Metformin-induced inhibition of the mitochondrial respiratory chain increases FGF21 expression via ATF4 activation

Biochem Biophys Res Commun. 2013 Oct 11;440(1):76-81. doi: 10.1016/j.bbrc.2013.09.026. Epub 2013 Sep 13.

Abstract

Fibroblast growth factor 21 (FGF21) is an endocrine hormone that exhibits anti-obesity and anti-diabetes effects. Because metformin is widely used as a glucose-lowering agent in patients with type 2 diabetes (T2D), we investigated whether metformin modulates FGF21 expression in cell lines, and in mice or human subjects. We found that metformin increased the expression and release of FGF21 in a diverse set of cell types, including rat hepatoma FaO, primary mouse hepatocytes, and mouse embryonic fibroblasts (MEFs). Intriguingly, AMP-activated protein kinase (AMPK) was dispensable for the induction of FGF21 by metformin. Mammalian target of rapamycin complex 1 (mTORC1) and peroxisome proliferator-activated receptor α (PPARα), which are additional targets of metformin, were not involved in metformin-induced FGF21 expression. Importantly, inhibition of mitochondrial complex I activity by metformin resulted in FGF21 induction through PKR-like ER kinase (PERK)-eukaryotic translation factor 2α (eIF2α)-activating transcription factor 4 (ATF4). We showed that metformin activated ATF4 and increased FGF21 expression in the livers of mice, which led to increased serum levels of FGF21. We also found that serum FGF21 level was increased in human subjects with T2D after metformin therapy for 6 months. In conclusion, our results indicate that metformin induced expression of FGF21 through an ATF4-dependent mechanism by inhibiting mitochondrial respiration independently of AMPK. Therefore, FGF21 induction by metformin might explain a portion of the beneficial metabolic effects of metformin.

Keywords: AMPK; ATF4; Diabetes; FGF21; Metformin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Activating Transcription Factor 4 / metabolism*
  • Animals
  • Cell Line
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetes Mellitus, Type 2 / metabolism
  • Electron Transport / drug effects
  • Eukaryotic Initiation Factor-2 / metabolism
  • Fibroblast Growth Factors / blood
  • Fibroblast Growth Factors / genetics*
  • Humans
  • Hypoglycemic Agents / pharmacology*
  • Hypoglycemic Agents / therapeutic use
  • Male
  • Metformin / pharmacology*
  • Metformin / therapeutic use
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Rats
  • Up-Regulation / drug effects*
  • eIF-2 Kinase / metabolism

Substances

  • Eukaryotic Initiation Factor-2
  • Hypoglycemic Agents
  • fibroblast growth factor 21
  • Activating Transcription Factor 4
  • Fibroblast Growth Factors
  • Metformin
  • PERK kinase
  • eIF-2 Kinase
  • AMP-Activated Protein Kinases