title: 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.
authors.affiliation: Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong Gangnam-gu, Seoul 135-710, South Korea; Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University School of Medicine, 50 Irwon-dong Gangnam-gu, Seoul 135-710, South Korea.
authors.forename: Kook Hwan
authors.initials: KH
authors.lastname: Kim
authors.forename: Yeon Taek
authors.initials: YT
authors.lastname: Jeong
authors.forename: Seong Hun
authors.initials: SH
authors.lastname: Kim
authors.forename: Hye Seung
authors.initials: HS
authors.lastname: Jung
authors.forename: Kyong Soo
authors.initials: KS
authors.lastname: Park
authors.forename: Hae-Youn
authors.initials: HY
authors.lastname: Lee
authors.forename: Myung-Shik
authors.initials: MS
authors.lastname: Lee
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D051701:Activating Transcription Factor 4 / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D004579:Electron Transport / Q000187:drug effects; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000097:blood / Q000235:genetics*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008687:Metformin / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D015854:Up-Regulation / Q000187:drug effects*; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D055372:AMP-Activated Protein Kinases; D051701:Activating Transcription Factor 4; D015852:Eukaryotic Initiation Factor-2; D005346:Fibroblast Growth Factors; D007004:Hypoglycemic Agents; D008687:Metformin; D019892:eIF-2 Kinase; C414620:fibroblast growth factor 21
keywords: AMPK; ATF4; Diabetes; FGF21; Metformin