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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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“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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BackgroundInfluentialFatty liver and FGF21 physiology
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“Fgf21 knockout mice displayed an impaired ability to adapt to chronic cold exposure with diminished browning of WAT (Fisher et al., 2012).”
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“The browning and thermogenesis of WAT reveal the important regulatory effect of FGF21 on the energy metabolism and body weight of the mice.”
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“FGF21 is a potent regulator of whole-body glucose and energy metabolism [46,48,68].”
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InfluentialRole of brown adipose tissue in metabolic syndrome, aging, and cancer cachexia
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“Increase in PGC1- , indicate a better function of the mitochondria, which can be reflected in an increased energy expenditure [35].”
BackgroundLaeger, T., Baumeier, C., Wilhelmi, I., Würfel, J., Kamitz, A., & Schürmann, A. (2017) · Diabetologia · doi:10.1007/s00125-017-4389-x · Cited by 59
“FGF21 increases EE in NZO mice Studies show that pharmacological FGF21 treatment acts both in the brain and directly on adipose tissue to increase EE, stimulate sympathetic outflow and upregulate thermogenic markers in BAT and WAT [14, 17, 41, 42].”
BackgroundInfluentialBrown and beige fat: From molecules to physiology and pathophysiology
Carobbio, S., Guénantin, A.-C., Samuelson, I., Bahri, M., & Vidal‐Puig, A. (2018) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2018.05.013 · Cited by 62
Struik, D., Dommerholt, M. B., & Jonker, J. W. (2019) · Current Opinion in Lipidology · doi:10.1097/mol.0000000000000599 · Cited by 61
Adiponectin restrains ILC2 activation by AMPK-mediated feedback inhibition of IL-33 signaling
Wang, L., Luo, Y., Luo, L., Wu, D., Ding, X., Zheng, H., Wu, H., Liu, B., Yang, X., Silva, F. D., et al. (2020) · The Journal of Experimental Medicine · doi:10.1084/jem.20191054 · Cited by 58
“Beige or brite adipocytes, which are enriched in subcutaneous fat such as inguinal fat, have high thermogenic capacity and have become a new therapeutic target for the treatment of obesity (Boström et al., 2012; Fisher et al., 2012; Petrovic et al., 2010).”
BackgroundHepatic CPT1A Facilitates Liver–Adipose Cross Talk via Induction of FGF21 in Mice
Sun, W., Nie, T., Li, K., Wu, W., Long, Q., Feng, T., Mao, L., Gao, Y. Z., Liu, Q., Gao, X., et al. (2021) · Diabetes · doi:10.2337/db21-0363 · Cited by 63
Scalzo, R. L., Peltonen, G. L., Giordano, G., Binns, S. E., Klochak, A. L., Paris, H. L. R., Schweder, M. M., Szallar, S. E., Wood, L. M., Larson, D. G., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0090696 · Cited by 60
“[4,5,10,11]; is also positively related to insulin sensitivity and weight loss [10].”
BackgroundInfluentialGlucagon's Metabolic Action in Health and Disease
Zeigerer, A., Sekar, R., Kleinert, M., Nason, S. R., Habegger, K. M., & Müller, T. D. (2021) · Comprehensive physiology · doi:10.1002/cphy.c200013 · Cited by 87
Adaptive and maladaptive roles for ChREBP in the liver and pancreatic islets
Katz, L. S., Baumel-Alterzon, S., Scott, D. K., & Herman, M. A. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.100623 · Cited by 60
“These improvements in systemic fuel metabolism are associated with browning of white adipose tissue, which may increase energy expenditure and protect against weight gain although other mechanisms are also likely involved (113, 114).”
BackgroundHepatic PTEN deficiency improves muscle insulin sensitivity and decreases adiposity in mice
Peyrou, M., Bourgoin, L., Poher, A.-L., Altirriba, J., Maeder, C., Caillon, A., Fournier, M., Montet, X., Rohner‐Jeanrenaud, F., & Foti, M. (2014) · Journal of Hepatology · doi:10.1016/j.jhep.2014.09.012 · Cited by 59
Chou, C., Lin, Y.-Y., Wang, H.-K., Zhu, X., Giovarelli, M., Briata, P., Gherzi, R., Garvey, W. T., & Chen, C. (2014) · Diabetes · doi:10.2337/db13-1901 · Cited by 58
Zhang, H., Zhang, W., Yun, D., Li, L., Zhao, W., Li, Y., Liu, X., & Liu, Z. (2020) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2020.108403 · Cited by 60
Chen, M. Z., Chang, J. C., Zavala-Solorio, J., Kates, L., Thai, M., Ogasawara, A., Bai, X., Flanagan, S., Nunez, V., Phamluong, K., et al. (2017) · Molecular Metabolism · doi:10.1016/j.molmet.2017.09.003 · Cited by 58
Uncovering the Role of p38 Family Members in Adipose Tissue Physiology
Leiva, M., Matesanz, N., Pulgarín-Alfaro, M., Nikolić, I., & Sabio, G. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.572089 · Cited by 62
Croon, M., Szczepanowska, K., Popović, M., Lienkamp, C., Senft, K., Brandscheid, C. P., Bock, T., Gnatzy-Feik, L., Ashurov, A., Acton, R., et al. (2022) · Science Advances · doi:10.1126/sciadv.abn7105 · Cited by 60
Matrix-Assisted Transplantation of Functional Beige Adipose Tissue
Tharp, K. M., Jha, A. K., Kraiczy, J., Yesian, A. R., Karateev, G., Sinisi, R., Goun, E. A., Healy, K. E., & Stahl, A. (2015) · Diabetes · doi:10.2337/db15-0728 · Cited by 58
“In our future studies, generation of UCP-1 positive adipocytes could be enhanced with matrices presenting heparin binding growth factors, specifically BMP7 and FGF21, which have been implicated in BAT differentiation(47).”
BackgroundChoi, S. H., Hong, E. S., & Lim, S. K. (2013) · Frontiers in Endocrinology · doi:10.3389/fendo.2013.00097 · Cited by 59
Mottillo, E. P., Desjardins, E. M., Fritzen, A. M., Zou, V. Z., Crane, J. D., Yabut, J. M., Kiens, B., Erion, D. M., Lanba, A., Granneman, J. G., et al. (2017) · Molecular Metabolism · doi:10.1016/j.molmet.2017.04.001 · Cited by 57
White adipose tissue browning and obesity
Cui, X., & Chen, S. (2017) · Journal of Biomedical Research · doi:10.7555/jbr.31.20160101 · Cited by 57
“In addition, fibroblast growth factor 21 (FGF21) acts in an autocrine and paracrine manner to enhance WAT browning([12]).”
BackgroundHepatic Crtc2 controls whole body energy metabolism via a miR-34a-Fgf21 axis
Han, H.-S., Choi, B. H., Kim, J. S., Kang, G. W., & Koo, S. (2017) · Nature Communications · doi:10.1038/s41467-017-01878-6 · Cited by 58
Gasparin, F. R. S., Carreño, F. O., Mewes, J. M., Gilglioni, E. H., Pagadigorria, C. L. S., Natali, M. R. M., Utsunomiya, K. S., Constantin, R. P., Ouchida, A. T., Curti, C., et al. (2018) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2018.04.004 · Cited by 62
Allard, C., Bonnet, F., Xu, B., Coons, L. A., Albarado, D. C., Hill, C. M., Fagherazzi, G., Korach, K. S., Levin, E. R., Lefante, J. J., et al. (2019) · Molecular Metabolism · doi:10.1016/j.molmet.2019.02.002 · Cited by 58
“In mouse models, manipulations inducing metabolic dysregulation can promote Fgf21 mRNA expression in inguinal white adipose tissue (iWAT) [23], brown adipose tissue (BAT) [24,25] or skeletal muscle [22,26], which can increase circulating FGF21 serum concentrations.”
BackgroundGrowth Factors as Immunotherapeutic Targets in Cardiovascular Disease
Mindur, J. E., & Świrski, F. K. (2019) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.119.311994 · Cited by 58
Minakhina, S., Bansal, S., Zhang, A., Brotherton, M., Janodia, R., Oliveira, V. D., Tadepalli, S., & Wondisford, F. E. (2020) · Thyroid · doi:10.1089/thy.2019.0763 · Cited by 58
Muise, E. S., Souza, S., Chi, A., Tan, Y., Zhao, X., Liu, F., Dallas-yang, Q., Wu, M., Sarr, T., Zhu, L., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0073011 · Cited by 57
“Others have known functions and their regulation by FGF21 either supports (increased expression of Ucp1 and energy expenditure [20]) or seems to contradict (decreased expression of Sfrp5 and a worsening of metabolic dysfunction [33]) a beneficial role of FGF21.”
BackgroundInfluentialWanders, D., Stone, K. P., Dille, K., Simon, J., Pierse, A., & Gettys, T. W. (2015) · BioFactors · doi:10.1002/biof.1240 · Cited by 57
Deis, J. A., Guo, H., Wu, Y., Liu, C., Bernlohr, D., & Chen, X. (2019) · Molecular Metabolism · doi:10.1016/j.molmet.2019.03.007 · Cited by 58
“For example, fibroblast growth factor 21 (FGF21) secreted from adipose tissue and cardiac natriuretic peptides both promote expression of UCP1 in WAT [23,24].”
BackgroundLee, Y.-H., Kim, S. H., Kim, S.-N., Kwon, H.-J., Kim, J.-D., Oh, J. Y., & Jung, Y.-S. (2016) · Oncotarget · doi:10.18632/oncotarget.10506 · Cited by 59
“We examined expression levels of FGF21, which has been reported to have a brown adipogenic endocrine function [34], in order to determine whether it plays a molecular role in inducing the browning of white adipose tissue.”
BackgroundLiu, X., Wang, Y., Hou, L., Xiong, Y., & Zhao, S. (2016) · Journal of Cellular Physiology · doi:10.1002/jcp.25735 · Cited by 56
“In addition, FGF21 has been shown to contribute to the thermogenic activation (Fisher et al., 2012) and potentiation of PGC1a expression induced by AMPK (Chau et al., 2010).”
BackgroundSomm, E., Henry, H., Bruce, S. J., Aeby, S., Rosikiewicz, M., Sykiotis, G. P., Asrih, M., Jornayvaz, F. R., Denechaud, P., Albrecht, U., et al. (2017) · JCI Insight · doi:10.1172/jci.insight.91809 · Cited by 58
“ulates glucose uptake and lipolysis in adipose tissue (5, 6) and activates thermogenesis (7, 8), thus making it of significant interest as a biologic drug to treat metabolic diseases.”
BackgroundThe weight of nutrients: kynurenine metabolites in obesity and exercise
Dadvar, S., Ferreira, D. M. S., Červenka, I., & Ruas, J. L. (2018) · Journal of Internal Medicine · doi:10.1111/joim.12830 · Cited by 59
Neuroendocrine Regulation of Energy Metabolism Involving Different Types of Adipose Tissues
Zhu, Q., Glazier, B. J., Hinkel, B. C., Cao, J., Liu, L., Liang, C., & Shi, H. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20112707 · Cited by 61
Ayari, A., Rosa‐Calatrava, M., Lancel, S., Barthelemy, J., Pizzorno, A., Mayeuf-Louchart, A., Baron, M., Hot, D., Deruyter, L., Soulard, D., et al. (2020) · Communications Biology · doi:10.1038/s42003-020-0965-6 · Cited by 62
Association between serum FGF21 level and sarcopenia in older adults
Jung, H.-W., Park, J. H., Kim, D. A., Jang, I.-Y., Park, S. J., Lee, J. Y., Lee, S., Kim, J. H., Yi, H.-S., Lee, E., et al. (2021) · Bone · doi:10.1016/j.bone.2021.115877 · Cited by 55
Pérez‐Martí, A., Garcia‐Guasch, M., Tresserra‐Rimbau, A., Carrilho‐Do‐Rosário, A., Estruch, R., Salas‐Salvadó, J., Martínez‐González, M. Á., Lamuela‐Raventós, R., Marrero, P. F., Haro, D., et al. (2017) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201600725 · Cited by 56
Mueller, E. (2013) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2013.05.031 · Cited by 58
“Recent studies have demonstrated that PGC1α1 plays a critical role, not only in brown fat tissue, but also in the regulation of white adipose depots browning, as shown by the effect observed after administration of FGF21 on PGC1α1 protein levels and stability in white fat tissue and by the decreased levels of browning…”
BackgroundFeraco, A., Armani, A., Mammi, C., Fabbri, A., Rosano, G. M. C., & Caprio, M. (2013) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2013.02.012 · Cited by 58
Jiao, J., Han, S.-F., Zhang, W., Xu, J., Tong, X., Yin, X.-B., Yuan, L., & Qin, L. (2016) · Food & Nutrition Research · doi:10.3402/fnr.v60.31304 · Cited by 56
“In addition, adipose-derived FGF21 acts to increase UCP1 expression by enhancing the PGC-1 protein level of adipose tissues (37).”
BackgroundT Cells in Adipose Tissue in Aging
Antony, A. K., Lian, Z., & Wu, H. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02945 · Cited by 57
Rial, S. A., Jutras-Carignan, A., Bergeron, K., & Mounier, C. (2019) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2019.158582 · Cited by 57
Takahashi, H., Kotani, K., Tanaka, K., Egucih, Y., & Anzai, K. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00588 · Cited by 55
“Although the direct effect of FGF21 on liver is still controversial because of the lack of an FGF receptor 1 in hepatocytes, NAFLD might be alleviated through the effect of training on adipose tissues: namely, the development of brown fat-like cells in white adipose tissue (the “beiging” phenomenon) and increased leve…”
BackgroundInagaki, T. (2015) · Frontiers in Endocrinology · doi:10.3389/fendo.2015.00147 · Cited by 55
Fibroblast growth factor 21 (FGF21) and bone: is there a relationship in humans?
Lee, P., Linderman, J. D., Smith, S. M., Brychta, R. J., Perron, R., Idelson, C. R., Werner, C., Chen, K. Y., & Celi, F. S. (2013) · Osteoporosis International · doi:10.1007/s00198-013-2464-9 · Cited by 55
“Because BAT secretes FGF21 [12] and women havemore BAT thanmen [13], it is possible that BAT-secreted FGF21 mechanistically links higher FGF21 levels and greater BAT mass with higher BMD.”
Background
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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