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

• Published in: Cell metabolism Vol. 25; no. 2; pp. 463 - 471
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07-02-2017
• Subjects: AMP-Activated Protein Kinases - metabolism; AMPK; Animals; Dose-Response Relationship, Drug; hepatocytes; Hepatocytes - drug effects; Hepatocytes - metabolism; Humans; liver; Liver - drug effects; Liver - metabolism; Mechanistic Target of Rapamycin Complex 1; metformin; Metformin - pharmacology; Mice, Inbred C57BL; Mice, Knockout; mTOR; mTORC1; Multiprotein Complexes - metabolism; Organ Specificity - drug effects; Protein Biosynthesis - drug effects; protein synthesis; Signal Transduction - drug effects; TOR Serine-Threonine Kinases - metabolism; TSC1; TSC2; Tuberous Sclerosis - metabolism; tuberous sclerosis complex; tuberous sclerosis complex; liver; mTOR; metformin; AMPK; TSC2; protein synthesis; TSC1; mTORC1; hepatocytes
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2016.12.009

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 strongly inhibits mTORC1 in mouse liver and mouse and human hepatocytes•AMPK is required for inhibition of hepatic mTORC1 signaling with low-dose metformin•The TSC complex is required for inhibition of hepatic mTORC1 with low-dose metformin•Metformin attenuates protein synthesis in hepatocytes through the TSC complex
Howell et al. address the controversy around mechanisms of metformin action using mouse genetics and show that metformin inhibits mTORC1 signaling in the liver through the AMPK-TSC axis in a dose- and time-dependent manner. AMPK is required for metformin to inhibit mTORC1 only when a low dose is used.