The DOI matches its Crossref record; 38 of the 38 references it cites were found in a registry or an index.
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“and possibly mediates an hepatokine–myokine crosstalk via activation of PGC-1α [43]”
From The Role of Exercise in the Interplay between Myokines, Hepatokines, Osteokines, Adipokines, and Modulation of Inflammation for Energy Substrate Redistribution and Fat Mass Loss: A Review (2020) · cites this paper as [43]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“have also been described to induce WAT browning directly (6).”
From The Role of Exercise in the Interplay between Myokines, Hepatokines, Osteokines, Adipokines, and Modulation of Inflammation for Energy Substrate Redistribution and Fat Mass Loss: A Review (2020) · cites this paper as [43]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“In WAT, it induces lipolysis [166] and browning [43], likely via upregulation of PGC-1α [192].”
The check wasn’t confident either way, so it gives no verdict — never disputed.
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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
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
Cited by
Sorted by citations
Beige Adipocytes Are a Distinct Type of Thermogenic Fat Cell in Mouse and Human
Wu, J., Boström, P., Sparks, L. M., Li, Y., Choi, J. H., Giang, A.-H., Khandekar, M. J., Virtanen, K. A., Nuutila, P., Schaart, G., et al. (2012) · Cell · doi:10.1016/j.cell.2012.05.016 · Cited by 3,406
“Other polypeptide hormones that brown white adipose tissues in rodents, such as FGF21 (Fisher et al., 2012) and ANP (Bordicchia et al.”
BackgroundBrown and beige fat: Development, function and therapeutic potential
Harms, M., & Seale, P. (2013) · Nature Medicine · doi:10.1038/nm.3361 · Cited by 2,328
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
Adipose tissue browning and metabolic health
Bartelt, A., & Heeren, J. (2014) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2013.204 · Cited by 1,177
Adipokines in health and disease
Fasshauer, M., & Blüher, M. (2015) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2015.04.014 · Cited by 1,050
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
Brown and Beige Fat: Physiological Roles beyond Heat Generation
Kajimura, S., Spiegelman, B. M., & Seale, P. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.09.007 · Cited by 1,028
Rao, R. R., Long, J. Z., White, J. P., Svensson, K. J., Lou, J., Lokurkar, I., Jedrychowski, M. P., Ruas, J. L., Wrann, C. D., Lo, J. C., et al. (2014) · Cell · doi:10.1016/j.cell.2014.03.065 · Cited by 973
“This mechanism distinguishes Metrnl from other known polypeptide inducers of thermogenesis, such as Irisin and Fgf-21, which both act directly on adipocytes to stimulate thermogenesis (Boström et al., 2012; Fisher et al., 2012; Zhang et al., 2013).”
BackgroundMethodUnderstanding 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
Exerkines in health, resilience and disease
Chow, L. S., Gerszten, R. E., Taylor, J. M., Pedersen, B. K., van Praag, H., Trappe, S., Febbraio, M. A., Galis, Z. S., Gao, Y., Haus, J. M., et al. (2022) · Nature Reviews Endocrinology · doi:10.1038/s41574-022-00641-2 · Cited by 927
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
“FGF21 improves the expression of UCP1 in WAT by upregulating PGC-1α protein level and promoting browning of WAT in adaptive thermogenesis.(559,566) FGF21 knockout mice show diminished browning of WAT and a decreased adaption to chronic cold exposure.”
BackgroundThe effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes
Gaich, G., Chien, J. Y., Fu, H., Glass, L. C., Deeg, M. A., Holland, W. L., Kharitonenkov, A., Bumol, T., Schilske, H. K., & Moller, D. E. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.08.005 · Cited by 885
“, 2005), reduced hepatic lipogenesis, and the induction of energy expenditure via brown fat activation (Coskun et al., 2008; Fisher et al., 2012; Kharitonenkov et al., 2005).”
BackgroundA review of clinical photoacoustic imaging: Current and future trends
Attia, A. B. E., Balasundaram, G., Moothanchery, M., Dinish, U. S., Bi, R., Ntziachristos, V., & Olivo, M. (2019) · Photoacoustics · doi:10.1016/j.pacs.2019.100144 · Cited by 895
Cohen, P., Levy, J. D., Zhang, Y., Frontini, A., Kolodin, D., Svensson, K. J., Lo, J. C., Zeng, X., Ye, L., Khandekar, M. J., et al. (2014) · Cell · doi:10.1016/j.cell.2013.12.021 · Cited by 891
“Cells from Adipo-PRDM16 KO mice also showed a blunted response to stimuli that induce browning, such as isoproterenol and FGF21 (Figures S2F ad S2G) (Fisher et al., 2012; Wu et al., 2013).”
BackgroundAdaptive thermogenesis in adipocytes: Is beige the new brown?
Wu, J., Cohen, P., & Spiegelman, B. M. (2013) · Genes & Development · doi:10.1101/gad.211649.112 · Cited by 828
“More recently, FGF21 has been shown to play a role in adaptive thermogenesis in both BATs and WATs (Hondares et al. 2010; Fisher et al. 2012).”
BackgroundInfluentialBrown Remodeling of White Adipose Tissue by SirT1-Dependent Deacetylation of Pparγ
Qiang, L., Wang, L., Kon, N., Zhao, W., Lee, S., Zhang, Y., ROSENBAUM, M. S., Zhao, Y., Gu, W. J., Farmer, S. R., et al. (2012) · Cell · doi:10.1016/j.cell.2012.06.027 · Cited by 816
“, 2005) are insulin-sensitizers with browning properties (Fisher et al., 2012; Vernochet et al., 2009) that promote Pparg sumoylation.”
Kim, K. H., Jeong, Y. T., Oh, H., Kim, S. H., Cho, J. M., Kim, Y.-N., Kim, S. S., Kim, D. H., Hur, K. Y., Kim, H. K., et al. (2013) · Nature Medicine · doi:10.1038/nm.3014 · Cited by 774
Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance
Fang, S., Suh, J. M., Reilly, S. M., Yu, E., Osborn, O., Lackey, D., Yoshihara, E., Perino, A., Jacinto, S., Lukasheva, Y., et al. (2015) · Nature Medicine · doi:10.1038/nm.3760 · Cited by 738
Targeting adipose tissue in the treatment of obesity-associated diabetes
Kusminski, C. M., Bickel, P. E., & Scherer, P. E. (2016) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.75 · Cited by 678
Adipose tissue in control of metabolism
Luo, L., & Liu, M. (2016) · Journal of Endocrinology · doi:10.1530/joe-16-0211 · Cited by 764
“Consistent with this, PGC1α is upregulated by FGF21 and mediates the prompting effect of FGF21 on browning of WAT (Fisher et al. 2012).”
BackgroundBrown and beige fat in humans: thermogenic adipocytes that control energy and glucose homeostasis
Sidossis, L. S., & Kajimura, S. (2015) · Journal of Clinical Investigation · doi:10.1172/jci78362 · Cited by 715
“As listed in Figure 3, such factors include BMP4 (66), BMP7 (67, 68), BMP8b (69), FGF19 (70, 71), FGF21 (72, 73), growth differentiation fac-tor-5 (GDF5) (74), natriuretic peptides (75), prostaglandins (76, 77), VEGF (78, 79), and β -aminoisobutyric acid (BAIBA) (80).”
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
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 697
Human BAT Possesses Molecular Signatures That Resemble Beige/Brite Cells
Sharp, L. Z., Shinoda, K., Ohno, H., Scheel, D. W., Tomoda, E., Ruiz, L., Hu, H., Wang, L. L., Pavlova, Z., Gilsanz, V., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0049452 · Cited by 652
“Alternatively, using endogenous hormones such as FGF21 [49], natriuretic peptides [50], prostaglandin [51,52], or Irisin [53] to promote browning of white fat would be a plausible approach.”
BackgroundThe therapeutic potential of FGF21 in metabolic diseases: from bench to clinic
Geng, L., Lam, K. S. L., & Xu, A. (2020) · Nature Reviews Endocrinology · doi:10.1038/s41574-020-0386-0 · Cited by 607
FGF21 is an endocrine signal of protein restriction
Laeger, T., Henagan, T. M., Albarado, D. C., Redman, L. M., Bray, G. A., Noland, R. C., Münzberg, H., Hutson, S. M., Gettys, T. W., Schwartz, M. W., et al. (2014) · Journal of Clinical Investigation · doi:10.1172/jci74915 · Cited by 593
White, Brown, Beige/Brite: Different Adipose Cells for Different Functions?
Giralt, M., & Villarroya, F. (2013) · Endocrinology · doi:10.1210/en.2013-1403 · Cited by 586
The cellular and functional complexity of thermogenic fat
Cohen, P., & Kajimura, S. (2021) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-021-00350-0 · Cited by 572
The Common and Distinct Features of Brown and Beige Adipocytes
Ikeda, K., Maretich, P., & Kajimura, S. (2018) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2018.01.001 · Cited by 564
“Of note, FGF21 increases intracellular Ca levels in adipocytes [79] and induces browning in a cell-autonomous fashion [80] – even though recent studies have reported that the pharmacological action of FGF21 on body weight and glucose metabolism is UCP1-independent [81,82], and that neither FGF21 nor UCP1 is required f…”
Hu, M. C., Shiizaki, K., Kuro-o, M., & Moe, O. W. (2013) · Annual Review of Physiology · doi:10.1146/annurev-physiol-030212-183727 · Cited by 587
FGF21 acts centrally to induce sympathetic nerve activity, energy expenditure, and weight loss
Owen, B. M., Ding, X., Morgan, D. A., Coate, K. C., Bookout, A. L., Rahmouni, K., Kliewer, S. A., & Mangelsdorf, D. J. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.07.012 · Cited by 523
“FGF21 also promotes the browning of scWAT (Fisher et al., 2012), an effect that in vivo involves bKlotho in the nervous system.”
InfluentialImmune Regulation of Metabolic Homeostasis in Health and Disease
Brestoff, J. R., & Artis, D. (2015) · Cell · doi:10.1016/j.cell.2015.02.022 · Cited by 510
“, 2011), fibroblast growth factor 21 (FGF21) (Fisher et al., 2012), irisin (Wu et al.”
The Browning of White Adipose Tissue: Some Burning Issues
Nedergaard, J., & Cannon, B. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.07.005 · Cited by 509
“There are indications that, for example, FGF21 KO leads to both a revef/anapyrexia and a diminished browning (Fisher et al., 2012), which may thus be understandable as a consequence of the revef.”
BackgroundXu, L., Nagata, N., Nagashimada, M., Zhuge, F., Ni, Y., Chen, G., Mayoux, E., Kaneko, S., & Ota, T. (2017) · EBioMedicine · doi:10.1016/j.ebiom.2017.05.028 · Cited by 512
“FGF21 also activates the β3-adrenergic receptor inWAT and regulates the recruitment of beige adipocytes (Fisher et al., 2012).”
BackgroundTalukdar, S., Zhou, Y., Li, D., Rossulek, M., Dong, J., Somayaji, V., Weng, Y., Clark, R., Lanba, A., Owen, B. M., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.02.001 · Cited by 496
“In rodents, FGF21 treatment induces a ‘‘browning’’ response in white adipose tissue (WAT) depots that is characterized by induction of the genes encoding mitochondrial uncoupling protein 1 (UCP1) and type II iodothyronine deiodinase (Dio2) (Fisher et al., 2012).”
BackgroundMitochondrial Uncoupling: A Key Controller of Biological Processes in Physiology and Diseases
Demine, S., Renard, P., & Arnould, T. (2019) · Cells · doi:10.3390/cells8080795 · Cited by 476
Estradiol Regulates Brown Adipose Tissue Thermogenesis via Hypothalamic AMPK
de Morentin, P. B. M., González‐García, I., Martins, L., Lage, R., Fernández-Mallo, D., Martínez‐Sánchez, N., Ruíz-Pino, F., Liu, J. T., Morgan, D. A., Pinilla, L., et al. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.03.031 · Cited by 455
“SC administration of E2 increased the mRNA expression or protein content of thermogenic markers, such as uncoupling protein-1 (UCP1), peroxisome-proliferator-activated receptor-gamma coactivator 1 alpha (PGC1a) and beta (PGC1b) in the BAT (Figures 2C and 2D), while no changes in browning markers (Waldén et al., 2012;…”
BackgroundKajimura, S., & Saito, M. (2013) · Annual Review of Physiology · doi:10.1146/annurev-physiol-021113-170252 · Cited by 439
“FGF-21 also induces beige/brite cell differentiation in WAT by enhancing adipose tissue PGC-1α protein levels (114).”
InfluentialTherapeutic 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
Signaling pathways in obesity: mechanisms and therapeutic interventions
Wen, X., Zhang, B., Wu, B., Xiao, H., Li, Z., Li, R., Xu, X., & Li, T. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01149-x · Cited by 490
“Several lines of evidence have proven that FGF21 administration promotes energy expenditure and losses weight through PGC-1α and CCL11 mediated WAT browning(621) and central thermogenic hormones-mediated BAT activation.(622) Furthermore, central infusion of FGF21 in lean rats activates the hypothalamic-pituitarythyroi…”
BackgroundPeirce, V. J., Carobbio, S., & Vidal‐Puig, A. (2014) · Nature · doi:10.1038/nature13477 · Cited by 430
Villena, J. A. (2014) · FEBS Journal · doi:10.1111/febs.13175 · Cited by 413
βKlotho Is Required for Fibroblast Growth Factor 21 Effects on Growth and Metabolism
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
Brown-fat paucity due to impaired BMP signalling induces compensatory browning of white fat
Schulz, T. J., Huang, P. C., Huang, T. L., Xue, R., McDougall, L. E., Townsend, K. L., Cypess, A. M., Mishina, Y. M., Gussoni, E., & Tseng, Y. (2013) · Nature · doi:10.1038/nature11943 · Cited by 389
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 404
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
Cinti, S. (2012) · Disease Models & Mechanisms · doi:10.1242/dmm.009662 · Cited by 370
“, 2011) • Activation of the growth factor FGF21 (Hondares et al., 2010; Fisher et al., 2012) • Induction of myokine irisin (Boström et al.”
BackgroundLu, Q., Zhu, Y., Deng, C., Liang, Z., Chen, J., Chen, Y., Wang, X., Liu, Y., Tian, Y., & Yang, Y. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01756-w · Cited by 391
Transcriptional and epigenetic control of brown and beige adipose cell fate and function
Inagaki, T., Sakai, J., & Kajimura, S. (2016) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2016.62 · Cited by 347
Restoration of metabolic health by decreased consumption of branched‐chain amino acids
Richardson, N. E., Williams, E. M., Kasza, I., Konon, E. N., Schaid, M. D., Schmidt, B., Poudel, C., Sherman, D. S., Yu, D., Apelo, S. I. A., et al. (2017) · The Journal of Physiology · doi:10.1113/jp275075 · Cited by 348
“A more dramatic difference is observed between mice fed these two diets with regard to the hormone FGF21, which has pleiotropic effects on glucose metabolism and energy expenditure (Berglund et al. 2009; Fisher et al. 2012; Emanuelli et al. 2014; Laeger et al. 2014, 2016; Markan et al. 2014; Owen et al. 2014; Stone et…”
BackgroundInfluentialBeyond adiponectin and leptin: adipose tissue-derived mediators of inter-organ communication
Funcke, J., & Scherer, P. E. (2019) · Journal of Lipid Research · doi:10.1194/jlr.r094060 · Cited by 357
Brown 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 343
FGF21 gene therapy as treatment for obesity and insulin resistance
Jiménez, V., Jambrina, C., Casana, E., Sacristan, V., MUÑOZ, S. A., Darriba, S., Rodó, J., Mallol, C., García, M., León, X., et al. (2018) · EMBO Molecular Medicine · doi:10.15252/emmm.201708791 · Cited by 319
“An FGF21-mediated induction of UCP1 has also been described for iWAT (Hondares et al, 2010; Adams et al, 2012a,b; Fisher et al, 2012; Emanuelli et al, 2014; Douris et al, 2015).”
BackgroundShan, T., Liang, X., Bi, P., & Kuang, S. (2013) · The FASEB Journal · doi:10.1096/fj.12-225755 · Cited by 301
Adipo-myokines: two sides of the same coin–mediators of inflammation and mediators of exercise
Raschke, S., & Eckel, J. (2013) · Mediators of Inflammation · doi:10.1155/2013/320724 · Cited by 296
Myokines and Adipokines: Involvement in the Crosstalk between Skeletal Muscle and Adipose Tissue
Li, F., Li, Y., Duan, Y., Hu, C.-A. A., Tang, Y., & Yin, Y. (2017) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2016.10.003 · Cited by 288
Development of insulin resistance in mice lacking PGC-1α in adipose tissues
Kleiner, S., Mepani, R. J., Laznik, D., Li, Y., Jurczak, M. J., Jornayvaz, F. R., Estall, J. L., Bhowmick, D. C., Shulman, G. I., & Spiegelman, B. M. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1207287109 · Cited by 291
“Isolation of adipose SV fraction and differentiation of primary adipocytes was done as described previously (50).”
MethodTissue-specific actions of the metabolic hormones FGF15/19 and FGF21
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
O-GlcNAc Transferase Enables AgRP Neurons to Suppress Browning of White Fat
Ruan, H.-B., Dietrich, M. O., Liu, Z.-W., Zimmer, M. R., Li, M.-D., Singh, J. P., Zhang, K., Yin, R., Wu, J., Horvath, T. L., et al. (2014) · Cell · doi:10.1016/j.cell.2014.09.010 · Cited by 281
“Four adipose depots including classic BAT, gonadal WAT (gWAT), and two major depots that have the potential of browning—retroperitoneal and inguinal WAT (rWAT and iWAT)—from ad libitum fed and 24 hr-fasted mice were collected (Fisher et al., 2012; Guerra et al., 1998; Nedergaard and Cannon, 2013).”
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 286
Giordano, A., Smorlesi, A., Frontini, A., Barbatelli, G., & Cinti, S. (2014) · European Journal of Endocrinology · doi:10.1530/eje-13-0945 · Cited by 298
Li, Y., Wong, K., Giles, A. J., Jiang, J., Lee, J. W., Adams, A. C., Kharitonenkov, A., Yang, Q., Gao, B., Guarente, L., et al. (2013) · Gastroenterology · doi:10.1053/j.gastro.2013.10.059 · Cited by 283
Gonzalez-Gil, A. M., & Elizondo-Montemayor, L. (2020) · Nutrients · doi:10.3390/nu12061899 · Cited by 278
“Myokines myostatin↔ irisin [44,49] METRNL→ ↑irisin, BAIBA* [92,100] FGF21→ ↑irisin* [43] follistatin→ ↓myostatin [184] SeP→ ↓adiponectin [136], ↓irisin, BAIBA, METRNL (via ↓PGC-1α due to ↓OS)* [50] irisin→ ↑adiponectin [51], ?↓leptin [54,55] IL-15→↑adiponectin [86] BAIBA→ ↑leptin [109] irisin→ ↓TNF-α, IL-1β, IL-6, MCP…”
BackgroundInfluentialA 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
The Ever-Expanding Myokinome: Discovery Challenges and Therapeutic Implications
Whitham, M., & Febbraio, M. A. (2016) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.153 · Cited by 279
Lee, J. H., Park, A., Oh, K., Lee, S. C., Kim, W. K., & Bae, K. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20194924 · Cited by 280
“Furthermore, fibroblast growth factor 21 (FGF21) potentiates cold-induced thermogenesis by promoting thermogenic gene expression and WAT browning [130].”
BackgroundUCP1 Dependent and Independent Thermogenesis in Brown and Beige Adipocytes
Ikeda, K., & Yamada, T. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.00498 · Cited by 294
Distinction of white, beige and brown adipocytes derived from mesenchymal stem cells
Park, A. (2014) · World Journal of Stem Cells · doi:10.4252/wjsc.v6.i1.33 · Cited by 291
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
Lin, Z., Pan, X., Wu, F., Ye, D., Zhang, Y., Wang, Y., Jin, L., Lian, Q., Huang, Y., Ding, H., et al. (2015) · Circulation · doi:10.1161/circulationaha.115.015308 · Cited by 271
Inhibition of Notch signaling promotes browning of white adipose tissue and ameliorates obesity
Bi, P., Shan, T., Liu, W., Yue, F., Yang, X., Liang, X.-R., Wang, J., Li, J., Carlesso, N., Liu, X., et al. (2014) · Nature Medicine · doi:10.1038/nm.3615 · Cited by 271
The breadth of FGF21's metabolic actions are governed by FGFR1 in adipose tissue
Adams, A. C., Yang, C., Coskun, T., Cheng, C. C., Gimeno, R. E., Luo, Y., & Kharitonenkov, A. (2013) · Molecular Metabolism · doi:10.1016/j.molmet.2012.08.007 · Cited by 266
Adipocyte lineages: Tracing back the origins of fat
Sánchez-Gurmaches, J., & Guertin, D. A. (2013) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2013.05.027 · Cited by 277
Vernochet, C., Mourier, A., Bezy, O., Macotela, Y., Boucher, J., Rardin, M. J., An, D., Lee, K. Y., Ilkayeva, O. R., Zingaretti, C. M., et al. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.10.016 · Cited by 245
“Strategies to combat obesity and improve insulin sensitivity include increasing BAT mass and/or activity and ‘‘browning’’ of white adipose tissue (Cao et al., 2011; Boström et al., 2012; Fisher et al., 2012; Bordicchia et al., 2012; Vernochet et al., 2010).”
BackgroundLan, T., Morgan, D. A., Rahmouni, K., Sonoda, J., Fu, X., Burgess, S. C., Holland, W. L., Kliewer, S. A., & Mangelsdorf, D. J. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.09.005 · Cited by 261
“FGF21 also acts directly on adipocytes to stimulate glucose uptake, thermogenic gene expression and adiponectin secretion (Fisher et al., 2012; Holland et al., 2013; Hondares et al., 2010; Kharitonenkov et al., 2005; Lin et al., 2013).”
BackgroundFisher, F. M., Chui, P. C., Nasser, I. A., Popov, Y., Cunniff, J. C., Lundasen, T., Kharitonenkov, A., Schuppan, D., Flier, J. S., & Maratos-Flier, E. (2014) · Gastroenterology · doi:10.1053/j.gastro.2014.07.044 · Cited by 263
Schlein, C., Talukdar, S., Heine, M., Fischer, A. W., Krott, L. M., Nilsson, S. K., Brenner, M. B., Heeren, J., & Scheja, L. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.01.006 · Cited by 252
“This demonstrates that an impact of FGF21 on TRL metabolism does not require long-term adaptations such as browning of WAT (Fisher et al., 2012).”
BackgroundResultInterplay between FGF21 and insulin action in the liver regulates metabolism
Emanuelli, B., Vienberg, S. G., Smyth, G., Cheng, C., Stanford, K. I., Arumugam, M., Michael, M. D., Adams, A. C., Kharitonenkov, A., & Kahn, C. R. (2014) · Journal of Clinical Investigation · doi:10.1172/jci67353 · Cited by 251
“Similar results were reported earlier (33).”
Curcumin induces brown fat-like phenotype in 3T3-L1 and primary white adipocytes
Lone, J. B., Choi, J. H., Kim, S. W., & Yun, J. W. (2015) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2015.09.006 · Cited by 246
“More recent studies identified novel brite-specific markers such as PRDM16 that have been targeted for identification of brown fat-stimulating agents [16,17].”
BackgroundBrown 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 240
Convertible visceral fat as a therapeutic target to curb obesity
Giordano, A., Frontini, A., & Cinti, S. (2016) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.31 · Cited by 241
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 233
Brown adipose tissue and thermogenesis
Fenzl, A., & Kiefer, F. W. (2014) · Hormone Molecular Biology and Clinical Investigation · doi:10.1515/hmbci-2014-0022 · Cited by 239
“Accumulating evidence suggests an important role for FGF21 in the activation of BAT thermogenesis and browning of WAT upon cold exposure involving PGC1α-dependent mechanisms [50, 120, 123].”
BackgroundPerivascular adipose tissue (PVAT) in atherosclerosis: a double-edged sword
Qi, X.-Y., Qu, S.-L., Xiong, W., Rom, O., Chang, L., & Jiang, Z. (2018) · Cardiovascular Diabetology · doi:10.1186/s12933-018-0777-x · Cited by 239
SGLT2 inhibition reprograms systemic metabolism via FGF21-dependent and -independent mechanisms
Osataphan, S. A., Macchi, C., Singhal, G., CHIMENE-WEISS, J. I., Sales, V., Kozuka, C., Dreyfuss, J. M., Pan, H., Tangcharoenpaisan, Y., Morningstar, J. E., et al. (2019) · JCI Insight · doi:10.1172/jci.insight.123130 · Cited by 232
An adipocentric perspective on the development and progression of non-alcoholic fatty liver disease
Lee, E., Korf, H., & Vidal‐Puig, A. (2023) · Journal of Hepatology · doi:10.1016/j.jhep.2023.01.024 · Cited by 235
Keipert, S., Ost, M., Johann, K., Imber, F., Jastroch, M., van Schothorst, E. M., Keijer, J., & Klaus, S. (2014) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00330.2013 · Cited by 221
“At confluence, differentiation was started using a white fat differentiation cocktail as described previously (19) containing growth medium with 1 M dexamethasone, 0.”
BackgroundMethodGut-Derived Serotonin Is a Multifunctional Determinant to Fasting Adaptation
Sumara, G., Sumara, O., Kim, J. K., & Karsenty, G. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.09.014 · Cited by 236
“Circulating levels of insulin and leptin were normal in fed and fasted Tph1gutD/D mice (Figures S2D and S2E), and there was no evidence of transformation of white fat into brown fat in Tph1gutD/D mice as reported for FGF21-deficient animals (Fisher et al., 2012) (Figure S2C).”
BackgroundDoğan, Ş. A., Pujol, C., Maiti, P., Kukat, A., Wang, S., Hermans, S., Senft, K., Wibom, R., Rugarli, E. I., & Trifunović, A. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.02.004 · Cited by 222
“High amounts of FGF21 are most likely responsible for the upregulation of steady-state PGC-1a levels, given that we detected no changes in Pgc-1a transcripts (Figure S4F), in agreement with the previous reports showing that FGF21 mediates PGC-1a stabilization without affecting the expression of this protein (Fisher et…”
ResultJeremic, N., Chaturvedi, P., & Tyagi, S. C. (2017) · Journal of Cellular Physiology · doi:10.1002/jcp.25450 · Cited by 211
“They showed clear function for FGF21 in regulating chronic adaptive thermogenesis by increasing the transcription of thermogenic genes and enhancing the thermogenic capacity of the organism by “browning” white fat (Fisher et al., 2012).”
BackgroundMachado, S. A., Pasquarelli-do-Nascimento, G., da Silva, D. S., Farias, G. R., Santos, I. D. O., Baptista, L. B., & Magalhães, K. G. (2022) · Nutrition & Metabolism · doi:10.1186/s12986-022-00694-0 · Cited by 239
“The action of FGF21 in WAT includes paracrine and autocrine actions and is mediated through the induction of PGC-1α protein in cold and through the enhanced levels of the thermogenic protein UCP1, which is a key protein for heat production [174].”
BackgroundFibroblast 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
“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).”
BackgroundResultAdipose tissue plasticity from WAT to BAT and in between
Lee, Y., Mottillo, E. P., & Granneman, J. G. (2013) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2013.05.011 · Cited by 236
“Fibroblast growth factor 21 (FGF21) has been suggested to drive BAT-dependent thermogenesis after birth [237] and contribute to browning of white fat in adults [238, 239].”
BackgroundThe Immune System as a Sensor of the Metabolic State
Odegaard, J. I., & Chawla, A. (2013) · Immunity · doi:10.1016/j.immuni.2013.04.001 · Cited by 219
“…adrenergic signaling might activate long-term adaptations in white adipose tissue in addition to short-term thermogenic responses, possibly via fibroblast growth factor 21 signaling, which was recently implicated in cold-induced browning of white adipocytes (Fisher et al., 2012).”
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
Self-citationWhite-to-brown transdifferentiation of omental adipocytes in patients affected by pheochromocytoma
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 218
Browning of white fat: agents and implications for beige adipose tissue to type 2 diabetes
Kaisanlahti, A., & Glumoff, T. (2018) · Journal of Physiology and Biochemistry · doi:10.1007/s13105-018-0658-5 · Cited by 224
“Fisher et al. demonstrated that in addition to having ameliorating effect on classical BAT and metabolism, FGF21 expression is also necessary for the coldinduced recruitment of beige adipocytes in WAT.”
BackgroundInfluentialTillman, E. J., & Rolph, T. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.601290 · Cited by 214
Defining the Nutritional and Metabolic Context of FGF21 Using the Geometric Framework
Solon-Biet, S. M., Cogger, V. C., Pulpitel, T., Heblinski, M., Wahl, D., McMahon, A. C., Warren, A., Durrant-Whyte, J., Walters, K. A., Krycer, J. R., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.09.001 · Cited by 212
“Consistent with these results, recent evidence has shown that FGF21 increases expression of UCP1 in adipose tissue to induce thermogenesis (Fisher et al., 2012) and can explain the suppression of hepatic gluconeogenesis (Sarruf et al., 2010; Xu et al., 2009) in this condition.”
FGF21 and the late adaptive response to starvation in humans
Fazeli, P. K., Lun, M., Kim, S. M., Bredella, M. A., Wright, S., Zhang, Y., Lee, H., Catana, C., Klibanski, A., Patwari, P., et al. (2015) · Journal of Clinical Investigation · doi:10.1172/jci83349 · Cited by 214
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
