The FGF21-CCL11 Axis Mediates Beiging of White Adipose Tissues by Coupling Sympathetic Nervous System to Type 2 Immunity
Open accessAbstract
Type 2 cytokines are important signals triggering biogenesis of thermogenic beige adipocytes in white adipose tissue (WAT) during cold acclimation. However, how cold activates type 2 immunity in WAT remains obscure. Here we show that cold-induced type 2 immune responses and beiging in subcutaneous WAT (scWAT) are abrogated in mice with adipose-selective ablation of FGF21 or its co-receptor β-Klotho, whereas such impairments are reversed by replenishment with chemokine CCL11. Mechanistically, FGF21 acts on adipocytes in an autocrine manner to promote the expression and secretion of CCL11 via activation of ERK1/2, which drives recruitment of eosinophils into scWAT, leading to increases in accumulation of M2 macrophages, and proliferation and commitment of adipocyte precursors into beige adipocytes. These FGF21-elicited type 2 immune responses and beiging are blocked by CCL11 neutralization. Thus, the adipose-derived FGF21-CCL11 axis triggers cold-induced beiging and thermogenesis by coupling sympathetic nervous system to activation of type 2 immunity in scWAT.
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During acute cold, FGF21 signals directly to adipose tissue to regulate adipose thermogenesis by inducing the expression and secretion of CCL11.
“During acute cold, FGF21 signals directly to adipose tissue to regulate adipose thermogenesis by inducing the expression and secretion of the chemokine CCL11 (52).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [52]
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).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [52]
Both Fgf21 total knockout mice and adipose-specific Fgf21 knockout mice exhibit reduced body temperature in response to acute cold exposure.
“Consistent with a functional role for FGF21 during cold, both Fgf21 total knockout mice (36) and adipose-specific Fgf21 knockout mice (52) exhibit reduced body temperature in response to acute cold exposure.”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [52]
CCL11 recruits eosinophils to subcutaneous adipose tissues, which promotes the beiging of WAT depots.
“CCL11 then functions to recruit eosinophils to subcutaneous adipose tissues, which promotes the beiging of WAT depots (52).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [52]
In response to cold, Fgf21 mRNA expression is upregulated in both WAT and BAT.
“Fgf21 mRNA expression is upregulated in both WAT (36, 52) and BAT (15, 36, 49, 52) in response to cold.”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [52]
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- Authors
- Huang, Z., Zhong, L., Lee, J. T. H., Zhang, J., Wu, D., Geng, L., Wang, Y., Wong, C.-M., & Xu, A.
- Affiliations
- University of Hong Kong (HK)
- Chinese Academy of Sciences (CN)
- Corresponding author
- Wong, Chi-Ming
- Xu, Aimin
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2017-09
- Volume
- 26
- Issue
- 3
- Pages
- 493-508.e4
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W2748419786
- Cited by
- 147
- References
- 51
- Citations by year
- 2026: 10 · 2025: 11 · 2024: 18 · 2023: 13 · 2022: 14 · 2021: 24 · 2020: 20 · 2019: 16 · 2018: 20
- FWCI
- 11.33
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- The HKU Scholars Hub (University of Hong Kong) (submittedVersion)
- Funders
- National 973 Basic Research Program of China (2015CB553603)
- Research Grant Council of Hong Kong (17161016, C7055-14G)
- National Health and Medical Research Council of Australia (NHMRC)
- National Science Foundation of China (NSFC) (81561128016)
- HKU
- Topics
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- FGF21, eotaxin, white adipose tissue browning, beige adipocytes, Th2 immune response, cold acclimation, sympathetic nervous system, β-Klotho, eosinophils, M2 macrophages, ERK signaling, thermogenesis, adipocyte precursors, subcutaneous adipose tissue
- MeSH terms
- Adipose Tissue, Beige, Klotho Proteins, Adaptation, Physiological, Animals, Cold Temperature, Eosinophils, Fibroblast Growth Factors, Glucuronidase, Immunity, Macrophages, Male, Mice, Inbred C57BL, Recombinant Proteins, Stem Cells, Sympathetic Nervous System, Signal Transduction, Adipocytes, Mice, Knockout, Autocrine Communication, Thermogenesis, Extracellular Signal-Regulated MAP Kinases, Cell Proliferation, Adipose Tissue, White, Chemokine CCL11
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