Fibroblast Growth Factor-21 Regulates PPARγ Activity and the Antidiabetic Actions of Thiazolidinediones
Open accessAbstract
Fibroblast growth factor-21 (FGF21) is a circulating hepatokine that beneficially affects carbohydrate and lipid metabolism. Here, we report that FGF21 is also an inducible, fed-state autocrine factor in adipose tissue that functions in a feed-forward loop to regulate the activity of peroxisome proliferator-activated receptor γ (PPARγ), a master transcriptional regulator of adipogenesis. FGF21 knockout (KO) mice display defects in PPARγ signaling including decreased body fat and attenuation of PPARγ-dependent gene expression. Moreover, FGF21-KO mice are refractory to both the beneficial insulin-sensitizing effects and the detrimental weight gain and edema side effects of the PPARγ agonist rosiglitazone. This loss of function in FGF21-KO mice is coincident with a marked increase in the sumoylation of PPARγ, which reduces its transcriptional activity. Adding back FGF21 prevents sumoylation and restores PPARγ activity. Collectively, these results reveal FGF21 as a key mediator of the physiologic and pharmacologic actions of PPARγ.
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In white adipocytes, FGF21 expression is regulated by both PPARγ and PPARα.
“Similar mechanisms may upregulate FGF21 expression in white adipocytes during cold, but FGF21 expression is also regulated by both PPARγ (32, 49, 94) and PPARα (49) in white adipocytes.”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [32]
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- Authors
- Dutchak, P. A., Katafuchi, T., Bookout, A. L., Choi, J. H., Yu, R. T., Mangelsdorf, D. J., & Kliewer, S. A.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Harvard University (US)
- Salk Institute for Biological Studies (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Mangelsdorf, David J.
- Kliewer, Steven A.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2012-02
- Volume
- 148
- Issue
- 3
- Pages
- 556-567
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3273727
- OpenAlex
- W2032787352
- Cited by
- 537
- References
- 59
- Citations by year
- 2026: 8 · 2025: 23 · 2024: 19 · 2023: 19 · 2022: 31 · 2021: 37 · 2020: 30 · 2019: 43 · 2018: 40 · 2017: 42 · 2016: 49 · 2015: 49 · 2014: 51 · 2013: 58 · 2012: 36
- FWCI
- 24.96
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 563 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Scholarworks@UNIST (Ulsan National Institute of Science and Technology) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institute of General Medical Sciences (T32GM007062, GM007062, RL1GM084436)
- National Institute of Diabetes and Digestive and Kidney Diseases (U19 DK-62434, U19DK062434, R56DK089600, R01DK067158)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- FGF21, PPARγ, thiazolidinediones, rosiglitazone, SUMOylation, adipose tissue, insulin sensitivity, adipogenesis, autocrine signaling, FGF21 knockout mice, type 2 diabetes, weight gain
- MeSH terms
- Rosiglitazone, Animals, Drug Resistance, Fibroblast Growth Factors, Hypoglycemic Agents, Lipodystrophy, Liver, Transcription, Genetic, Adipocytes, Mice, Knockout, Autocrine Communication, Paracrine Communication, Thiazolidinediones, PPAR gamma, Lipid Metabolism, Mice, Adipose Tissue, White, Sumoylation
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