Irisin and FGF21 are cold-induced endocrine activators of brown fat function in humans
Open accessAbstract
Rediscovery of cold-activated brown adipose tissue (BAT) in humans has boosted research interest in identifying BAT activators for metabolic benefits. Of particular interest are cytokines capable of fat browning. Irisin, derived from FNDC5, is an exercise-induced myokine that drives brown-fat-like thermogenesis in murine white fat. Here we explored whether cold exposure is an afferent signal for irisin secretion in humans and compared it with FGF21, a brown adipokine in rodents. Cold exposure increased circulating irisin and FGF21. We found an induction of irisin secretion proportional to shivering intensity, in magnitude similar to exercise-stimulated secretion. FNDC5 and/or FGF21 treatment upregulated human adipocyte brown fat gene/protein expression and thermogenesis in a depot-specific manner. These results suggest exercise-induced irisin secretion could have evolved from shivering-related muscle contraction, serving to augment brown fat thermogenesis in concert with FGF21. Irisin-mediated muscle-adipose crosstalk may represent a thermogenic, cold-activated endocrine axis that is exploitable in obesity therapeutics development.
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Irisin and FGF21, both induced by submaximal exercise, have a function in promoting the browning of adipose tissue to meet the increased demand for fat oxidation.
“More recently, Lee et al. (2014) shown that irisin and FGF21, both induced by submaximal exercise, have a function in promoting the browning of adipose tissue to meet the increased demand for fat oxidation.”
From Physical Exercise-Induced Myokines and Muscle-Adipose Tissue Crosstalk: A Review of Current Knowledge and the Implications for Health and Metabolic Diseases (2018) · cites this paper as Lee et al., 2014
The Results and Discussion report that submaximal exercise raised serum irisin and that FNDC5/irisin and FGF21 promoted BAT-like changes and thermogenesis in cultured human adipocytes. But the section on shivering and non-shivering thermogenesis says FGF21 levels trended lower during the exercise tests, not that submaximal exercise induced FGF21. The paper frames the browning response as increasing heat-generating capacity during cold exposure; it does not establish that exercise-induced browning meets an increased demand for fat oxidation. (LLM, conf=0.90)
Experimental — accuracy not yet measuredFGF21 treatment increases both thermogenic gene expression and cellular respiration in human primary neck adipocytes.
“In addition, treating human primary neck adipocytes with FGF21 increases both thermogenic gene expression and cellular respiration (76).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [76]
Cold‐induced muscle shivering can increase circulating irisin levels and promote brown fat thermogenesis.
“Interestingly, cold‐induced muscle shivering can increase circulating irisin levels and promote brown fat thermogenesis 118 (Fig 3).”
From Inter‐organ communication: a gatekeeper for metabolic health (2019) · cites this paper as [118]
Under cold exposure, when shivering thermogenesis is induced, FGF21 can synergize with irisin to promote BAT non‐shivering thermogenesis.
“Moreover, under cold exposure, when shivering thermogenesis is induced, FGF21 can synergize with irisin to promote BAT non‐shivering thermogenesis 118.”
From Inter‐organ communication: a gatekeeper for metabolic health (2019) · cites this paper as [118]
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“Irisin Ob: ↑ [39]+; T2DM: ↓ [39]+ AE: ↑ (aerobic or resistance) [40]+ CE: ↓? (aerobic or resistance) [41]+ ↑ (via PGC-1α): cold-induced shivering [42], ↑AMP:ATP ratio (via AMPK-PGC-1α pathway), FGF21* [43], and METRNL (via ↑PGC-1α4)* [44] ↓: proinflammatory cytokines [45] (possibly via NF-kB-mediated inhibition of PGC…”
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Does PGC1α/FNDC5/BDNF Elicit the Beneficial Effects of Exercise on Neurodegenerative Disorders?
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“Notably, IL-15, fibroblast growth factor (FGF)21, or irisin have been reported to induce cardiometabolic benefits through promoting the browning of white adipose tissue (WAT), and enhancing glucose homeostasis (Busquets et al., 2006; Nielsen et al., 2008; Elbelt et al., 2013; Kim H. J. et al., 2013; Woo et al., 2013;…”
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“FGF-21 activates brown adipose tissue thermogenesis in humans (12).”
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- Authors
- Lee, P., Linderman, J. D., Smith, S., Brychta, R. J., Wang, J., Idelson, C., Perron, R. M., Werner, C. D., Phan, G. Q., Kammula, U. S., Kebebew, E., Pacak, K., Chen, K. Y., & Celi, F. S.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Celi, Francesco S.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2014-02
- Volume
- 19
- Issue
- 2
- Pages
- 302-309
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC7647184
- OpenAlex
- W2163644328
- Cited by
- 802
- References
- 32
- Citations by year
- 2026: 31 · 2025: 39 · 2024: 50 · 2023: 50 · 2022: 78 · 2021: 61 · 2020: 69 · 2019: 57 · 2018: 57 · 2017: 82 · 2016: 80 · 2015: 103 · 2014: 43 · 2013: 1
- FWCI
- 67.64
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5r01dk071014-09)
- National Cancer Institute (ZIABC011275)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK071013, Z01DK071013, R01‐DK‐071014, Z01-DK071044, Z01DK071014, Z01-DK047057-02, Z01DK047057)
- 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
- irisin, FGF21, brown adipose tissue, cold exposure, thermogenesis, FNDC5, myokines, shivering, adipocyte browning, hormone signaling, obesity treatment
- MeSH terms
- Adult, Adipose Tissue, Brown, Female, Fibroblast Growth Factors, Fibronectins, Humans, Male, Shivering, Exercise, Adipocytes, Adipokines, Young Adult
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