Cited by 112Fibroblast Growth Factor ResearchMetabolism, Diabetes, and CancerEndoplasmic Reticulum Stress and Disease

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

Kim, Kook Hwan, Jeong, Yeon Taek, Kim, Seong Hun, Jung, Hye Seung, Park, Kyong Soo, Lee, Hae-Youn, Lee, Myung-Shik·2013·Biochemical and Biophysical Research Communications

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.

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Crossref · 10.1016/j.bbrc.2013.09.026

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Authors
Kim, K. H., Jeong, Y. T., Kim, S. H., Jung, H. S., Park, K. S., Lee, H.-Y., & Lee, M.-S.
Affiliations
  • Samsung Medical Center (KR)
  • Sungkyunkwan University (KR)
  • Seoul National University (KR)
Corresponding author
Lee, Myung-Shik
Venue
Biochemical and Biophysical Research Communications
Publisher
Elsevier BV
Published
2013-10
Volume
440
Issue
1
Pages
76-81
ISSN
0006-291X (ISSN-L)
OpenAlex
W2043635031
Cited by
112
References
24
Citations by year
2026: 7 · 2025: 1 · 2024: 6 · 2023: 9 · 2022: 7 · 2021: 5 · 2020: 11 · 2019: 10 · 2018: 10 · 2017: 8 · 2016: 15 · 2015: 14 · 2014: 8 · 2013: 1
FWCI
5.68
Type
journal article
Language
en
Open access
closed
Locations
  • Biochemical and Biophysical Research Communications (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Research Foundation of Korea (K21004000003-12A0500-00310)
  • Ministry of Education, Science and Technology (20120006344)
  • Samsung Biomedical Research Institute (SP1-B2-051-2)
  • Ministry of Health and Welfare (A084065-1222-0000300)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
Keywords
metformin, FGF21, ATF4, mitochondrial respiratory chain, mitochondrial complex I inhibition, PERK-eIF2α signaling, AMPK, type 2 diabetes, liver, hepatocytes, anti-obesity
MeSH terms
Animals, Cell Line, Diabetes Mellitus, Type 2, Electron Transport, Fibroblast Growth Factors, Humans, Hypoglycemic Agents, Male, Metformin, Mice, Inbred C57BL, Mitochondria, Eukaryotic Initiation Factor-2, Up-Regulation, eIF-2 Kinase, Mice, Rats, Activating Transcription Factor 4, AMP-Activated Protein Kinases

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