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FGF21 regulates PGC-1α and browning of white adipose tissues in adaptive thermogenesis
Open accessAbstract
Certain white adipose tissue (WAT) depots are readily able to convert to a "brown-like" state with prolonged cold exposure or exposure to β-adrenergic compounds. This process is characterized by the appearance of pockets of uncoupling protein 1 (UCP1)-positive, multilocular adipocytes and serves to increase the thermogenic capacity of the organism. We show here that fibroblast growth factor 21 (FGF21) plays a physiologic role in this thermogenic recruitment of WATs. In fact, mice deficient in FGF21 display an impaired ability to adapt to chronic cold exposure, with diminished browning of WAT. Adipose-derived FGF21 acts in an autocrine/paracrine manner to increase expression of UCP1 and other thermogenic genes in fat tissues. FGF21 regulates this process, at least in part, by enhancing adipose tissue PGC-1α protein levels independently of mRNA expression. We conclude that FGF21 acts to activate and expand the thermogenic machinery in vivo to provide a robust defense against hypothermia.
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In the citing paper
“and possibly mediates an hepatokine–myokine crosstalk via activation of PGC-1α [43]”
From The Role of Exercise in the Interplay between Myokines, Hepatokines, Osteokines, Adipokines, and Modulation of Inflammation for Energy Substrate Redistribution and Fat Mass Loss: A Review (2020) · cites this paper as [43]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“have also been described to induce WAT browning directly (6).”
From The Role of Exercise in the Interplay between Myokines, Hepatokines, Osteokines, Adipokines, and Modulation of Inflammation for Energy Substrate Redistribution and Fat Mass Loss: A Review (2020) · cites this paper as [43]
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In the citing paper
“In WAT, it induces lipolysis [166] and browning [43], likely via upregulation of PGC-1α [192].”
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In the citing paper
“the exercise-induced hepatokines FGF21 [43] and follistatin [185], both upregulated by glucagon (5)”
From The Role of Exercise in the Interplay between Myokines, Hepatokines, Osteokines, Adipokines, and Modulation of Inflammation for Energy Substrate Redistribution and Fat Mass Loss: A Review (2020) · cites this paper as [43]
Experimental — accuracy not yet measuredIn the citing paper
“The direct effect of Fgf21 on adipocyte browning has also been demonstrated by others [284].”
From Mitochondrial Uncoupling: A Key Controller of Biological Processes in Physiology and Diseases (2019) · cites this paper as [284]
In the citing paper
“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 [36]
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 [36]
In the citing paper
“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 [36]
In the citing paper
“Consistent with its role in regulating thermogenesis, FGF21 treatment is sufficient to increase thermogenic gene expression in mouse primary white adipocytes (36).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [36]
In the citing paper
“Some teams have reported that FGF21 knockout mice have impaired adaptation to chronic cold exposure and decreased browning of WAT 92.”
From Inter‐organ communication: a gatekeeper for metabolic health (2019) · cites this paper as [92]
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“The mechanism of action for the metabolic effects of FGF-21 is associated with its ability to activate peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1-α), which is a master regulator of mitochondrial biogenesis and oxidative metabolism.(32) In addition, there is a positive role for FGF-21 in…”
CREG1 stimulates brown adipocyte formation and ameliorates diet‐induced obesity in mice
Hashimoto, M., Kusudo, T., Takeuchi, T., Kataoka, N., Mukai, T., & Yamashita, H. (2019) · The FASEB Journal · doi:10.1096/fj.201802147rr · Cited by 21
The implication of hepatokines in metabolic syndrome
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Relationship between FGF21 and drug or nondrug therapy of type 2 diabetes mellitus
Guo, C. Y., Zhao, L., Li, Y., Deng, X., & Yuan, G. (2020) · Journal of Cellular Physiology · doi:10.1002/jcp.29879 · Cited by 21
“The “browning” of WAT is characterized by the decrease in adipocyte size, the formation of multiple lipid drops, and increased thermogenesis (Fisher et al., 2012; Lo & Sun, 2013).”
BackgroundFischer, A. W., Behrens, J. R., Sass, F., Schlein, C., Heine, M., Pertzborn, P., Scheja, L., & Heeren, J. (2020) · Journal of Lipid Research · doi:10.1194/jlr.ra119000455 · Cited by 21
“FGF21 has been shown to stimulate WAT browning by altering sympathetic tone (86-88) and promote lipid disposal into thermogenic adipose tissues (32).”
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“been shown to be induced by FGF-21 [44, 45].”
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Wu, G., Liu, Y., Feng, W., An, X., Lin, W., & Tang, C. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.01279 · Cited by 20
“However, adiposederived FGF21 acts locally to modulate PPARg activity in autocrine or paracrine manner involving in the browning of white adipose tissue (Dutchak et al., 2012; Fisher et al., 2012) and is not associated with lipolysis (Arner et al., 2008; Li et al., 2009).”
BackgroundBone morphogenic protein 9 is a novel thermogenic hepatokine secreted in response to cold exposure
Um, J., Park, S., Hur, J. H., Lee, H., Jeong, K., Cho, Y., Lee, S.-H., Yoon, S.-M., Choe, S., & Choi, C. S. (2022) · Metabolism · doi:10.1016/j.metabol.2022.155139 · Cited by 22
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“The ADSCs of subcutaneous WATs and scapular BATs were isolated from C57BL/6J mice by collagenase digestion as described previously (6, 54) and cultured in α-minimal essential medium with 10% FBS and 1× GlutaMAX, 37 C, 5% CO2.”
MethodThe immunomodulatory effects of social isolation in mice are linked to temperature control
Hamilton, A., Rizzo, R., Brod, S., Ono, M., Perretti, M., Cooper, D., & D’Acquisto, F. (2022) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2022.02.022 · Cited by 22
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“WAT browning produces beige adipocytes, which exhibit UCP1-dependent thermogenesis, and fibroblast growth factor 21 (FGF21) was shown to play an important role in this thermogenesis (30).”
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“Another study suggested that fibroblast growth factor 21 (FGF21) functioned as an upstream activator to increase PGC1 α levels in WAT, thereby stimulating the expression of UCP1 and other thermo-genic genes (Fisher et al., 2012).”
BackgroundChu, Y., Gui, S., Zheng, Y., Zhao, J., Zhao, Y., Li, Y., & Chen, X. (2024) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2024.176438 · Cited by 22
White-to-Beige and Back: Adipocyte Conversion and Transcriptional Reprogramming
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Adipose tissue plasticity and new therapeutic targets
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The role of innate immunity in the regulation of brown and beige adipogenesis
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“It potently induces beige adipogenesis by stabilizing the peroxisome proliferator-activated receptorgamma (PPARgamma) coactivator-1alpha (PGC1a) [51], which is a central regulator in the expression of UCP-1 and other thermogenic genes [4,52,53].”
BackgroundAcute endurance exercise lowers serum fibroblast growth factor 21 levels in Japanese men
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“The effects of FGF21 on energy expenditure are mainly regulated via activation of UCP1 in BAT and WAT in both mice and humans [120, 122], although recent research in rodents suggests that some”
BackgroundCurrent understanding and controversies on the clinical implications of fibroblast growth factor 21
Badakhshi, Y., & Jin, T. (2020) · Critical Reviews in Clinical Laboratory Sciences · doi:10.1080/10408363.2020.1864278 · Cited by 20
“A number of investigations have shown the stimulatory effect of FGF21 on the expression of uncoupling protein 1 (UCP1) in adipocytes as well as the “browning” effect of FGF21 on WAT [21,88,89].”
BackgroundDetection of thermogenesis in rodents in response to anti-obesity drugs and genetic modification
Arch, J. R. S., & Trayhurn, P. (2013) · Frontiers in Physiology · doi:10.3389/fphys.2013.00064 · Cited by 20
“…of activation of brown adipose tissue, the induction of genes involved in oxidative metabolism in liver and adipose tissue, and the conversion of white adipocytes to cells that have some of the characteristics of brown adipocytes (Xu et al., 2009; Hondares et al., 2010; Fisher et al., 2012).”
BackgroundBeneficial Effects of Low-Grade Mitochondrial Stress on Metabolic Diseases and Aging
Min, S. H., Kang, G. M., Park, J.-W., & Kim, M. (2024) · Yonsei Medical Journal · doi:10.3349/ymj.2023.0131 · Cited by 20
“…white adipose tissues and skeletal muscle, and its expression levels are upregulated under metabolic stress conditions induced by star-vation, 69 amino acid depletion, 70 ketogenic diet, 71 overnutrition or obesity, 72 cold exposure, 73 and exercise, 74 all of which accompany mitochondrial stress.”
BackgroundEffects of Hyperthyroidism on Adipose Tissue Activity and Distribution in Adults
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“Further, Nrg4 and FGF-21 have thermogenic properties by enhancing sympathetic innervation of BAT and WAT and induction of PGC1 a , respectively (8,9).”
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“On the other hand, both rodent and human studies showed that prolonged low temperatures induced the expression of FGF21 in adipose tissue, thereby enhancing lipolysis and thermogenesis responses through WAT browning [27,29].”
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“In vitro studies have also clarified the underlying molecular mechanisms mediating the thermogenic response to CL316243, highlighting that this compound caused an increased mRNA expression of PGC1α [67], a gene involved in cold-induced thermogenesis and browning [68].”
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Metadata
- Authors
- 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., & Spiegelman, B. M.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Harvard University (US)
- Eli Lilly (United States) (US)
- ORCID
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2012-02-01
- Volume
- 26
- Issue
- 3
- Pages
- 271-281
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC3278894
- OpenAlex
- W2145142659
- Cited by
- 1,478
- References
- 38
- Citations by year
- 2026: 44 · 2025: 58 · 2024: 90 · 2023: 82 · 2022: 100 · 2021: 122 · 2020: 112 · 2019: 121 · 2018: 128 · 2017: 126 · 2016: 131 · 2015: 127 · 2014: 101 · 2013: 94 · 2012: 40
- Type
- posted content
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (DK028082, DK31405)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK028082, R01DK031405, DK-31405, R01DK028082, R37DK028082, R37DK031405)
- Topics
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- 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
- Keywords
- FGF21, PGC-1α, white adipose tissue browning, adaptive thermogenesis, UCP1, cold exposure, thermogenic gene expression, autocrine and paracrine signaling
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Adaptation, Physiological, Animals, Adipose Tissue, Brown, Cell Differentiation, Cells, Cultured, Cold Temperature, Fibroblast Growth Factors, Gene Expression Regulation, Male, Mice, Inbred C57BL, RNA Processing, Post-Transcriptional, Transcription Factors, Trans-Activators, Thermogenesis, Mice, Adipose Tissue, White
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