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

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

Research output: Contribution to journalArticle

94 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)463-471
Number of pages9
JournalCell Metabolism
Volume25
Issue number2
DOIs
StatePublished - Feb 7 2017
Externally publishedYes

Keywords

  • AMPK
  • TSC1
  • TSC2
  • hepatocytes
  • liver
  • mTOR
  • mTORC1
  • metformin
  • protein synthesis
  • tuberous sclerosis complex

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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    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. (2017). Metformin Inhibits Hepatic mTORC1 Signaling via Dose-Dependent Mechanisms Involving AMPK and the TSC Complex. Cell Metabolism, 25(2), 463-471. https://doi.org/10.1016/j.cmet.2016.12.009