The DOI matches its Crossref record; 32 of the 32 references it cites were found in a registry or an index.
Thermogenic Activation Induces FGF21 Expression and Release in Brown Adipose Tissue
Open accessAbstract
FGF21 is a novel metabolic regulator involved in the control of glucose homeostasis, insulin sensitivity, and ketogenesis. The liver has been considered the main site of production and release of FGF21 into the blood. Here, we show that, after thermogenic activation, brown adipose tissue becomes a source of systemic FGF21. This is due to a powerful cAMP-mediated pathway of regulation of FGF21 gene transcription. Norepinephrine, acting via β-adrenergic, cAMP-mediated, mechanisms and subsequent activation of protein kinase A and p38 MAPK, induces FGF21 gene transcription and also FGF21 release in brown adipocytes. ATF2 binding to the FGF21 gene promoter mediates cAMP-dependent induction of FGF21 gene transcription. FGF21 release by brown fat in vivo was assessed directly by analyzing arteriovenous differences in FGF21 concentration across interscapular brown fat, in combination with blood flow to brown adipose tissue and assessment of FGF21 half-life. This analysis demonstrates that exposure of rats to cold induced a marked release of FGF21 by brown fat in vivo, in association with a reduction in systemic FGF21 half-life. The present findings lead to the recognition of a novel pathway of regulation the FGF21 gene and an endocrine role of brown fat, as a source of FGF21 that may be especially relevant in conditions of activation of thermogenic activity.
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In the citing paper
“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 [11]
In the citing paper
“However, while an increase in circulating levels of FGF21 has been reported in response to cold in mice (49), this has not been observed in other studies (36, 52).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [49]
In the citing paper
“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 [49]
In the citing paper
“In brown adipocytes, norepinephrine activates β-adrenergic receptors and cyclic adenosine monophosphate (cAMP)-dependent, protein kinase A (PKA)- and p38 mitogen-activated protein kinase (MAPK)-mediated mechanisms to regulate ATF2 binding to the Fgf21 promoter to induce FGF21 production (Figure 3a) (49).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [49]
In the citing paper
“Under cold exposure, FGF21 can be secreted by BAT and WAT, have a paracrine effect, and stimulate the expression of thermogenic genes 91.”
From Inter‐organ communication: a gatekeeper for metabolic health (2019) · cites this paper as [91]
Citations
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Cited by
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Brown and beige fat: Development, function and therapeutic potential
Harms, M., & Seale, P. (2013) · Nature Medicine · doi:10.1038/nm.3361 · Cited by 2,328
Chait, A., & den Hartigh, L. J. (2020) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2020.00022 · Cited by 1,529
FGF21 regulates PGC-1α and browning of white adipose tissues in adaptive thermogenesis
Fisher, F. M., Kleiner, S., Douris, N., Fox, E. C., Mepani, R. J., Verdeguer, F., Wu, J., Kharitonenkov, A., Flier, J. S., Maratos-Flier, E., et al. (2012) · Genes & Development · doi:10.1101/gad.177857.111 · Cited by 1,478
Adipose Tissue Remodeling: Its Role in Energy Metabolism and Metabolic Disorders
Choe, S. S., Huh, J. Y., Hwang, I. J., Kim, J. I., & Kim, J. B. (2016) · Frontiers in Endocrinology · doi:10.3389/fendo.2016.00030 · Cited by 1,206
Adapting to obesity with adipose tissue inflammation
Reilly, S. M., & Saltiel, A. R. (2017) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2017.90 · Cited by 1,204
Metadata
- Authors
- Hondares, E., Iglesias, R., Giralt, A., Gonzalez, F. J., Giralt, M., Mampel, T., & Villarroya, F.
- Affiliations
- Centro de Investigación Biomédica en Red (ES)
- National Institutes of Health (US)
- Corresponding author
- Hondares, Elayne
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2011-04
- Volume
- 286
- Issue
- 15
- Pages
- 12983-12990
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3075644
- OpenAlex
- W1986602268
- Cited by
- 623
- References
- 32
- Citations by year
- 2026: 14 · 2025: 32 · 2024: 42 · 2023: 41 · 2022: 34 · 2021: 52 · 2020: 47 · 2019: 65 · 2018: 47 · 2017: 48 · 2016: 40 · 2015: 57 · 2014: 37 · 2013: 28 · 2012: 27
- FWCI
- 13.23
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- FGF21, brown adipose tissue, thermogenesis, cAMP signaling, protein kinase A, p38 MAPK, ATF2, norepinephrine, beta-adrenergic signaling, cold exposure, brown adipocytes
- MeSH terms
- Cyclic AMP, Animals, Adipose Tissue, Brown, Cells, Cultured, Cold Temperature, Endocrine Glands, Enzyme Activation, Fibroblast Growth Factors, Gene Expression Regulation, Male, Mice, Mutant Strains, Transcription, Genetic, Rats, Wistar, Cyclic AMP-Dependent Protein Kinases, Thermogenesis, p38 Mitogen-Activated Protein Kinases, Mice, Rats
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