
Issue: 2
Pages: 463-471
ISSN: 1550-4131 (ISSN-L)
DOI: 10.1016/j.cmet.2016.12.009
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: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 371 d)
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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Metformin Inhibits Hepatic mTORC1 Signaling via Dose-Dependent Mechanisms Involving AMPK and the TSC Complex

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