Fibroblast growth factor 21 participates in adaptation to endoplasmic reticulum stress and attenuates obesity-induced hepatic metabolic stress
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Aims/hypothesis Fibroblast growth factor 21 (FGF21) is an endocrine hormone that exhibits anti-diabetic and anti-obesity activity. FGF21 expression is increased in patients with and mouse models of obesity or nonalcoholic fatty liver disease (NAFLD). However, the functional role and molecular mechanism of FGF21 induction in obesity or NAFLD are not clear. As endoplasmic reticulum (ER) stress is triggered in obesity and NAFLD, we investigated whether ER stress affects FGF21 expression or whether FGF21 induction acts as a mechanism of the unfolded protein response (UPR) adaptation to ER stress induced by chemical stressors or obesity.Methods Hepatocytes or mouse embryonic fibroblasts deficient in UPR signalling pathways and liver-specific eIF2α mutant mice were employed to investigate the in vitro and in vivo effects of ER stress on FGF21 expression, respectively. The in vivo importance of FGF21 induction by ER stress and obesity was determined using inducible Fgf21-transgenic mice and Fgf21-null mice with or without leptin deficiency.Results We found that ER stressors induced FGF21 expression, which was dependent on a PKR-like ER kinase-eukaryotic translation factor 2α-activating transcription factor 4 pathway both in vitro and in vivo. Fgf21-null mice exhibited increased expression of ER stress marker genes and augmented hepatic lipid accumulation after tunicamycin treatment. However, these changes were attenuated in inducible Fgf21-transgenic mice. We also observed that Fgf21-null mice with leptin deficiency displayed increased hepatic ER stress response and liver injury, accompanied by deteriorated metabolic variables.Conclusions/interpretation Our results suggest that FGF21 plays an important role in the adaptive response to ER stress- or obesity-induced hepatic metabolic stress.
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FGF21's triglyceride-lowering effects are mediated by altered adipose and liver metabolism: accelerated lipoprotein catabolism, suppression of postprandial lipolysis, decreased hepatic ER and oxidative stress, and increased beta-oxidation of lipids in the liver.
“Pharmacological administration of FGF21 or FGF21 analogues exerts lipid-lowering effects through accelerated lipoprotein catabolism108, suppression of postprandial lipolysis in adipose tissues88, decreased hepatic endoplasmic reticulum and oxidative stress109,110, and increased beta-oxidation of lipids in the liver62”
From Metabolic messengers: FGF21 (2021) · cites this paper as [110]
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- Authors
- Kim, S. H., Kim, K. H., Kim, H.-K., Kim, M.-J., Back, S. H., Konishi, M., Itoh, N., & Lee, M.-S.
- Affiliations
- Samsung Medical Center (KR)
- University of Ulsan (KR)
- Kobe Pharmaceutical University (JP)
- Kyoto University (JP)
- Corresponding author
- Kim, Kook Hwan
- Lee, Myung-Shik
- Venue
- Diabetologia
- Published
- 2014-12-24
- Volume
- 58
- Issue
- 4
- Pages
- 809-818
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- OpenAlex
- W2058165691
- Cited by
- 124
- References
- 37
- Citations by year
- 2026: 11 · 2025: 11 · 2024: 6 · 2023: 9 · 2022: 13 · 2021: 7 · 2020: 14 · 2019: 11 · 2018: 11 · 2017: 12 · 2016: 12 · 2015: 7
- FWCI
- 4.23
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Diabetologia (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Research Foundation (2014R1A6A1030318)
- Ministry of Science, ICT and Future Planning (2014R1A6A1030318, 2014M3A9D8034459)
- National Research Foundation of Korea (2014R1A6A1030318, 2014M3A9D8034459, 2013R1A6A3A04065825, K21004000003‐10A0500‐00310)
- Weill Cornell Medical College
- Japan Society for the Promotion of Science (26460084)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Keywords
- FGF21, endoplasmic reticulum stress, unfolded protein response, obesity, non-alcoholic fatty liver disease, eIF2α, ATF4, leptin deficiency, hepatic lipid accumulation, liver injury, tunicamycin
- MeSH terms
- Adaptation, Physiological, Animals, Disease Models, Animal, Endoplasmic Reticulum, Fibroblast Growth Factors, Humans, Mice, Obese, Obesity, Stress, Physiological, Time Factors, Transfection, Signal Transduction, Eukaryotic Initiation Factor-2, Mice, Knockout, eIF-2 Kinase, Hepatocytes, RNA Interference, Activating Transcription Factor 4, Unfolded Protein Response, Hep G2 Cells, Endoplasmic Reticulum Stress
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