Adipose Fibroblast Growth Factor 21 Is Up-Regulated by Peroxisome Proliferator-Activated Receptor γ and Altered Metabolic States
Abstract
Adipose tissue is a metabolically responsive endocrine organ that secretes a myriad of adipokines. Antidiabetic drugs such as peroxisome proliferator-activated receptor (PPAR) gamma agonists target adipose tissue gene expression and correct hyperglycemia via whole-body insulin sensitization. The mechanism by which altered gene expression in adipose tissue affects liver and muscle insulin sensitivity (and thus glucose homeostasis) is not fully understood. One possible mechanism involves the alteration in adipokine secretion, in particular the up-regulation of secreted factors that increase whole-body insulin sensitivity. Here, we report the use of transcriptional profiling to identify genes encoding for secreted proteins the expression of which is regulated by PPARgamma agonists. Of the 379 genes robustly regulated by two structurally distinct PPARgamma agonists in the epididymal white adipose tissue (EWAT) of db/db mice, 33 encoded for known secreted proteins, one of which was FGF21. Although FGF21 was recently reported to be up-regulated in cultured adipocytes by PPARgamma agonists and in liver by PPARalpha agonists and induction of ketotic states, we demonstrate that the protein is transcriptionally up-regulated in adipose tissue in vivo by PPARgamma agonist treatment and under a variety of physiological conditions, including fasting and high fat diet feeding. In addition, we found that circulating levels of FGF21 protein were increased upon treatment with PPARgamma agonists and under ketogenic states. These results suggest a role for FGF21 in mediating the antidiabetic activities of PPARgamma agonists.
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FGF21 is expressed and released into the general circulation by several tissues such as the liver, white adipose tissue, brown adipose tissue, and the heart.
“The metabolic regulator FGF21 is expressed and released into the general circulation by several tissues such as the liver, WAT, BAT, and the heart.7, 8, 9, 10, 11”
From Fibroblast growth factor 21 controls mitophagy and muscle mass (2019) · cites this paper as [10]
Starvation is one of the stress conditions known to induce FGF21 expression in the liver, white adipose tissue, and skeletal muscle.
“Starvation is one of the stress conditions known to induce FGF21 expression in the liver,8, 32 WAT,10 and skeletal muscle (Figure 2A).6”
From Fibroblast growth factor 21 controls mitophagy and muscle mass (2019) · cites this paper as [10]
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 [94]
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James, N. M., & Stanford, K. I. (2025) · Endocrine Reviews · doi:10.1210/endrev/bnaf017 · Cited by 20 · see citing works
- Authors
- Muise, E. S., Azzolina, B., Kuo, D. W., El-Sherbeini, M., Tan, Y., Yuan, X., Mu, J., Thompson, J. R., Berger, J. P., & Wong, K. K.
- Affiliations
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- Venue
- Molecular Pharmacology
- Publisher
- Elsevier BV
- Published
- 2008-08
- Volume
- 74
- Issue
- 2
- Pages
- 403-412
- ISSN
- 0026-895X (ISSN-L)
- OpenAlex
- W2134810803
- Cited by
- 294
- References
- 42
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 21 · 2023: 11 · 2022: 12 · 2021: 11 · 2020: 11 · 2019: 19 · 2018: 15 · 2017: 27 · 2016: 26 · 2015: 24 · 2014: 25 · 2013: 15 · 2012: 26
- FWCI
- 5.48
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- 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 › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- FGF21, PPARγ agonists, adipose tissue, epididymal adipose tissue, adipokines, insulin sensitivity, glucose homeostasis, fasting, high-fat diet, db/db mice, antidiabetic drugs, secreted proteins, gene expression profiling
- MeSH terms
- Adipose Tissue, Amino Acid Sequence, Animals, Fibroblast Growth Factors, Male, Mice, Inbred C57BL, Mice, Mutant Strains, Molecular Sequence Data, Rabbits, Up-Regulation, 3T3-L1 Cells, PPAR gamma, Mice
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