Thermogenic Activation Induces FGF21 Expression and Release in Brown Adipose Tissue
Open accessAbstract
FGF21 is a novel metabolic regulator involved in the control of glucose homeostasis, insulin sensitivity, and ketogenesis. The liver has been considered the main site of production and release of FGF21 into the blood. Here, we show that, after thermogenic activation, brown adipose tissue becomes a source of systemic FGF21. This is due to a powerful cAMP-mediated pathway of regulation of FGF21 gene transcription. Norepinephrine, acting via β-adrenergic, cAMP-mediated, mechanisms and subsequent activation of protein kinase A and p38 MAPK, induces FGF21 gene transcription and also FGF21 release in brown adipocytes. ATF2 binding to the FGF21 gene promoter mediates cAMP-dependent induction of FGF21 gene transcription. FGF21 release by brown fat in vivo was assessed directly by analyzing arteriovenous differences in FGF21 concentration across interscapular brown fat, in combination with blood flow to brown adipose tissue and assessment of FGF21 half-life. This analysis demonstrates that exposure of rats to cold induced a marked release of FGF21 by brown fat in vivo, in association with a reduction in systemic FGF21 half-life. The present findings lead to the recognition of a novel pathway of regulation the FGF21 gene and an endocrine role of brown fat, as a source of FGF21 that may be especially relevant in conditions of activation of thermogenic activity.
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FGF21 is expressed and released into the general circulation by several tissues such as the liver, white adipose tissue, brown adipose tissue, and the heart.
“The metabolic regulator FGF21 is expressed and released into the general circulation by several tissues such as the liver, WAT, BAT, and the heart.7, 8, 9, 10, 11”
From Fibroblast growth factor 21 controls mitophagy and muscle mass (2019) · cites this paper as [11]
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 [49]
In white adipocytes, FGF21 expression is regulated by both PPARγ and PPARα.
“Similar mechanisms may upregulate FGF21 expression in white adipocytes during cold, but FGF21 expression is also regulated by both PPARγ (32, 49, 94) and PPARα (49) in white adipocytes.”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [49]
In brown adipocytes, norepinephrine induces FGF21 production via β-adrenergic receptors and cAMP/PKA/p38 MAPK mechanisms regulating ATF2 binding to the Fgf21 promoter.
“In brown adipocytes, norepinephrine activates β-adrenergic receptors and cyclic adenosine monophosphate (cAMP)-dependent, protein kinase A (PKA)- and p38 mitogen-activated protein kinase (MAPK)-mediated mechanisms to regulate ATF2 binding to the Fgf21 promoter to induce FGF21 production (Figure 3a) (49).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [49]
Under cold exposure, FGF21 can be secreted by BAT and WAT, have a paracrine effect, and stimulate the expression of thermogenic genes.
“Under cold exposure, FGF21 can be secreted by BAT and WAT, have a paracrine effect, and stimulate the expression of thermogenic genes 91.”
From Inter‐organ communication: a gatekeeper for metabolic health (2019) · cites this paper as [91]
Cites
Brown Adipose Tissue: Function and Physiological Significance
CANNON, B., & NEDERGAARD, J. (2004) · Physiological Reviews · doi:10.1152/physrev.00015.2003 · Cited by 6,433 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
Raingeaud, J., Whitmarsh, A. J., Barrett, T., Dérijard, B., & Davis, R. J. (1996) · Molecular and Cellular Biology · doi:10.1128/mcb.16.3.1247 · Cited by 1,280 · see citing works
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 · see citing works
Fibroblast Growth Factor 21 Corrects Obesity in Mice
Coskun, T., Bina, H. A., Schneider, M. A., Dunbar, J. D., Hu, C. C., Chen, Y., Moller, D. E., & Kharitonenkov, A. (2008) · Endocrinology · doi:10.1210/en.2008-0816 · Cited by 1,031 · see citing works
Potthoff, M. J., Inagaki, T., Satapati, S., Ding, X., He, T., Goetz, R., Mohammadi, M., Finck, B. N., Mangelsdorf, D. J., Kliewer, S. A., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0904187106 · Cited by 704 · see citing works
Foster, D. O., & Frydman, M. L. (1979) · Canadian Journal of Physiology and Pharmacology · doi:10.1139/y79-039 · Cited by 518 · see citing works
Gälman, C., Lundåsen, T., Kharitonenkov, A., Bina, H. A., Eriksson, M., Hafström, I., Dahlin, M., Åmark, P., Angelin, B., & Rudling, M. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2008.06.014 · Cited by 512 · see citing works
FGF21 is an Akt‐regulated myokine
Izumiya, Y., Bina, H. A., Ouchi, N., Akasaki, Y., Kharitonenkov, A., & Walsh, K. (2008) · FEBS Letters · doi:10.1016/j.febslet.2008.10.021 · Cited by 415 · see citing works
Hondares, E., Rosell, M., Gonzalez, F. J., Giralt, M., Iglesias, R., & Villarroya, F. (2010) · Cell Metabolism · doi:10.1016/j.cmet.2010.02.001 · Cited by 377 · see citing works
Self-citationEnerbäck, S. (2010) · Cell Metabolism · doi:10.1016/j.cmet.2010.03.008 · Cited by 371 · see citing works
Fibroblast Growth Factor 21-Deficient Mice Demonstrate Impaired Adaptation to Ketosis
Badman, M. K., Koester, A., Flier, J. S., Kharitonenkov, A., & Maratos-Flier, E. (2009) · Endocrinology · doi:10.1210/en.2009-0532 · Cited by 362 · see citing works
Hotta, Y., Nakamura, H., Konishi, M., Murata, Y., Takagi, H., Matsumura, S., Inoue, K., Fushiki, T., & Itoh, N. (2009) · Endocrinology · doi:10.1210/en.2009-0119 · Cited by 352 · see citing works
Xu, J., Stanislaus, S., Chinookoswong, N., Lau, Y. Y., Hager, T., Patel, J., Ge, H., Weiszmann, J., Lu, S.-C., Graham, M., et al. (2009) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00348.2009 · Cited by 340 · see citing works
Berglund, E. D., Li, C. Y., Bina, H. A., Lynes, S. E., Michael, M. D., Shanafelt, A. B., Kharitonenkov, A., & Wasserman, D. H. (2009) · Endocrinology · doi:10.1210/en.2009-0221 · Cited by 297 · see citing works
Muise, E. S., Azzolina, B., Kuo, D. W., El-Sherbeini, M., Tan, Y., Yuan, X., Mu, J., Thompson, J. R., Berger, J. P., & Wong, K. K. (2008) · Molecular Pharmacology · doi:10.1124/mol.108.044826 · Cited by 294 · see citing works
Transcriptional control of brown adipocyte development and physiological function—of mice and menPreprint
Seale, P., Kajimura, S., & Spiegelman, B. M. (2009) · Genes & Development · doi:10.1101/gad.1779209 · Cited by 289 · see citing works
Sarruf, D. A., Thaler, J. P., Morton, G. J., German, J. P., Fischer, J. D., Ogimoto, K., & Schwartz, M. W. (2010) · Diabetes · doi:10.2337/db09-1878 · Cited by 287 · see citing works
FGF21 attenuates lipolysis in human adipocytes – A possible link to improved insulin sensitivity
Arner, P., Pettersson, A., Mitchell, P. J., Dunbar, J. D., Kharitonenkov, A., & Rydén, M. (2008) · FEBS Letters · doi:10.1016/j.febslet.2008.04.038 · Cited by 234 · see citing works
Orphan nuclear receptor estrogen-related receptor α is essential for adaptive thermogenesis
Villena, J. A., Hock, M. B., Chang, W. Y., Barcas, J. E., Giguère, V., & Kralli, A. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0607696104 · Cited by 215 · see citing works
Silva, J. E., & Larsen, P. R. (1985) · Journal of Clinical Investigation · doi:10.1172/jci112239 · Cited by 207 · see citing works
Molecular determinants of FGF‐21 activity—synergy and cross‐talk with PPARγ signaling
Moyers, J. S., Shiyanova, T. L., Mehrbod, F., Dunbar, J. D., Noblitt, T. W., Otto, K. A., Reifel-Miller, A. E., & Kharitonenkov, A. (2006) · Journal of Cellular Physiology · doi:10.1002/jcp.20847 · Cited by 193 · see citing works
Collins, S., Cao, W., & Robidoux, J. (2004) · Molecular Endocrinology · doi:10.1210/me.2004-0193 · Cited by 179 · see citing works
Mai, K., Andres, J., Biedasek, K., Weicht, J., Bobbert, T., Sabath, M., Meinus, S., Reinecke, F., Möhlig, M., Weickert, M. O., et al. (2009) · Diabetes · doi:10.2337/db08-1775 · Cited by 159 · see citing works
Thermogenically competent nonadrenergic recruitment in brown preadipocytes by a PPARγ agonist
Petrovič, N., Shabalina, I. G., Timmons, J. A., Cannon, B., & Nedergaard, J. (2008) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00035.2008 · Cited by 134 · see citing works
Muramatsu, M., Kaibuchi, K., & Arai, K. (1989) · Molecular and Cellular Biology · doi:10.1128/mcb.9.2.831 · Cited by 102 · see citing works
Carmona, M. C., Hondares, E., CONCEPCIÓN, M. L. R. D. L., Rodríguez‐Sureda, V., Peinado‐Onsurbe, J., Poli, V., Iglesias, R., Villarroya, F., & Giralt, M. (2005) · Biochemical Journal · doi:10.1042/bj20050009 · Cited by 59 · see citing works
Self-citationFernandez, J. A., Mampel, T., Villarroya, F., & Iglesias, R. (1987) · Biochemical Journal · doi:10.1042/bj2430281 · Cited by 59 · see citing works
Self-citationBukowiecki, L. J. (1989) · Canadian Journal of Physiology and Pharmacology · doi:10.1139/y89-062 · Cited by 43 · see citing works
Jones, R., & Williamson, D. H. (1984) · Bioscience Reports · doi:10.1007/bf01122507 · Cited by 25 · see citing works
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Sorted by citations
Brown and beige fat: Development, function and therapeutic potential
Harms, M., & Seale, P. (2013) · Nature Medicine · doi:10.1038/nm.3361 · Cited by 2,328 · see citing works
Chait, A., & den Hartigh, L. J. (2020) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2020.00022 · Cited by 1,529 · see citing works
FGF21 regulates PGC-1α and browning of white adipose tissues in adaptive thermogenesis
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., et al. (2012) · Genes & Development · doi:10.1101/gad.177857.111 · Cited by 1,478 · see citing works
Brown adipose tissue regulates glucose homeostasis and insulin sensitivity
Stanford, K. I., Middelbeek, R. J. W., Townsend, K. L., An, D., Nygaard, E. B., Hitchcox, K. M., Markan, K. R., Nakano, K., Hirshman, M. F., Tseng, Y.-H., et al. (2013) · Journal of Clinical Investigation · doi:10.1172/jci62308 · Cited by 1,180 · see citing works
Adipose Tissue Remodeling: Its Role in Energy Metabolism and Metabolic Disorders
Choe, S. S., Huh, J. Y., Hwang, I. J., Kim, J. I., & Kim, J. B. (2016) · Frontiers in Endocrinology · doi:10.3389/fendo.2016.00030 · Cited by 1,206 · see citing works
Adapting to obesity with adipose tissue inflammation
Reilly, S. M., & Saltiel, A. R. (2017) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2017.90 · Cited by 1,204 · see citing works
Activation of Human Brown Adipose Tissue by a β3-Adrenergic Receptor Agonist
Cypess, A. M., Weiner, L. S., Roberts‐Toler, C., Franquet, E., Kessler, S., Kahn, P. A., English, J., Chatman, K., Trauger, S. A., Doria, A., et al. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2014.12.009 · Cited by 1,030 · see citing works
Understanding the Physiology of FGF21
Fisher, F. M., & Maratos-Flier, E. (2016) · Annual Review of Physiology · doi:10.1146/annurev-physiol-021115-105339 · Cited by 912 · see citing works
FGF/FGFR signaling in health and disease
Xie, Y., Su, N., Yang, J., Tan, Q., Huang, S., Jin, M., Ni, Z., Zhang, B., Zhang, D., Luo, F., et al. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-00222-7 · Cited by 904 · see citing works
Irisin and FGF21 are cold-induced endocrine activators of brown fat function in humans
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., et al. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2013.12.017 · Cited by 802 · see citing works
Brown Adipose Tissue Improves Whole-Body Glucose Homeostasis and Insulin Sensitivity in Humans
Chondronikola, M., Volpi, E., Børsheim, E., Porter, C. C., Annamalai, P., Enerbäck, S., Lidell, M. E., Saraf, M. K., Labbé, S. M., Hurren, N. M., et al. (2014) · Diabetes · doi:10.2337/db14-0746 · Cited by 789 · see citing works
Adipose tissue in control of metabolism
Luo, L., & Liu, M. (2016) · Journal of Endocrinology · doi:10.1530/joe-16-0211 · Cited by 707 · see citing works
Extracellular Vesicles Provide a Means for Tissue Crosstalk during Exercise
Whitham, M., Parker, B. L., Friedrichsen, M. H., Hingst, J. R., Hjorth, M., Hughes, W. E., Egan, C. L., Cron, L., Watt, K. I., Kuchel, R. P., et al. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2017.12.001 · Cited by 689 · see citing works
Lin, Z., Tian, H., Lam, K. S. L., Lin, S., Hoo, R. C. L., Konishi, M., Itoh, N., Wang, Y., Bornstein, S. R., Xu, A., et al. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.04.005 · Cited by 691 · see citing works
The endocrine function of adipose tissues in health and cardiometabolic disease
Scheja, L., & Heeren, J. (2019) · Nature Reviews Endocrinology · doi:10.1038/s41574-019-0230-6 · Cited by 663 · see citing works
Brown adipose tissue as a secretory organ
Villarroya, F., Cereijo, R., Villarroya, J., & Giralt, M. (2016) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2016.136 · Cited by 679 · see citing works
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Giralt, M., & Villarroya, F. (2013) · Endocrinology · doi:10.1210/en.2013-1403 · Cited by 556 · see citing works
Self-citationEndocrine fibroblast growth factors 15/19 and 21: from feast to famine
Potthoff, M. J., Kliewer, S. A., & Mangelsdorf, D. J. (2012) · Genes & Development · doi:10.1101/gad.184788.111 · Cited by 442 · see citing works
Therapeutic potential of the endocrine fibroblast growth factors FGF19, FGF21 and FGF23
Degirolamo, C., Sabbà, C., & Moschetta, A. (2016) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2015.9 · Cited by 424 · see citing works
Skeletal muscle as an endocrine organ: PGC-1α, myokines and exercise
Schnyder, S., & Handschin, C. (2015) · Bone · doi:10.1016/j.bone.2015.02.008 · Cited by 419 · see citing works
Peirce, V. J., Carobbio, S., & Vidal‐Puig, A. (2014) · Nature · doi:10.1038/nature13477 · Cited by 414 · see citing works
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Ding, X., Boney-Montoya, J., Owen, B. M., Bookout, A. L., Coate, K. C., Mangelsdorf, D. J., & Kliewer, S. A. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.08.002 · Cited by 403 · see citing works
Cheng, L., Wang, J., Dai, H., Duan, Y., An, Y., Shi, L., Lv, Y., Li, H., Wang, C., Ma, Q., et al. (2021) · Adipocyte · doi:10.1080/21623945.2020.1870060 · Cited by 377 · see citing works
Fibroblast growth factor 21 protects against cardiac hypertrophy in mice
Planavila, A., Redondo‐Angulo, I., Hondares, E., Vinciguerra, M., Munts, C., Iglesias, R., Gabrielli, L., Sitges, M., Giralt, M., van Bilsen, M., et al. (2013) · Nature Communications · doi:10.1038/ncomms3019 · Cited by 371 · see citing works
Self-citationBrown fat fuel utilization and thermogenesis
Townsend, K. L., & Tseng, Y. (2014) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2013.12.004 · Cited by 331 · see citing works
FGF21 as Modulator of Metabolism in Health and Disease
Tezze, C., Romanello, V., & Sandri, M. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.00419 · Cited by 313 · see citing works
Fibroblast Growth Factor 21 as an emerging metabolic regulator: clinical perspectives
Woo, Y. C., Xu, A., Wang, Y., & Lam, K. S. L. (2012) · Clinical Endocrinology · doi:10.1111/cen.12095 · Cited by 302 · see citing works
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Owen, B. M., Mangelsdorf, D. J., & Kliewer, S. A. (2015) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2014.10.002 · Cited by 286 · see citing works
Pharmacological and nutritional agents promoting browning of white adipose tissue
Bonet, M. L., Oliver, P., & Palou, A. (2012) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2012.12.002 · Cited by 276 · see citing works
A Dozen Years of Discovery: Insights into the Physiology and Pharmacology of FGF21
Kliewer, S. A., & Mangelsdorf, D. J. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.01.004 · Cited by 273 · see citing works
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Whitham, M., & Febbraio, M. A. (2016) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.153 · Cited by 279 · see citing works
Fibroblast Growth Factor 21—Metabolic Role in Mice and Men
Staiger, H., Keuper, M., Berti, L., Hrabě de Angelis, M., & Häring, H.-U. (2017) · Endocrine Reviews · doi:10.1210/er.2017-00016 · Cited by 270 · see citing works
Fibroblast growth factor 21 protects the heart from oxidative stress
Planavila, A., Redondo‐Angulo, I., Ribas‐Aulinas, F., Garrabou, G., Casademont, J., Giralt, M., & Villarroya, F. (2014) · Cardiovascular Research · doi:10.1093/cvr/cvu263 · Cited by 265 · see citing works
Self-citationWu, A., Feng, B., Yu, J., Yan, L., Che, L., Zhuo, Y., Luo, Y., Yu, B., Wu, D., & Chen, D. (2021) · Redox Biology · doi:10.1016/j.redox.2021.102131 · Cited by 261 · see citing works
Brown Adipose Tissue Transplantation Reverses Obesity in Ob/Ob Mice
Liu, X., Wang, S., You, Y., Meng, M., Zheng, Z., Dong, M., Lin, J., Zhao, Q., Zhang, C., Yuan, X., et al. (2015) · Endocrinology · doi:10.1210/en.2014-1598 · Cited by 258 · see citing works
Brown Adipose Tissue Responds to Cold and Adrenergic Stimulation by Induction of FGF21
Chartoumpekis, D. V., Habeos, I. G., Ziros, P. G., Psyrogiannis, A. I., Kyriazopoulou, V. E., & Papavassiliou, A. G. (2011) · Molecular Medicine · doi:10.2119/molmed.2011.00075 · Cited by 252 · see citing works
Activating transcription factor 4-dependent induction of FGF21 during amino acid deprivation
De Sousa-Coelho, A. L., Marrero, P. F., & Haro, D. (2012) · Biochemical Journal · doi:10.1042/bj20111748 · Cited by 246 · see citing works
Lockie, S. H., Heppner, K. M., Chaudhary, N., Chabenne, J. R., Morgan, D. A., Veyrat‐Durebex, C., Ananthakrishnan, G., Rohner‐Jeanrenaud, F., Drucker, D. J., DiMarchi, R. D., et al. (2012) · Diabetes · doi:10.2337/db11-1556 · Cited by 238 · see citing works
Fibroblast growth factor 21 controls mitophagy and muscle mass
Oost, L. J., Kustermann, M., Armani, A., Blaauw, B., & Romanello, V. (2019) · Journal of Cachexia, Sarcopenia and Muscle · doi:10.1002/jcsm.12409 · Cited by 231 · see citing works
Cereijo, R., Gavaldà-Navarro, A., Cairó, M., Quesada-López, T., Villarroya, J., Morón-Ros, S., Sánchez-Infantes, D., Peyrou, M., Iglesias, R., Mampel, T., et al. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.07.015 · Cited by 236 · see citing works
Self-citationBrown Fat and Browning for the Treatment of Obesity and Related Metabolic Disorders
Kim, S. H., & Plutzky, J. (2016) · Diabetes & Metabolism Journal · doi:10.4093/dmj.2016.40.1.12 · Cited by 232 · see citing works
The lipid sensor GPR120 promotes brown fat activation and FGF21 release from adipocytes
Quesada‐López, T., Cereijo, R., Turatsinze, J., Planavila, A., Cairó, M., Gavaldà‐Navarro, A., Peyrou, M., Moure, R., Iglesias, R., Giralt, M., et al. (2016) · Nature Communications · doi:10.1038/ncomms13479 · Cited by 231 · see citing works
Self-citationBrown adipose tissue and thermogenesis
Fenzl, A., & Kiefer, F. W. (2014) · Hormone Molecular Biology and Clinical Investigation · doi:10.1515/hmbci-2014-0022 · Cited by 227 · see citing works
Softic, S., Meyer, J. G., Wang, G.-X., Gupta, M. K., Batista, T. M., Lauritzen, H. P. M. M., Fujisaka, S., Serra, D., Herrero, L., Willoughby, J., et al. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.09.003 · Cited by 227 · see citing works
Human Brown Adipose Tissue: What We Have Learned So Far
Betz, M. J., & Enerbäck, S. (2015) · Diabetes · doi:10.2337/db15-0146 · Cited by 223 · see citing works
Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis
BonDurant, L. D., & Potthoff, M. J. (2018) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-071816-064800 · Cited by 222 · see citing works
Emerging Complexities in Adipocyte Origins and Identity
Sánchez-Gurmaches, J., Hung, C., & Guertin, D. A. (2016) · Trends in Cell Biology · doi:10.1016/j.tcb.2016.01.004 · Cited by 214 · see citing works
Central Fibroblast Growth Factor 21 Browns White Fat via Sympathetic Action in Male Mice
Douris, N., Stevanovic, D. M., Fisher, F. M., Cisu, T. I., Chee, M. J., Nguyen, N. L., Zarebidaki, E., Adams, A. C., Kharitonenkov, A., Flier, J. S., et al. (2015) · Endocrinology · doi:10.1210/en.2014-2001 · Cited by 215 · see citing works
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Frontini, A., Vitali, A., Perugini, J., Murano, I., Romiti, C., Ricquier, D., Guerrieri, M., & Cinti, S. (2013) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2013.02.005 · Cited by 211 · see citing works
Omega-3 fatty acids and adipose tissue function in obesity and metabolic syndrome
Martínez‐Fernández, L., Laiglesia, L. M., Huerta, A. E., Martínez, J. A., & Moreno-Aliaga, M. J. (2015) · Prostaglandins & Other Lipid Mediators · doi:10.1016/j.prostaglandins.2015.07.003 · Cited by 208 · see citing works
Metabolic 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 · see citing works
Brown 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 207 · see citing works
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 206 · see citing works
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 206 · see citing works
Pharmacologic 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 · see citing works
Differential Role of Adipose Tissues in Obesity and Related Metabolic and Vascular Complications
Gómez‐Hernández, A., Beneit, N., Díaz-Castroverde, S., & Escribano, Ó. (2016) · International Journal of Endocrinology · doi:10.1155/2016/1216783 · Cited by 204 · see citing works
FGF21 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 · see citing works
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 · see citing works
Self-citationCrosstalk between adipokines and myokines in fat browning
Rodrı́guez, A., Becerril, S., Ezquerro, S., Méndez-Giménez, L., & Frühbeck, G. (2016) · Acta Physiologica · doi:10.1111/apha.12686 · Cited by 192 · see citing works
Factors 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 189 · see citing works
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 184 · see citing works
Self-citationAdipose 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 · see citing works
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 179 · see citing works
Ge, X., Chen, C., Hui, X. H., Wang, Y., Lam, K. S. L., & Xu, A. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.248591 · Cited by 181 · see citing works
FGF21 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 · see citing works
Inter‐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 · see citing works
Lee, M.-W., Lee, M., & Oh, K. (2019) · Journal of Clinical Medicine · doi:10.3390/jcm8060854 · Cited by 180 · see citing works
Wu, A.-L., Kolumam, G., Stawicki, S., Chen, Y., Li, J., Zavala-Solorio, J., Phamluong, K., Feng, B., Li, L., Marsters, S., et al. (2011) · Science Translational Medicine · doi:10.1126/scitranslmed.3002669 · Cited by 184 · see citing works
New insights into the secretory functions of brown adipose tissue
Villarroya, J., Cereijo, R., Gavaldà‐Navarro, A., Peyrou, M., Giralt, M., & Villarroya, F. (2019) · Journal of Endocrinology · doi:10.1530/joe-19-0295 · Cited by 175 · see citing works
Self-citationAdipokines, 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 175 · see citing works
Townsend, K. L., & Tseng, Y. (2012) · Adipocyte · doi:10.4161/adip.18951 · Cited by 172 · see citing works
Brown adipose tissue: Development, metabolism and beyond
Schulz, T. J., & Tseng, Y.-H. (2013) · Biochemical Journal · doi:10.1042/bj20130457 · Cited by 173 · see citing works
Differential Specificity of Endocrine FGF19 and FGF21 to FGFR1 and FGFR4 in Complex with KLB
Yang, C., Jin, C., Li, X., Wang, F., McKeehan, W. L., & Luo, Y. (2012) · PLoS ONE · doi:10.1371/journal.pone.0033870 · Cited by 173 · see citing works
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 165 · see citing works
Adipose Organ Development and Remodeling
Cinti, S. (2018) · Comprehensive physiology · doi:10.1002/cphy.c170042 · Cited by 187 · see citing works
Brown adipose tissue and its therapeutic potential
Lidell, M. E., Betz, M. J., & Enerbäck, S. (2014) · Journal of Internal Medicine · doi:10.1111/joim.12255 · Cited by 163 · see citing works
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 163 · see citing works
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 163 · see citing works
Fibroblast growth factor 21 and its novel association with oxidative stress
Gómez-Sámano, M. Á., Grajales-Gómez, M., Zuarth-Vázquez, J. M., Navarro-Flores, M. F., Martínez-Saavedra, M., Juárez-León, Ó. A., Morales-García, M., Enriquez-Estrada, V. M., Gomez-Perez, F. J., & Ramos, D. C. (2016) · Redox Biology · doi:10.1016/j.redox.2016.12.024 · Cited by 164 · see citing works
Free radicals and male reproduction.
Agarwal, A. K., & Allamaneni, S. S. R. (2011) · PubMed · Cited by 154 · see citing works
Insulin Resistance and Mitochondrial Dysfunction
González-Franquesa, A., & Patti, M. (2017) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-55330-6_25 · Cited by 154 · see citing works
Discrete 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 · see citing works
ATF2, a paradigm of the multifaceted regulation of transcription factors in biology and disease
Watson, G. W., Ronai, Z. A., & Lau, E. K. (2017) · Pharmacological Research · doi:10.1016/j.phrs.2017.02.004 · Cited by 154 · see citing works
FGF21: 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 · see citing works
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 · see citing works
Fibroblast 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 146 · see citing works
Self-citationZhang, T., Chen, J., Tang, X., Luo, Q., Xu, D., & Yu, B. (2019) · Lipids in Health and Disease · doi:10.1186/s12944-019-1170-9 · Cited by 149 · see citing works
Huang, 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 · see citing works
Kim, K. H., & Lee, M.-S. (2014) · Diabetes & Metabolism Journal · doi:10.4093/dmj.2014.38.4.245 · Cited by 146 · see citing works
The endocrine role of brown adipose tissue: An update on actors and actions
Gavaldà‐Navarro, A., Villarroya, J., Cereijo, R., Giralt, M., & Villarroya, F. (2021) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-021-09640-6 · Cited by 145 · see citing works
Self-citationLee, 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 · see citing works
Chen, W., Hoo, R. L. C., Konishi, M., Itoh, N., Lee, P.-C., Ye, H., Lam, K. S. L., & Xu, A. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.285965 · Cited by 141 · see citing works
Li, X. (2019) · Frontiers of Medicine · doi:10.1007/s11684-019-0711-y · Cited by 139 · see citing works
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 135 · see citing works
Sun, W., Dong, H., Becker, A. S., Dapito, D. H., Modica, S., Grandl, G., Opitz, L., Efthymiou, V., Straub, L. G., Sarker, G., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0102-y · Cited by 134 · see citing works
Serum FGF21 levels are associated with brown adipose tissue activity in humans
Hanssen, M. J. W., Broeders, E. P. M., Samms, R. J., Vosselman, M. J., van der Lans, A. A. J. J., Cheng, C., Adams, A. C., Lichtenbelt, W. D. V. M., & Schrauwen, P. (2015) · Scientific Reports · doi:10.1038/srep10275 · Cited by 131 · see citing works
Stress-induced FGF21 and GDF15 in obesity and obesity resistance
Keipert, S., & Ost, M. (2021) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2021.08.008 · Cited by 131 · see citing works
Interplay of skeletal muscle and adipose tissue: sarcopenic obesity.
Park, M., & Choi, K. M. (2023) · Metabolism: Clinical and Experimental · doi:10.1016/j.metabol.2023.155577 · Cited by 106 · see citing works
The Biological Role of Klotho Protein in the Development of Cardiovascular Diseases
Olejnik, A., Franczak, A., Krzywonos‐Zawadzka, A., Kałużna‐Oleksy, M., & Bil‐Lula, I. (2018) · BioMed Research International · doi:10.1155/2018/5171945 · Cited by 129 · see citing works
Brown adipocyte glucose metabolism: a heated subject
Hankir, M. K., & Klingenspor, M. (2018) · EMBO Reports · doi:10.15252/embr.201846404 · Cited by 124 · see citing works
- Authors
- Hondares, E., Iglesias, R., Giralt, A., Gonzalez, F. J., Giralt, M., Mampel, T., & Villarroya, F.
- Affiliations
- Centro de Investigación Biomédica en Red (ES)
- National Institutes of Health (US)
- Corresponding author
- Hondares, Elayne
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2011-04
- Volume
- 286
- Issue
- 15
- Pages
- 12983-12990
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3075644
- OpenAlex
- W1986602268
- Cited by
- 623
- References
- 32
- Citations by year
- 2026: 14 · 2025: 32 · 2024: 42 · 2023: 41 · 2022: 34 · 2021: 52 · 2020: 47 · 2019: 65 · 2018: 47 · 2017: 48 · 2016: 40 · 2015: 57 · 2014: 37 · 2013: 28 · 2012: 27
- FWCI
- 13.23
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- FGF21, brown adipose tissue, thermogenesis, cAMP signaling, protein kinase A, p38 MAPK, ATF2, norepinephrine, beta-adrenergic signaling, cold exposure, brown adipocytes
- MeSH terms
- Cyclic AMP, Animals, Adipose Tissue, Brown, Cells, Cultured, Cold Temperature, Endocrine Glands, Enzyme Activation, Fibroblast Growth Factors, Gene Expression Regulation, Male, Mice, Mutant Strains, Transcription, Genetic, Rats, Wistar, Cyclic AMP-Dependent Protein Kinases, Thermogenesis, p38 Mitogen-Activated Protein Kinases, Mice, Rats
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