Cited by 623Fibroblast Growth Factor ResearchAdipose Tissue and MetabolismAdipokines, Inflammation, and Metabolic Diseases

Thermogenic Activation Induces FGF21 Expression and Release in Brown Adipose Tissue

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Hondares, Elayne, Iglesias, Roser, Giralt, Albert, Gonzalez, Frank J., Giralt, Marta, Mampel, Teresa, Villarroya, Francesc·2011·Journal of Biological Chemistry

Abstract

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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Crossref · 10.1074/jbc.m110.215889

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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”
  • In mice, circulating FGF21 levels increase in response to cold in some studies but not in others.

    “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).”
  • 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.”
  • In brown adipocytes, norepinephrine induces FGF21 production via β-adrenergic receptors and cAMP/PKA/p38 MAPK mechanisms regulating ATF2 binding to the Fgf21 promoter.

    “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).”
  • Under cold exposure, FGF21 can be secreted by BAT and WAT, have a paracrine effect, and stimulate the expression of thermogenic genes.

    “Under cold exposure, FGF21 can be secreted by BAT and WAT, have a paracrine effect, and stimulate the expression of thermogenic genes 91.”

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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)
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
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 › Adipose Tissue and Metabolism
  • Health Sciences › Medicine › Epidemiology › 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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