Metformin-induced inhibition of the mitochondrial respiratory chain increases FGF21 expression via ATF4 activation
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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FGF21 and GDF15 are synthesized in response to mitochondrial stress.
“a number of molecules that are synthesized in response to mitochondrial stress have been identified, including FGF21 (10) and GDF15 (15).”
From Human Aging and Longevity Are Characterized by High Levels of Mitokines (2019) · cites this paper as [10]
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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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