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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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1 retracted
Romanatto, T., Roman, E. A., Arruda, A. P., Denis, R., Solon, C., Milanski, M., Moraes, J. C., Bonfleur, M. L., Degasperi, G. R., Picardi, P. K., et al. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.030874 · Cited by 156
RetractedWu, Z., Puigserver, P., Andersson, U., Zhang, C., Adelmant, G., Mootha, V., Troy, A., Cinti, S., Lowell, B., Scarpulla, R. C., et al. (1999) · Cell · doi:10.1016/s0092-8674(00)80611-x · Cited by 4,139
PRDM16 controls a brown fat/skeletal muscle switch
Seale, P., Bjork, B., Yang, W., Kajimura, S., Chin, S., Kuang, S., Scimè, A., Devarakonda, S., Conroe, H. M., Erdjument-Bromage, H., et al. (2008) · Nature · doi:10.1038/nature07182 · Cited by 2,347
FGF-21 as a novel metabolic regulator
Kharitonenkov, A., Shiyanova, T. L., Koester, A., Ford, A. M., Micanovic, R., Galbreath, E. J., Sandusky, G. E., Hammond, L. J., Moyers, J. S., Owens, R. A., et al. (2005) · Journal of Clinical Investigation · doi:10.1172/jci23606 · Cited by 2,125
Inagaki, T., Dutchak, P., Zhao, G., Ding, X., Gautron, L., Parameswara, V., Li, Y., Goetz, R., Mohammadi, M., Esser, V., et al. (2007) · Cell Metabolism · doi:10.1016/j.cmet.2007.05.003 · Cited by 1,504
Badman, M. K., Pissios, P., Kennedy, A. R., Koukos, G., Flier, J. S., & Maratos-Flier, E. (2007) · Cell Metabolism · doi:10.1016/j.cmet.2007.05.002 · Cited by 1,495
Feldmann, H. M., Golozoubova, V., Cannon, B., & Nedergaard, J. (2009) · Cell Metabolism · doi:10.1016/j.cmet.2008.12.014 · Cited by 1,318
Prdm16 determines the thermogenic program of subcutaneous white adipose tissue in mice
Seale, P., Conroe, H. M., Estall, J. L., Kajimura, S., Frontini, A., Ishibashi, J., Cohen, P., Cinti, S., & Spiegelman, B. M. (2010) · Journal of Clinical Investigation · doi:10.1172/jci44271 · Cited by 1,273
Petrovic, N., Walden, T. B., Shabalina, I. G., Timmons, J. A., Cannon, B., & Nedergaard, J. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.053942 · Cited by 1,263
Xu, J., Lloyd, D. J., Hale, C., Stanislaus, S., Chen, M., Sivits, G., Vonderfecht, S., Hecht, R., Li, Y.-S., Lindberg, R. A., et al. (2009) · Diabetes · doi:10.2337/db08-0392 · Cited by 1,151
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Turning WAT into BAT: a review on regulators controlling the browning of white adipocytes
Lo, K. A., & Sun, L. (2013) · Bioscience Reports · doi:10.1042/bsr20130046 · Cited by 225
Brown adipose tissue activity as a target for the treatment of obesity/insulin resistance
Poher, A.-L., Altirriba, J., Veyrat‐Durebex, C., & Rohner‐Jeanrenaud, F. (2015) · Frontiers in Physiology · doi:10.3389/fphys.2015.00004 · Cited by 219
“Under this condition, FGF21 expression was indeed decreased in the liver, but enhanced in BAT, as well as in WAT, where it acted to markedly increase UCP1 expression and the “browning” of subcutaneous tissue (Fisher et al., 2012).”
BackgroundInfluentialMetabolic adaptation in obesity and type ii diabetes: myokines, adipokines and hepatokines
Oh, K.-J., Lee, D., Kim, W., Han, B., Lee, S., & Bae, K.-H. (2016) · International Journal of Molecular Sciences · doi:10.3390/ijms18010008 · Cited by 210
Cohen, P., & Spiegelman, B. M. (2016) · Molecular Biology of the Cell · doi:10.1091/mbc.e15-10-0749 · Cited by 217
Beyond the Sympathetic Tone: The New Brown Fat Activators
Villarroya, F., & Vidal-Puig, A. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.02.020 · Cited by 209
Laeger, T., Albarado, D. C., Burke, S. J., Trosclair, L., Hedgepeth, J. W., Berthoud, H.-R., Gettys, T. W., Collier, J. J., Münzberg, H., & Morrison, C. D. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.06.044 · Cited by 206
“FGF21 also promotes thermogenic activity in BAT and WAT (Adams et al., 2012; Douris et al., 2015; Fisher et al., 2012; Lee et al., 2014), and it might therefore be expected that the chronic induction of FGF21 induces thermogenic activation of these tissues (De Sousa-Coelho et al., 2013).”
BackgroundBrown Adipose Tissue in Adult Humans: A Metabolic Renaissance
Lee, P. C., Swarbrick, M. M., & Ho, K. K. Y. (2013) · Endocrine Reviews · doi:10.1210/er.2012-1081 · Cited by 224
Functional thermogenic beige adipogenesis is inducible in human neck fat
Lee, P., Werner, C., Kebebew, E., & Celi, F. S. (2013) · International Journal of Obesity · doi:10.1038/ijo.2013.82 · Cited by 213
The brown fat secretome: metabolic functions beyond thermogenesis
Wang, G.-X., Zhao, X.-Y., & Lin, J. D. (2015) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2015.03.002 · Cited by 212
Brown and Beige Adipose Tissue and Aging
Zoico, E., Rubele, S., Caro, A. D., Nori, N., Mazzali, G., Fantin, F., Rossi, A. P., & Zamboni, M. M. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00368 · Cited by 219
Exosomes as Mediators of the Systemic Adaptations to Endurance Exercise
Safdar, A., & Tarnopolsky, M. A. (2018) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a029827 · Cited by 203
“…cross talk and mediate the endocrine effects on peripheral tissues to mitigate various aspects of metabolic syndrome, including fatty liver, dysglycemia, insulin resistance, increased adiposity, and exercise intolerance (Boström et al. 2012; Fisher et al. 2012; Lee et al. 2014; Rao et al. 2014).”
BackgroundLees, E. K., Król, E., Grant, L., Shearer, K., Wyse, C. A., Moncur, E. M., Bykowska, A. S., Mody, N., Gettys, T. W., & Delibegović, M. (2014) · Aging Cell · doi:10.1111/acel.12238 · Cited by 203
“Previous results have also found MR to increase circulating (Ables et al., 2012) and hepatic gene expression of FGF21 (Ables et al., 2012; Perrone et al., 2012) and one of its target genes, PGC1a (Perrone et al., 2010).”
BackgroundInfluentialPharmacologic Effects of FGF21 Are Independent of the “Browning” of White Adipose Tissue
Véniant, M. M., Sivits, G., Helmering, J., Komorowski, R., Lee, J., Fan, W., Moyer, C., & Lloyd, D. J. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.04.019 · Cited by 204
“Cold exposure markedly induces classic BAT and brite adipocytes (Fisher et al., 2012) and”
BackgroundResultInfluentialFGF21 as a Hepatokine, Adipokine, and Myokine in Metabolism and Diseases
Itoh, N. (2014) · Frontiers in Endocrinology · doi:10.3389/fendo.2014.00107 · Cited by 198
“Adipokine WAT Thermogenesis Autocrine/paracrine (10)”
BackgroundMechanisms of Increased In Vivo Insulin Sensitivity by Dietary Methionine Restriction in Mice
Stone, K. P., Wanders, D., Orgeron, M., Cortez, C. C., & Gettys, T. W. (2014) · Diabetes · doi:10.2337/db14-0464 · Cited by 201
“For example, FGF-21 directly affects adiponectin secretion from adipocytes (15), increases lipogenic gene expression in WAT (33), promotes browning of WAT (41), and increases thermogenic gene expression in BAT and WAT (41).”
BackgroundBrowning of white adipose tissue: lessons from experimental models
Bargut, T. C. L., Souza‐Mello, V., Águila, M. B., & Mandarim‐de‐Lacerda, C. A. (2017) · Hormone Molecular Biology and Clinical Investigation · doi:10.1515/hmbci-2016-0051 · Cited by 212
“It is secreted predominantly by the liver, but is also secreted by BAT and sWAT after a suitable stimulation (cold exposure or adrenergic stimulation) [51, 52].”
BackgroundThe origin and definition of brite versus white and classical brown adipocytes
Rosenwald, M., & Wolfrum, C. (2013) · Adipocyte · doi:10.4161/adip.26232 · Cited by 220
Vernia, S., Cavanagh, J., García-Haro, L., Sabio, G., Barrett, T., Jung, D. Y., Kim, J. K., Xu, J. L., Shulha, H. P., Garber, M. G., et al. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.06.010 · Cited by 200
Geng, L., Liao, B., Jin, L., Huang, Z. P., Triggle, C. R., Ding, H., Zhang, J., Huang, Y., Lin, Z., & Xu, A. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.02.014 · Cited by 208
Brown Adipose Tissue—A Translational Perspective
Carpentier, A. C., Blondin, D. P., Haman, F., & Richard, D. (2022) · Endocrine Reviews · doi:10.1210/endrev/bnac015 · Cited by 218
Inventing new medicines: The FGF21 story
Kharitonenkov, A., & Adams, A. C. (2014) · Molecular Metabolism · doi:10.1016/j.molmet.2013.12.003 · Cited by 198
Gestational Hypoxia and Developmental Plasticity
Ducsay, C. A., Goyal, R., Pearce, W. J., Wilson, S. M., Hu, X., & Zhang, L. (2018) · Physiological Reviews · doi:10.1152/physrev.00043.2017 · Cited by 208
Toward an understanding of how immune cells control brown and beige adipobiology
Villarroya, F., Cereijo, R., Villarroya, J., Gavaldà-Navarro, A., & Giralt, M. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.04.006 · Cited by 198
The Sense of Smell Impacts Metabolic Health and Obesity
Riera, C. E., Tsaousidou, E., Halloran, J., Follett, P., Hahn, O., Pereira, M. M. A., Ruud, L. E., Alber, J., Tharp, K., Anderson, C. M., et al. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.06.015 · Cited by 191
“In addition, cold stimulation or pharmacological activation of the b-adrenergic pathway enhances the formation of brown-like or beige adipocytes predominantly in the inguinal fat pads (iWAT) of rodents, which are characterized by a thermogenic gene expression program similar to that of brown adipose tissue, including…”
BackgroundAdipose Tissue and Metabolic Health
An, S.-M., Cho, S.-H., & Yoon, J. C. (2023) · Diabetes & Metabolism Journal · doi:10.4093/dmj.2023.0011 · Cited by 184
“Mice deficient in FGF21 had an impaired ability to convert WAT to beige fat [114].”
BackgroundCrosstalk between adipokines and myokines in fat browning
Rodríguez, A., Becerril, S., Ezquerro, S., Méndez-Giménez, L., & Frühbeck, G. (2016) · Acta Physiologica · doi:10.1111/apha.12686 · Cited by 196
“2015) and local (Fisher et al. 2012) mechanisms to provide a robust defence against hypothermia.”
BackgroundInfluentialFactors involved in white‐to‐brown adipose tissue conversion and in thermogenesis: a review
Montanari, T., Pošćić, N., & Colitti, M. (2017) · Obesity Reviews · doi:10.1111/obr.12520 · Cited by 193
“The activated receptor triggers the p38 MAPK pathway that in turn stimulates UCP1 expression inducing both BAT activity and WAT browning (45).”
BackgroundHypothalamic-autonomic control of energy homeostasis
Seoane‐Collazo, P., Fernø, J., González, F., Diéguez, C., Leis, R., Nogueiras, R., & López, M. (2015) · Endocrine · doi:10.1007/s12020-015-0658-y · Cited by 189
Ye, D., Wang, Y., Li, H., Jia, W., Man, K., Lo, C. M., Wang, Y., Lam, K. S. L., & Xu, A. (2014) · Hepatology · doi:10.1002/hep.27060 · Cited by 184
An endocrine role for brown adipose tissue?
Villarroya, J., Cereijo, R., & Villarroya, F. (2013) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00250.2013 · Cited by 193
Targeting fatty acid metabolism to improve glucose metabolism
Stinkens, R., Goossens, G. H., Jocken, J. W. E., & Blaak, E. E. (2015) · Obesity Reviews · doi:10.1111/obr.12298 · Cited by 183
“Currently, most promising may be dietary components affecting our microbial BA metabolism, leading to increased circulating FGF21, a mediator of lipid and carbohydrate metabolism, also inducing recruitment of brown adipocytes (216).”
BackgroundInfluentialFu, T., Seok, S., Choi, S., Huang, Z., Suino-Powell, K. M., Xu, H. E., KEMPER, B. W., & Kemper, J. K. (2014) · Molecular and Cellular Biology · doi:10.1128/mcb.00596-14 · Cited by 190
“Recent studies have shown that FGF21 promotes brown and beige fat formation in adaptive thermogenesis (14, 17).”
BackgroundThe Adipokine Hypothesis of Heart Failure With a Preserved Ejection Fraction
Packer, M. (2025) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2025.06.055 · Cited by 213
Ding, H., Chen, S., Pan, X., Dai, X., Pan, G., Li, Z., Mai, X., Tian, Y., Zhang, S., Liu, B., et al. (2021) · Journal of Cachexia Sarcopenia and Muscle · doi:10.1002/jcsm.12700 · Cited by 187
The adipose organ: white‐brown adipocyte plasticity and metabolic inflammation
Smorlesi, A., Frontini, A., Giordano, A., & Cinti, S. (2012) · Obesity Reviews · doi:10.1111/j.1467-789x.2012.01039.x · Cited by 189
Exosomal microRNA miR-92a concentration in serum reflects human brown fat activity
Chen, Y., Buyel, J. J., Hanssen, M. J. W., Siegel, F., Pan, R., Naumann, J., Schell, M. J., van der Lans, A. A. J. J., Schlein, C., Fröhlich, H., et al. (2016) · Nature Communications · doi:10.1038/ncomms11420 · Cited by 186
iNKT Cells Induce FGF21 for Thermogenesis and Are Required for Maximal Weight Loss in GLP1 Therapy
Lynch, L., Hogan, A. E., Duquette, D., Lester, C., Banks, A. S., LeClair, K. B., Cohen, D. E., Ghosh, A., Lü, B., Corrigan, M. A., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.08.003 · Cited by 185
“FGF21 has been implicated in inducing a thermogenic program in WAT through activation of PGC1a (Fisher et al., 2012), as well as by induction of adiponectin, leading to increased energy expenditure (Holland et al.”
InfluentialFGF21 Requires βklotho to Act In Vivo
Adams, A. C., Cheng, C. C., Coskun, T., & Kharitonenkov, A. (2012) · PLoS ONE · doi:10.1371/journal.pone.0049977 · Cited by 181
“Of note, the metabolic effects of FGF21 in WT mice were largely reflected at the transcriptional level with significant induction of ‘‘browning’’ related genes in WAT such as UCP1 and PGC1a (Table 1), a phenomenon which has recently become synonymous with the mode of action of FGF21 in vivo [19,26,32,33].”
BackgroundSelf-citationInter‐organ communication: a gatekeeper for metabolic health
Castillo‐Armengol, J., Fajas, L., & Lopez‐Mejia, I. C. (2019) · The EMBO Reports · doi:10.15252/embr.201947903 · Cited by 178
“Some teams have reported that FGF21 knockout mice have impaired adaptation to chronic cold exposure and decreased browning of WAT [92].”
Li, H., Wu, G., Fang, Q., Zhang, M., Hui, X., Sheng, B., Wu, L., Bao, Y., Li, P., Xu, A., et al. (2018) · Nature Communications · doi:10.1038/s41467-017-02677-9 · Cited by 178
Lee, M.-W., Lee, M., & Oh, K. (2019) · Journal of Clinical Medicine · doi:10.3390/jcm8060854 · Cited by 192
“In contrast, it was demonstrated that FGF21 also directly promotes UCP1-dependent thermogenesis in BAT and beige WAT [224].”
BackgroundMerrill, M. A. L., Karey, E., Moshier, E. L., Lindtner, C., Frano, M. R. L., Newman, J. W. I., & Buettner, C. (2014) · PLoS ONE · doi:10.1371/journal.pone.0103337 · Cited by 178
A self-sustained loop of inflammation-driven inhibition of beige adipogenesis in obesity
Chung, K.-J., Chatzigeorgiou, A., Economopoulou, M., Garcia-Martin, R., Alexaki, V. I., Mitroulis, I., Nati, M., Gebler, J., Ziemssen, T., Goelz, S. E., et al. (2017) · Nature Immunology · doi:10.1038/ni.3728 · Cited by 175
“The adipocytes used were generated from pre-adipocytes isolated from the stromal vascular fraction (SVF) of wild-type mouse SAT that maintain their ability to express beige-related genes including Ucp1 8 .”
The evolving view of thermogenic adipocytes — ontogeny, niche and function
Shamsi, F., Wang, C., & Tseng, Y. (2021) · Nature Reviews Endocrinology · doi:10.1038/s41574-021-00562-6 · Cited by 184
Adipokines, adiposity, and atherosclerosis
Liu, L., Shi, Z., Ji, X., Zhang, W., Luan, J., Zahr, T., & Qiang, L. (2022) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-022-04286-2 · Cited by 191
Brown adipose tissue: Development, metabolism and beyond
Schulz, T. J., & Tseng, Y.-H. (2013) · Biochemical Journal · doi:10.1042/bj20130457 · Cited by 173
Xu, Y., Wang, N., Tan, H., Li, S., Zhang, C., Zhang, Z., & Feng, Y. (2020) · Theranostics · doi:10.7150/thno.47746 · Cited by 178
Gong, Q., Hu, Z., Zhang, F., Cui, A., Chen, X., Jiang, H., Gao, J., Chen, X., Han, Y., Liang, Q., et al. (2016) · Hepatology · doi:10.1002/hep.28523 · Cited by 171
“The implication that FGF21 inhibits mTORC1 also provides a possible explanation for the opposite metabolic effects of FGF21 and mTORC1 on energy expenditure and growth.((22,25,36,37)) Collectively, the present study indicates that FGF21 enhances insulin sensitivity through inhibition of mTORC1 in livers.”
Mayoral, R., Osborn, O., McNelis, J., Johnson, A. M., Oh, D. Y., Llorente, C., Chung, H., Li, P., Través, P. G., Bandyopadhyay, G. K., et al. (2015) · Molecular Metabolism · doi:10.1016/j.molmet.2015.02.007 · Cited by 171
“FGF21 is a circulating factor, upregulated by fasting and HFD in liver and adipose tissue, that is associated with insulin sensitivity [25], plays a role in beigeing of adipose tissue [26] and also is selectively repressed by SIRT1 in adipocytes [27].”
BackgroundFGF19 subfamily members: FGF19 and FGF21
Dołęgowska, K., Marchelek‐Myśliwiec, M., Nowosiad-Magda, M., Sławiński, M., & Dołęgowska, B. (2019) · Journal of Physiology and Biochemistry · doi:10.1007/s13105-019-00675-7 · Cited by 175
“FGF21 regulates this process, at least partially, by increasing the peroxisome proliferator-activated receptor-γ co-activator 1α (PGC1α) protein level in adipose tissue, regardless of mRNA expression [11, 29, 47, 54, 75].”
Metabolic interplay between white, beige, brown adipocytes and the liver
Scheja, L., & Heeren, J. (2016) · Journal of Hepatology · doi:10.1016/j.jhep.2016.01.025 · Cited by 176
“7 found to induce browning of WAT [58] and glucose uptake in BAT [56].”
BackgroundGallic Acid Regulates Body Weight and Glucose Homeostasis Through AMPK Activation
Doan, K. V., Ko, C. M., Kinyua, A. W., Yang, D. J., Choi, Y., Oh, I. Y., Nguyen, N. M., Ko, A., Choi, J. W., Jeong, Y., et al. (2014) · Endocrinology · doi:10.1210/en.2014-1354 · Cited by 171
Myocardin-Related Transcription Factor A Regulates Conversion of Progenitors to Beige Adipocytes
McDonald, M. E., Li, C., Bian, H.-J., Smith, B. D., Layne, M. D., & Farmer, S. R. (2015) · Cell · doi:10.1016/j.cell.2014.12.005 · Cited by 167
“…Guerra et al., 1998; Nagase et al., 1996), PPARg agonist administration (Petrovic et al., 2010; Vernochet et al., 2009; Wilson-Fritch et al., 2004; Xue et al., 2005), or exposure to FGF21, irisin, or cardiac natriuretic peptides (Bordicchia et al., 2012; Boström et al., 2012; Fisher et al., 2012).”
Thyroid hormones induce browning of white fat
Martínez‐Sánchez, N., Moreno‐Navarrete, J. M., Contreras, C., Rial‐Pensado, E., Fernø, J., Nogueiras, R., Diéguez, C., Fernández‐Real, J. M., & López, M. (2016) · Journal of Endocrinology · doi:10.1530/joe-16-0425 · Cited by 169
Innate Immune Control of Adipose Tissue Homeostasis
Kane, H., & Lynch, L. (2019) · Trends in Immunology · doi:10.1016/j.it.2019.07.006 · Cited by 170
Pan, X., Shao, Y., Wu, F., Wang, Y., Xiong, R., Zheng, J., Tian, H., Wang, B., Wang, Y., Zhang, Y., et al. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.04.002 · Cited by 163
“Adipocytes are the primary target of FGF21, where it increases glucose uptake,modulates lipolysis (Chen et al., 2011), enhances mitochondrial oxidative capacity (Chau et al., 2010), augments PPARg activity (Murata et al., 2011), and promotes browning of white adipose tissue (Fisher et al., 2012).”
BackgroundAdipose Organ Development and Remodeling
Cinti, S. (2018) · Comprehensive physiology · doi:10.1002/cphy.c170042 · Cited by 197
FGF21-based pharmacotherapy – potential utility for metabolic disorders
Gimeno, R. E., & Moller, D. E. (2014) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2014.03.001 · Cited by 163
Brown, Beige, and White: The New Color Code of Fat and Its Pharmacological Implications
Pfeifer, A., & Hoffmann, L. S. (2014) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010814-124346 · Cited by 168
Contreras, C., González, F., Fernø, J., Diéguez, C., Rahmouni, K., Nogueiras, R., & López, M. (2014) · Annals of Medicine · doi:10.3109/07853890.2014.919727 · Cited by 167
Free radicals and male reproduction.
Agarwal, A. K., & Allamaneni, S. S. R. (2011) · PubMed · Cited by 154
Irisin as a muscle-derived hormone stimulating thermogenesis – A critical update
Hofmann, T., Elbelt, U., & Stengel, A. (2014) · Peptides · doi:10.1016/j.peptides.2014.01.016 · Cited by 162
Perivascular Adipose Tissue Regulates Vascular Function by Targeting Vascular Smooth Muscle Cells
Chang, L., Garcia-Barrio, M. T., & Chen, Y. E. (2020) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.120.312464 · Cited by 162
Ma, X., Lee, P., Chisholm, D. J., & James, D. E. (2015) · Frontiers in Endocrinology · doi:10.3389/fendo.2015.00001 · Cited by 167
“Whether FGF21 and irisin can be transformed into injectable recombinant proteins for obesity and/or diabetes treatment is under active research at present.”
BackgroundInfluentialBrown and Beige Adipose Tissues in Health and Disease
Rui, L. (2017) · Comprehensive physiology · doi:10.1002/cphy.c170001 · Cited by 186
A Secreted Slit2 Fragment Regulates Adipose Tissue Thermogenesis and Metabolic Function
Svensson, K. J., Long, J. Z., Jedrychowski, M. P., Cohen, P., Lo, J. C., Serag, S., Kır, S., Shinoda, K., Tartaglia, J. A., Rao, R. R., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.01.008 · Cited by 160
“Mouse models resistant to weight gain through enhanced brown and beige fat content or activity have demonstrated that activation of thermogenesis in fat can be a powerful strategy to improve metabolic health and prevent weight gain (Cederberg and Enerbäck, 2003; Fisher et al., 2012; Vegiopoulos et al., 2010; Ye et al.…”
BackgroundExercise-Released Myokines in the Control of Energy Metabolism
Laurens, C., Bergouignan, A., & Moro, C. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.00091 · Cited by 159
“FGF-21 has been described to regulate the expression of PGC-1α and favor the thermogenic program and browning in white adipose tissue (Fisher et al., 2012), as recently reviewed (Cuevas-Ramos et al., 2019).”
BackgroundFibroblast Activation Protein Cleaves and Inactivates Fibroblast Growth Factor 21
Dunshee, D. R., Bainbridge, T. W., Kljavin, N. M., Zavala-Solorio, J., Schroeder, A. C., Chan, R., Corpuz, R., Wong, M., Zhou, W., Deshmukh, G., et al. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.710582 · Cited by 158
“In mice, the metabolic activity of FGF21 is attributed to the stimulation of thermogenesis in brown adipose tissues (5, 6), white adipose tissue browning (7), hepatic fatty acid oxidation (8), amelioration of hepatic endoplasmic reticulum stress (9), and induction of the adipokine adiponectin (10, 11).”
BackgroundBrown adipose tissue-derived exosomes mitigate the metabolic syndrome in high fat diet mice
Zhou, X., Li, Z., Qi, M., Zhao, P., Duan, Y., Yang, G., & Yuan, L. (2020) · Theranostics · doi:10.7150/thno.43968 · Cited by 160
“Thomou et al reported that BAT-Exos might regulate FGF21 expression in the liver, suggesting potential effect of BAT-Exos on metabolism [43].”
BackgroundBeige Adipose Tissue Identification and Marker Specificity—Overview
Pilkington, A., Paz, H. A., & Wankhade, U. D. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.599134 · Cited by 163
“Beige adipocytes were originally observed to arise in response to cold exposure in rodents (7–9); however, studies have since identified that diet (10), exercise (11), pre-and probiotics (12), pharmaceutical agents, numerous plant-based bioactives, and even adipokines (13, 14), can also induce “beigeing” or “browning”…”
BackgroundDiscrete Aspects of FGF21 In Vivo Pharmacology Do Not Require UCP1
Samms, R. J., Smith, D. P., Cheng, C. C., Antonellis, P. P., Perfield, J. W., Kharitonenkov, A., Gimeno, R. E., & Adams, A. C. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.04.046 · Cited by 154
“Under this condition, FGF21 acts in an autocrine/paracrine manner to engage thermogenic pathways inbrownadipose tissue (BAT) andalso to induce thebrowning of white adipose tissue (WAT) (Fisher et al., 2012; Hondares et al., 2011).”
BackgroundInfluentialSelf-citationSun, Y., Xia, M., Yan, H., Han, Y., Zhang, F., Hu, Z., Cui, A., Ma, F., Liu, Z., Gong, Q., et al. (2017) · British Journal of Pharmacology · doi:10.1111/bph.14079 · Cited by 152
“Given that FGF21 regulates the browning of white adipose tissue (WAT) in adaptive thermogenesis (Fisher et al., 2012), we further investigated whether berberine alters the transcription of browning genes in WAT or thermogenic genes in brown adipose tissue (BAT).”
BackgroundInfluentialPark, H., He, A., Tan, M., Johnson, J. M., Dean, J. M., Pietka, T., Chen, Y., Zhang, X., Hsu, F., Razani, B., et al. (2018) · Journal of Clinical Investigation · doi:10.1172/jci120606 · Cited by 154
Wu, L., Mo, W., Feng, J., Li, J., Yu, Q., Li, S., Zhang, J., Chen, K., Ji, J., Dai, W., et al. (2020) · British Journal of Pharmacology · doi:10.1111/bph.15099 · Cited by 154
“Convincing evidence has shown that FGF21 can regulate PGC-1α (Fisher et al., 2012; Potthoff et al., 2009).”
BackgroundFGF21: A Novel Regulator of Glucose and Lipid Metabolism and Whole-Body Energy Balance
Szczepańska, E., & Gietka‐Czernel, M. (2022) · Hormone and Metabolic Research · doi:10.1055/a-1778-4159 · Cited by 155
“FGF21 also induces browning of white adipocytes and generation of dispersed brown-like adipocytes in white adipose depots [96].”
BackgroundDesai, B. N., Singhal, G., Watanabe, M., Stevanovic, D., Lundasen, T., Fisher, F. M., Mather, M. L., Vardeh, H. G., Douris, N., Adams, A. C., et al. (2017) · Molecular Metabolism · doi:10.1016/j.molmet.2017.08.004 · Cited by 150
Self-citationFlachs, P., Rossmeisl, M., Kuda, O., & Kopecký, J. (2013) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2013.02.003 · Cited by 154
Fibroblast growth factor 21 and browning of white adipose tissue
Cuevas-Ramos, D., Mehta, R., & Aguilar-Salinas, C. A. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.00037 · Cited by 149
“The consequence of these PGC1-alfa inducers is to promote adaptive thermogenesis with “browning” of WAT (Fisher et al., 2012).”
BackgroundInfluentialFibroblast growth factor-21, energy balance and obesity
Giralt, M., Gavaldà‐Navarro, A., & Villarroya, F. (2015) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2015.09.018 · Cited by 150
Gao, M., Ma, Y., & Liu, D. (2015) · PLoS ONE · doi:10.1371/journal.pone.0119784 · Cited by 156
“Thermogenic activation of BAT or pharmacologic induction of a thermogenic program in WAT is capable of generating benefits in diet induced metabolic disorders [34,35,36].”
BackgroundHuang, Z., Zhong, L., Lee, J. T. H., Zhang, J., Wu, D., Geng, L., Wang, Y., Wong, C.-M., & Xu, A. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.08.003 · Cited by 147
Gene silencing in adipose tissue macrophages regulates whole-body metabolism in obese mice
Aouadi, M., Tencerová, M., Vangala, P., Yawe, J. C., Nicoloro, S. M. C., Amano, S. U., Cohen, J. L., & Czech, M. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1300492110 · Cited by 154
“FGF21 has been shown to regulate brown adipose tissue (BAT) mass and activity (23, 24).”
BackgroundKim, K. H., & Lee, M.-S. (2014) · Diabetes & Metabolism Journal · doi:10.4093/dmj.2014.38.4.245 · Cited by 146
Adipose tissue dysfunction in cancer cachexia
Da'as, S. I., Rizeq, B. R., & Nasrallah, G. K. (2018) · Journal of Cellular Physiology · doi:10.1002/jcp.26811 · Cited by 144
“In WAT research, it was shown that in humans, FGF21, a key mediator of lipid metabolism and fatty acid oxidation secreted by the liver, acts through the stimulation of fatty acid oxidation and energy dissipation by inducing browning of adipocytes (Kleiner et al., 2012).”
BackgroundTranscriptional Regulatory Circuits Controlling Brown Fat Development and Activation
Seale, P. (2015) · Diabetes · doi:10.2337/db15-0203 · Cited by 145
“PGC-1a is however required for the expression of UCP1 in WAT and for the browning effect of FGF21 (62,63).”
Lee, P., Brychta, R. J., Linderman, J. D., Smith, S., Chen, K. Y., & Celi, F. S. (2012) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2012-3107 · Cited by 142
A muscle-liver-fat signalling axis is essential for central control of adaptive adipose remodelling
Shimizu, N., Maruyama, T., Yoshikawa, N., Matsumiya, R., Ma, Y., Ito, N., Tasaka, Y., Souta-Kuribara, A., Miyata, K., Oike, Y., et al. (2015) · Nature Communications · doi:10.1038/ncomms7693 · Cited by 138
Ghesmati, Z., Rashid, M., Fayezi, S., Gieseler, F., Alizadeh, E., & Darabi, M. (2024) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-023-09850-0 · Cited by 139
“…prostaglandin E2 analog (16,16-dimethyl 16-dimethyl 16-dimethyl PGE2), FGF21 regulates Pgc1a expression and WAT browning in adaptive thermogenesis [298, 299] Prostaglandin D synthase (PTGDS) has a positive relationship with BAT activity and WAT browning [300] Apelin, as an adipocyte-derived…”
BackgroundWang, L., Ishihara, T., Ibayashi, Y., Tatsushima, K., Setoyama, D., Hanada, Y., Takeichi, Y., Sakamoto, S., Yokota, S., Mihara, K., et al. (2015) · Diabetologia · doi:10.1007/s00125-015-3704-7 · Cited by 138
Circadian Rhythms of the Hypothalamus: From Function to Physiology
Drunen, R. V., & Eckel‐Mahan, K. L. (2021) · Clocks & Sleep · doi:10.3390/clockssleep3010012 · Cited by 146
“WAT is essential for energy storage while BAT is important for energy burning, otherwise known as thermogenesis [152,153].”
BackgroundThe Whitening of Brown Fat and Its Implications for Weight Management in Obesity
Shimizu, I., & Walsh, K. X. (2015) · Current Obesity Reports · doi:10.1007/s13679-015-0157-8 · Cited by 141
Fibroblast Growth Factor Signaling in Metabolic Regulation
Nies, V. J. M., Sancar, G., Liu, W., van Zutphen, T., Struik, D., Yu, R. T., Atkins, A. R., Evans, R. M., Jonker, J. W., & Downes, M. (2016) · Frontiers in Endocrinology · doi:10.3389/fendo.2015.00193 · Cited by 137
“These include upregulation of UCP1 and Acetyl CoA Carboxylase 2 (ACC2), increased core body temperature, and increased glucose uptake into BAT (60, 65, 72, 75).”
BackgroundResultInfluentialFibroblast growth factor 21 in non-alcoholic fatty liver disease
Tucker, B., Li, H., Long, X., Rye, K., & Ong, K. L. (2019) · Metabolism · doi:10.1016/j.metabol.2019.153994 · Cited by 132
Adipose tissue browning in mice and humans
Herz, C. T., & Kiefer, F. W. (2019) · Journal of Endocrinology · doi:10.1530/joe-18-0598 · Cited by 144
There and Back Again: Leptin Actions in White Adipose Tissue
Martínez‐Sánchez, N. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21176039 · Cited by 142
“Other factors implicated in the activation of browning are immune cells [39–41], the metabolic regulator fibroblast growth factor 21 (FGF21) [42], thyroid hormones [43], bone morphogenetic proteins (BMPs) [44,45], nicotine [46,47], cold exposure [48,49] and fasting [50,51].”
BackgroundWanders, D., Forney, L. A., Stone, K. P., Burk, D. H., Pierse, A., & Gettys, T. W. (2017) · Diabetes · doi:10.2337/db16-1212 · Cited by 137
“Together these findings illustrate that FGF21 is an essential mediator of the transcriptional programs induced by dietary MR in BAT and WAT.”
BackgroundInfluentialKim, H., Méndez, R., Zheng, Z., Chang, L., Cai, J., Zhang, R., & Zhang, K. (2014) · Endocrinology · doi:10.1210/en.2013-1490 · Cited by 134
“In the fed state, FGF21 regulates other important metabolic processes, including lipolysis and glucose uptake in the liver or other peripheral tissues, such as white adipose tissue in which FGF21 also plays a role in browning upon cold exposure (11).”
BackgroundLiu, T.-F., Tang, J.-J., Li, P.-S., Shen, Y., Li, J.-G., Miao, H.-H., Li, B.-L., & Song, B.-L. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.06.014 · Cited by 127
Blevins, J. E., & Baskin, D. G. (2015) · Physiology & Behavior · doi:10.1016/j.physbeh.2015.05.023 · Cited by 135
Xu, L., & Ota, T. (2017) · Adipocyte · doi:10.1080/21623945.2017.1413516 · Cited by 134
“Moreover, FGF21 also activates the b3-adrenergic receptor in WAT and regulates recruitment of beige adipocytes [61], thereby leading to increased energy utilization and browning.”
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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