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
Flagged first, then by citations
Cited by
Sorted by citations
Items 301–400 of 1,000
Henriksson, E., & Andersen, B. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.601349 · Cited by 97
“Moreover, FGF21treated mice are hyperphagic to overcome the increase in EE and the mice prefer protein over carbohydrate (69, 70).”
BackgroundLiver Derived FGF21 Maintains Core Body Temperature During Acute Cold Exposure
Ameka, M., Markan, K. R., Morgan, D. A., BonDurant, L. D., Idiga, S. O., Naber, M. C., Zhu, Z., Zingman, L. V., Grobe, J. L., Rahmouni, K., et al. (2019) · Scientific Reports · doi:10.1038/s41598-018-37198-y · Cited by 93
miRNA-32 Drives Brown Fat Thermogenesis and Trans-activates Subcutaneous White Fat Browning in Mice
Ng, R., Hussain, N. A., Zhang, Q., Chang, C. T., Li, H., Fu, Y., Cao, L., Han, W., Stünkel, W., & Xu, F. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.04.035 · Cited by 93
“In recent years, FGF21 has emerged as an important browning factor secreted by BAT and other tissues that has pleotropic effects on multiple tissues including browning of iWAT (Chartoumpekis et al., 2011; Fisher et al., 2012; Hondares et al., 2011; Owen et al., 2014).”
BackgroundResultInfluentialGong, X.-M., Li, Y., Luo, J., Wang, J., Wei, J. N., Wang, J.-Q., Xiao, T., Xie, C., Hong, J., Ning, G., et al. (2019) · Nature Metabolism · doi:10.1038/s42255-019-0065-4 · Cited by 93
Ziętak, M., & Kozak, L. P. (2015) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00485.2015 · Cited by 97
Thermogenic brown and beige/brite adipogenesis in humans
Cereijo, R., Giralt, M., & Villarroya, F. (2014) · Annals of Medicine · doi:10.3109/07853890.2014.952328 · Cited by 95
Activation and recruitment of brown adipose tissue as anti-obesity regimens in humans
Yoneshiro, T., & Saito, M. (2014) · Annals of Medicine · doi:10.3109/07853890.2014.911595 · Cited by 94
Hampton, M. E., Melvin, R. G., & Andrews, M. T. (2013) · PLoS ONE · doi:10.1371/journal.pone.0085157 · Cited by 91
FGF23-αKlotho as a paradigm for a kidney-bone network
Kuro‐o, M., & Moe, O. W. (2016) · Bone · doi:10.1016/j.bone.2016.11.013 · Cited by 93
“In white adipose tissue, FGF21 promotes lipolysis, mitochondrial respiration, and “browning” of white adipose for thermogenesis [63, 65-67].”
BackgroundAdipokines and the Endocrine Role of Adipose Tissues
Giralt, M., Cereijo, R., & Villarroya, F. (2015) · Handbook of experimental pharmacology · doi:10.1007/164_2015_6 · Cited by 97
Brown adipose tissue: Updates in cellular and molecular biology
Bargut, T. C. L., Águila, M. B., & Mandarim‐de‐Lacerda, C. A. (2016) · Tissue and Cell · doi:10.1016/j.tice.2016.08.001 · Cited by 96
“PPARgamma, in turn, is transcriptionally regulated by FGF21, creating a positive looping (Fisher et al., 2012; Wang et al., 2008).”
BackgroundKovacova, Z., Tharp, W. G., Liu, D., Wei, W., Xie, H., Collins, S., & Pratley, R. E. (2016) · Obesity · doi:10.1002/oby.21418 · Cited by 85
Brown adipose tissue as an anti‐obesity tissue in humans
Chechi, K., Nedergaard, J., & Richard, D. (2013) · Obesity Reviews · doi:10.1111/obr.12116 · Cited by 98
Hondares, E., Gallego-Escuredo, J. M., Flachs, P., Frontini, A., Cereijo, R., Goday, A., Perugini, J., Kopecky, P., Giralt, M., Cinti, S., et al. (2013) · Metabolism · doi:10.1016/j.metabol.2013.11.014 · Cited by 90
“[4] Fisher FM, Kleiner S, Douris N, et al.”
BackgroundChrysin induces brown fat–like phenotype and enhances lipid metabolism in 3T3-L1 adipocytes
Choi, J. H., & Yun, J. W. (2016) · Nutrition · doi:10.1016/j.nut.2016.02.007 · Cited by 92
“Recent 248 studies identified novel BAT-specific markers such as PRDM16 that have been targeted for 249 identification of brown fat-stimulating agents [42, 3].”
BackgroundThe clinical potential of adipogenesis and obesity-related microRNAs
Zaiou, M., Amri, H. E., & Bakillah, A. (2017) · Nutrition Metabolism and Cardiovascular Diseases · doi:10.1016/j.numecd.2017.10.015 · Cited by 92
Khalafi, M., Mohebbi, H., Symonds, M. E., Karimi, P., Akbari, A. M., Tabari, E., Faridnia, M., & Moghaddami, K. (2020) · Nutrients · doi:10.3390/nu12040925 · Cited by 96
“FGF-21 can promote browning [25,48] through enhanced PPAR-γ activity [49] and can have an autocrine/paracrine effect on PGC-1α in AT [48].”
BackgroundGarcía-Ruiz, E., Reynés, B., Díaz‐Rúa, R., Ceresi, E., Oliver, P., & Palou, A. (2015) · International Journal of Obesity · doi:10.1038/ijo.2015.112 · Cited by 92
Regulation of metabolic health by essential dietary amino acids
Green, C. L., & Lamming, D. W. (2018) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2018.07.004 · Cited by 91
“It is believed that this effect is due to the normal physiological role of FGF21 in adaptive thermogenesis; FGF21 mRNA is strongly induced in brown (BAT) and white adipose tissue (WAT) in response to cold exposure, and promotes the browning or beiging of white adipose tissue (Fisher et al., 2012).”
BackgroundRho-kinase/AMPK axis regulates hepatic lipogenesis during overnutrition
Hu, H., Lee, S., Sousa‐Lima, I., Kim, S. S., Hwang, W. M., Dagon, Y., Yang, W.-M., Cho, S., Kang, M., Seo, J. A., et al. (2018) · Journal of Clinical Investigation · doi:10.1172/jci63562 · Cited by 95
“Among hepatokines, FGF21 is shown to be involved in the regulation of energy metabolism by inducing thermogenic gene expression and a brown fat-like phenotype in white adipocytes (28, 29).”
Bhattacharya, A., Sun, S., Wang, H., Liu, M. R., Long, Q., Yin, L., Kersten, S., Zhang, K., & Qi, L. (2018) · The EMBO Journal · doi:10.15252/embj.201899277 · Cited by 88
“Moreover, similar to Fgf21 gain-of-function mouse models (Inagaki et al , 2007; Kharitonenkov et al , 2005; Owen et al , 2014) Fgf21 is known to affect white adipose tissue browning (BonDurant et al , 2017; Fisher et al , 2012; Hondares et al , 2010; Owen et al , 2014; Park et al , 2016a).”
The Impact of the Adipose Organ Plasticity on Inflammation and Cancer Progression
Corrêa, L. H., Cardoso, G. S. H. R., & Magalhães, K. G. (2019) · Cells · doi:10.3390/cells8070662 · Cited by 98
“This regulation is due to the increase of adipose tissue PGC-1α protein levels [36].”
BackgroundPPARγ and PPARα synergize to induce robust browning of white fat in vivo
Kroon, T., Harms, M., Maurer, S., Bonnet, L., Alexandersson, I., Lindblom, A., Ahnmark, A., Nilsson, D., Gennemark, P., O’Mahony, G., et al. (2020) · Molecular Metabolism · doi:10.1016/j.molmet.2020.02.007 · Cited by 92
“The liver is the main site of FGF21 production and it is transcriptionally induced in response to fasting and PPARa activation [38] and pharmacological FGF21 treatment has been shown to induce browning of white fat [41,42].”
BackgroundSearching for the link between inflammaging and sarcopenia
Wang, T. (2022) · Ageing Research Reviews · doi:10.1016/j.arr.2022.101611 · Cited by 90
Jiang, Z., Cowell, R. M., & Nakazawa, K. (2013) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2013.00116 · Cited by 91
Gerhard, G. S., Styer, A. M., Strodel, W. E., Roesch, S. L., Yavorek, A., Carey, D. J., Wood, G. C., Petrick, A. T., Gabrielsen, J. D., Ibele, A. R., et al. (2013) · International Journal of Obesity · doi:10.1038/ijo.2013.152 · Cited by 89
Fibroblast Growth Factor 21 and the Adaptive Response to Nutritional Challenges
Martínez‐Garza, Ú., Torres‐Oteros, D., Yarritu, A., Marrero, P. F., Haro, D., & Relat, J. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20194692 · Cited by 88
Wanders, D., Burk, D. H., Cortez, C. C., Van, N. T., Stone, K. P., Baker, M., Mendoza, T. M., Mynatt, R. L., & Gettys, T. W. (2015) · The FASEB Journal · doi:10.1096/fj.14-270348 · Cited by 88
“On the basis of recent studies showing that FGF21 is also involved in browning of WAT (28) while acting centrally to regulate SNSactivity (39), thehigher levels of FGF21(basal andMR induced) may be important to retention of the insulin sensitizing effects of MR in Ucp1 mice.”
BackgroundHe, M. X., Zhang, Q., Deng, C., Wang, H., Lian, J., & Huang, X. (2014) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2014.01.018 · Cited by 93
“Additionally, future studies on the effect of olanzapine on browning markers on white adipose tissue would be helpful (Fisher et al., 2012).”
BackgroundGonçalves, L. F., Machado, T. Q., Castro‐Pinheiro, C., de Souza, N. G., Oliveira, K. J., & Fernandes‐Santos, C. (2017) · International Journal of Experimental Pathology · doi:10.1111/iep.12228 · Cited by 88
“Fibroblast growth factor 21 (FGF21) acts in an autocrine/paracrine manner to increase UCP1 and PGC-1a thus promoting BAT thermogenesis and WAT browning (Fisher et al. 2012).”
HDAC3 is a molecular brake of the metabolic switch supporting white adipose tissue browning
Ferrari, A., Longo, R., Fiorino, E., Silva, R., Mitro, N., Cermenati, G., Gilardi, F., Desvergne, B., Andolfo, A., Magagnotti, C., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-00182-7 · Cited by 89
Non-canonical mTORC2 Signaling Regulates Brown Adipocyte Lipid Catabolism through SIRT6-FoxO1
Jung, S. M., Hung, C., Hildebrand, S. R., Sánchez-Gurmaches, J., Martínez-Pastor, B., Gengatharan, J. M., Wallace, M., Mukhopadhyay, D., Calejman, C. M., Luciano, A. K., et al. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.07.023 · Cited by 88
Fibroblast Growth Factor 21 As an Emerging Therapeutic Target for Type 2 Diabetes Mellitus
So, W. Y., & Leung, P. S. (2016) · Medicinal Research Reviews · doi:10.1002/med.21390 · Cited by 85
“The engineered FGF21, FGF21(1-171)-WD22, is functionally indistinguishable from native FGF21 in terms of signaling activation, receptor binding specificity, and induction of adipose glucose uptake, but has increased potency with the more tolerant C-terminal modification.”
BackgroundSingle cell approaches to address adipose tissue stromal cell heterogeneity
Rondini, E. A., & Granneman, J. G. (2020) · Biochemical Journal · doi:10.1042/bcj20190467 · Cited by 90
Keipert, S., Kutschke, M., Lamp, D., Brachthäuser, L., Neff, F., Meyer, C. W., Oelkrug, R., Kharitonenkov, A., & Jastroch, M. (2015) · Molecular Metabolism · doi:10.1016/j.molmet.2015.04.006 · Cited by 85
“Increased systemic FGF21 serum levels, either endogenously induced or exogenously administered, lead to the appearance of brown fat likestructures in WAT depots by the recruitment of beige fat cells e generally termed the “browning” of WAT [8,11,15,17].”
BackgroundFGF 21 deletion exacerbates diabetic cardiomyopathy by aggravating cardiac lipid accumulation
Yan, X., Chen, J., Zhang, C., Zhou, S., Zhang, Z., Chen, J., Feng, W., Li, X., & Tan, Y. (2015) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.12530 · Cited by 85
“Under hypothermic conditions, FGF21 can induce browning of white adipose tissues to up-regulate thermogenic activity, which could, at least in part, lead to a greater clearance of glucose [12].”
BackgroundActivation of estrogen receptor alpha induces beiging of adipocytes
Santos, R. D. S., Frank, A. P., de Fátima, L. A., Palmer, B. F., Öz, O. K., & Clegg, D. J. (2018) · Molecular Metabolism · doi:10.1016/j.molmet.2018.09.002 · Cited by 82
TFEB–GDF15 axis protects against obesity and insulin resistance as a lysosomal stress response
Kim, J., Kim, S., Kang, H., Lee, S., Park, S., Cho, Y., Lim, Y.-M., Ahn, J. W., Kim, Y.-H., Chung, S., et al. (2021) · Nature Metabolism · doi:10.1038/s42255-021-00368-w · Cited by 86
Sarcopenic obesity: Myokines as potential diagnostic biomarkers and therapeutic targets?
Guo, A., Li, K., & Xiao, Q. (2020) · Experimental Gerontology · doi:10.1016/j.exger.2020.111022 · Cited by 83
Brown adipose tissue activation by rutin ameliorates polycystic ovary syndrome in rat
Hu, T., Yuan, X., Ye, R., Zhou, H., Lin, J., Zhang, C., Zhang, H., Wei, G., Dong, M., Huang, Y., et al. (2017) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2017.04.012 · Cited by 83
Liu, C., Schönke, M., Zhou, E., Li, Z., Kooijman, S., Boon, M. R., Larsson, M., Wallenius, K., Dekker, N., Barlind, L., et al. (2021) · Cardiovascular Research · doi:10.1093/cvr/cvab076 · Cited by 81
“FGF21-induced weight loss has been reported to be caused in part by the induction of energy expenditure in obese rodents and humans, achieved by the recruitment of thermogenic pathways in brown fat and the browning of white fat.(25,41) Consistently, our histological and immunologic analyses showed that FGF21 treatment…”
BackgroundJouy, S. H., Mohan, S., Scichilone, G., Mostafa, A., & Mahmoud, A. M. (2024) · Biomedicines · doi:10.3390/biomedicines12092129 · Cited by 96
Adiponectin reduces thermogenesis by inhibiting brown adipose tissue activation in mice
Qiao, L., Yoo, H. S., Bosco, C., Lee, B., Feng, G., Schaack, J. B., Chi, N., & Shao, J. (2014) · Diabetologia · doi:10.1007/s00125-014-3180-5 · Cited by 80
Hankir, M. K., Kranz, M., Keipert, S., Weiner, J., Andreasen, S. G., Kern, M., Patt, M., Klöting, N., Heiker, J. T., Brust, P., et al. (2017) · Journal of Nuclear Medicine · doi:10.2967/jnumed.116.186460 · Cited by 81
“Cellular Bioenergetics and 2-Deoxy-3H-Glucose Assay Stromal vascular cells were isolated from interscapular BAT and differentiated as previously described (11).”
MethodRapamycin Blocks Induction of the Thermogenic Program in White Adipose Tissue
Tran, C. M., Mukherjee, S., Ye, L., Frederick, D. W., Kissig, M., Davis, J. G., Lamming, D. W., Seale, P., & Baur, J. A. (2016) · Diabetes · doi:10.2337/db15-0502 · Cited by 84
Imaging of Brown Adipose Tissue: State of the Art
Sampath, S. C., Sampath, S. C., Bredella, M. A., Cypess, A. M., & Torriani, M. (2016) · Radiology · doi:10.1148/radiol.2016150390 · Cited by 83
Endogenous FGF21-signaling controls paradoxical obesity resistance of UCP1-deficient mice
Keipert, S., Lutter, D., Schroeder, B. O., Brandt, D., Ståhlman, M., Schwarzmayr, T., Graf, E., Fuchs, H., de Angelis, M. H., Tschöp, M. H., et al. (2020) · Nature Communications · doi:10.1038/s41467-019-14069-2 · Cited by 84
The β3-adrenergic receptor is dispensable for browning of adipose tissues
de Jong, J. M. A., Wouters, R. T. F., Boulet, N., Cannon, B., Nedergaard, J., & Petrovič, N. (2017) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00437.2016 · Cited by 83
Mitochondrial uncoupling and longevity – A role for mitokines?
Klaus, S., & Ost, M. (2019) · Experimental Gerontology · doi:10.1016/j.exger.2019.110796 · Cited by 80
The significance of beige and brown fat in humans
Kiefer, F. W. (2017) · Endocrine Connections · doi:10.1530/ec-17-0037 · Cited by 82
Dietary inorganic nitrate: From villain to hero in metabolic disease?
McNally, B. D., Griffin, J. L., & Roberts, L. D. (2015) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201500153 · Cited by 81
“The switch from a white adipocyte-like to a brown adipocyte-like phenotype is known as the browning response and has anti-obesity and anti-diabetic effects [74, 79] Numerous activators of the browning response have been identified, including cardiac natriuretic peptides, fibroblast growth factor 21, irisin and -aminoi…”
BackgroundBrown adipose tissue: a potential target in the fight against obesity and the metabolic syndrome
Poekes, L., Lanthier, N., & Leclercq, I. A. (2015) · Clinical Science · doi:10.1042/cs20150339 · Cited by 83
Induction of thermogenic adipocytes: molecular targets and thermogenic small molecules
Song, N.-J., Chang, S., Li, D. Y., Villanueva, C. J., & Park, K. W. (2017) · Experimental & Molecular Medicine · doi:10.1038/emm.2017.70 · Cited by 81
OPA1 deletion in brown adipose tissue improves thermoregulation and systemic metabolism via FGF21
Pereira, R. O., Marti, A., Olvera, A. C., Tadinada, S. M., Bjorkman, S. H., Weatherford, E. T., Morgan, D. A., Westphal, M., Patel, P., Kirby, A. K., et al. (2021) · eLife · doi:10.7554/elife.66519 · Cited by 77
“FGF21 may directly promote browning of WAT in part, by induction of Ppargc1a (Fisher et al., 2012), and contributes to the induction of WAT browning during cold acclimation (Piao et al.”
BackgroundMethodInfluentialSchneider, K., Valdez, J. L., Nguyen, J. M., Vawter, M. P., Galke, B. L., Kurtz, T. W., & Chan, J. Y. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.673756 · Cited by 83
Effect of Various Exercise Regimens on Selected Exercise-Induced Cytokines in Healthy People
Domin, R., Dadej, D., Pytka, M., Zybek-Kocik, A., Ruchała, M., & Guzik, P. (2021) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph18031261 · Cited by 79
“Browning of white adipose tissue [57] Liver Adipose tissue Skeletal muscle Pancreas”
BackgroundActivin E controls energy homeostasis in both Brown and white adipose tissues as a hepatokine
Hashimoto, O., Funaba, M., Sekiyama, K., Doi, S., Shindo, D., Satoh, R., Itoi, H., Oiwa, H., Morita, M., Suzuki, C., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.10.008 · Cited by 77
“In addition, FGF21 increases expression levels of brown and beige adipocyte-selective genes including Ucp1 in cultured brown and beige adipocytes (Fisher et al., 2012).”
BackgroundInfluentialJung, Y. J., Kim, H. K., Cho, Y., Choi, J. S., Woo, C. H., Lee, K. S., Sul, J. H., Lee, C. M., Han, J., Park, J. H., et al. (2020) · Science Advances · doi:10.1126/sciadv.aay6721 · Cited by 79
The roles of FGF21 and GDF15 in mediating the mitochondrial integrated stress response
Jena, J., García-Peña, L. M., & Pereira, R. O. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1264530 · Cited by 78
“FGF21 and GDF15 can also be induced under physiological stress conditions, such as in response to an obesogenic diet (12, 13), exercise (14, 15) and cold exposure (16, 17).”
BackgroundMuscle mitochondrial stress adaptation operates independently of endogenous FGF21 action
Ost, M., Coleman, V., Voigt, A., van Schothorst, E. M., Keipert, S., van der Stelt, I., Ringel, S., Graja, A., Ambrosi, T., Kipp, A. P., et al. (2016) · Molecular Metabolism · doi:10.1016/j.molmet.2015.11.002 · Cited by 75
“During cold exposure, FGF21 expression was found to be increased in different adipose depots suggesting an autocrine/paracrine manner of action [19].”
FGF21-Mediated Improvements in Glucose Clearance Require Uncoupling Protein 1
Kwon, M. M., O’Dwyer, S. M., Baker, R. K., Covey, S. D., & Kieffer, T. J. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.10.021 · Cited by 77
Pathogenesis of Nonalcoholic Steatohepatitis and Hormone-Based Therapeutic Approaches
Kim, K. H., & Lee, M. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00485 · Cited by 77
Araki, M., Nakagawa, Y., Oishi, A., Han, S., Wang, Y., Kumagai, K., Ohno, H., Mizunoe, Y., IWASAKI, H. O., Sekiya, M., et al. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19072148 · Cited by 82
Jackson, T. C., & Kochanek, P. M. (2019) · Therapeutic Hypothermia and Temperature Management · doi:10.1089/ther.2019.0001 · Cited by 77
“Furthermore, in WAT, FGF21 increases uncoupling protein 1 (UCP1) levels via a post-transcriptional mechanism, which promotes browning and heat generation during cold adaptation (Fisher et al., 2012).”
BackgroundChen, L., Chen, Y.-H., Cheng, K., Chien, T.-Y., Chan, C.-H., Tsao, S., & Huang, H.-Y. (2017) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2017.11.004 · Cited by 75
CDK6 inhibits white to beige fat transition by suppressing RUNX1
Hou, X. S., Zhang, Y., Li, W., Hu, A. J., Luo, C., Zhou, W., Hu, J. K., Daniele, S. G., Wang, J., Sheng, J., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-03451-1 · Cited by 74
Pharmacological strategies for targeting BAT thermogenesis
Whittle, A. J., Relat, J., & Vidal‐Puig, A. (2013) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2013.04.004 · Cited by 82
Impact of Lipotoxicity on Tissue “Cross Talk” and Metabolic Regulation
Montgomery, M. K., Nardo, W. D., & Watt, M. J. (2019) · Physiology · doi:10.1152/physiol.00037.2018 · Cited by 82
Asrih, M., Altirriba, J., Rohner‐Jeanrenaud, F., & Jornayvaz, F. R. (2015) · PLoS ONE · doi:10.1371/journal.pone.0126364 · Cited by 75
Trans-Cinnamic Acid Stimulates White Fat Browning and Activates Brown Adipocytes
Kang, N. H., Mukherjee, S., & Yun, J. W. (2019) · Nutrients · doi:10.3390/nu11030577 · Cited by 76
AlZaim, I., Hammoud, S. H., Al-Koussa, H., Ghazi, A., Eid, A. H., & EL‐Yazbi, A. F. (2020) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2020.602088 · Cited by 78
García‐Alonso, V., López‐Vicario, C., Titos, E., Morán‐Salvador, E., González‐Périz, A., Rius, B., Párrizas, M., Werz, O., Arroyo, V., & Clària, J. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.468603 · Cited by 75
Stressed Liver and Muscle Call on Adipocytes with FGF21
Luo, Y., & McKeehan, W. L. (2013) · Frontiers in Endocrinology · doi:10.3389/fendo.2013.00194 · Cited by 75
“been suggested to create a state of futile cycling and enhanced energy expenditure that causes overall reduction of body weight and systemic lipids in the obese (1, 29, 40, 46, 49).”
BackgroundFibroblast growth factor 21 is not required for the antidiabetic actions of the thiazoladinediones
Adams, A. C., Coşkun, T., Cheng, C., O’Farrell, L. S., DuBois, S. L., & Kharitonenkov, A. (2013) · Molecular Metabolism · doi:10.1016/j.molmet.2013.05.005 · Cited by 75
Thermogenic Ability of Uncoupling Protein 1 in Beige Adipocytes in Mice
Okamatsu‐Ogura, Y., Fukano, K., Tsubota, A., Uozumi, A., Terao, A., Kimura, K., & Saito, M. (2013) · PLoS ONE · doi:10.1371/journal.pone.0084229 · Cited by 81
“Consistent with a previous report [35,36], fgf21 was highly expressed in BA compared with I- and G-WA, and cold acclimation increased its expression in all the three depots.”
BackgroundResultRole of bone morphogenetic protein 4 in the differentiation of brown fat-like adipocytes
Xue, R., Wan, Y., Zhang, S., Zhang, Q., Ye, H., & Li, Y. (2013) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00119.2013 · Cited by 80
“It is revealed that beige adipocytes are particularly sensitive to inductive factors, such as BMP7 (33), BMP8B (49), fibroblast growth factor 21 (12), and the myokine irisin (5).”
BackgroundIntact innervation is essential for diet-induced recruitment of brown adipose tissue
Fischer, A. W., Schlein, C., Cannon, B., Heeren, J., & Nedergaard, J. (2018) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00443.2018 · Cited by 74
Craft, C. S., Pietka, T. A., Schappe, T., Coleman, T., Combs, M. D., Klein, S., Abumrad, N. A., & Mecham, R. P. (2014) · Diabetes · doi:10.2337/db13-1604 · Cited by 73
“is protective against diet-induced diabetes (29-31), adipocyte browning was explored in the scWAT of Mfap2 -/mice.”
BackgroundKawabe, Y., Mori, J., Morimoto, H., Yamaguchi, M., Miyagaki, S., Ota, T., Tsuma, Y., Fukuhara, S., Nakajima, H., Oudit, G. Y., et al. (2019) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00311.2019 · Cited by 74
“FGF21 promotes browning of WAT (UCP1 expression) via PGC-1 in association with the increment of glucose uptake and oxidation (8).”
BackgroundChen, X., Tong, G., Fan, J., Shen, Y., Wang, N., Gong, W., Hu, Z., Zhu, K., Li, X., Jin, L., et al. (2021) · British Journal of Pharmacology · doi:10.1111/bph.15701 · Cited by 74
“Notably, ERK, which can be activated by FGF21 signalling (Fisher et al., 2012), was not involved in FGF21-mediated migration and induction of differentiation genes (data not shown).”
BackgroundJia, R., Luo, X.-Q., Wang, G., Lin, C. ‐., Qiao, H., Wang, N., Yao, T., Barclay, J. L., Whitehead, J. P., Luo, X., et al. (2016) · Acta Physiologica · doi:10.1111/apha.12688 · Cited by 71
“Paradoxically, some, but not all (Fisher et al. 2012, Barneda et al. 2013), studies have reported an increased Cidea expression in iBAT after 1–3 days of cold exposure (Barbatelli et al. 2010, Wang et al. 2013).”
BackgroundBerti, L., Irmler, M., Zdichavsky, M., Meile, T., Böhm, A., Stefan, N., Fritsche, A., Beckers, J., Königsrainer, A., Häring, H.-U., et al. (2015) · Molecular Metabolism · doi:10.1016/j.molmet.2015.04.002 · Cited by 73
Fibroblast growth factor 21, the endocrine FGF pathway and novel treatments for metabolic syndrome
Zhang, J., & Li, Y. (2013) · Drug Discovery Today · doi:10.1016/j.drudis.2013.10.021 · Cited by 73
The potential function and clinical application of FGF21 in metabolic diseases
Chen, Z., Yang, L., Liu, Y., Huang, P., Song, H., & Zheng, P. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.1089214 · Cited by 73
“Indeed, PPARα induces FGF21, which promotes lipolysis in WAT and liver through endocrine and autocrine/paracrine mechanisms, stimulating ketogenesis in vivo (Inagaki et al., 2007).”
BackgroundInfluentialRoles of FGFs as Adipokines in Adipose Tissue Development, Remodeling, and Metabolism
Ohta, H., & Itoh, N. (2014) · Frontiers in Endocrinology · doi:10.3389/fendo.2014.00018 · Cited by 77
“These findings indicate that adiponectin couples FGF21 actions as a downstream effector of FGF21 in white adipocytes and mediates the systemic effects of FGF21 on energy metabolism and insulin sensitivity in the liver and skeletal muscle (Figure 2B) (Table S1 in Supplementary Material) (25, 26).”
BackgroundInfluentialHanatani, S., Motoshima, H., Takaki, Y., Kawasaki, S., Igata, M., Matsumura, T., Kondo, T., Senokuchi, T., Ishii, N., Kawashima, J., et al. (2016) · Journal of Clinical Biochemistry and Nutrition · doi:10.3164/jcbn.16-23 · Cited by 73
Molecular mechanisms underlying metabolic syndrome: the expanding role of the adipocyte
Armani, A., Berry, A., Cirulli, F., & Caprio, M. (2017) · The FASEB Journal · doi:10.1096/fj.201601125rrr · Cited by 76
“WAT of raptorad2/2mice displays increased browning and subsequent resistance against diet-induced fat mass expansion (162).”
BackgroundInfluentialDes‐acyl ghrelin analogs prevent high‐fat‐diet‐induced dysregulation of glucose homeostasis
Delhanty, P. J. D., Huisman, M., Baldeón, L., den Berge, I. J. R.-V., Grefhorst, A., Abribat, T., Leenen, P. J. M., Themmen, A. P. N., & van der Lely, A. (2013) · The FASEB Journal · doi:10.1096/fj.12-221143 · Cited by 72
The Potential Role of Fibroblast Growth Factor 21 in Lipid Metabolism and Hypertension
Huang, Z. P., Xu, A., & Cheung, B. M. Y. (2017) · Current Hypertension Reports · doi:10.1007/s11906-017-0730-5 · Cited by 71
Wu, T., Liu, Q., Li, Y., Li, H., Chen, L., Yang, X., Tang, Q., Pu, S., Kuang, J., Li, R., et al. (2021) · The Journal of Experimental Medicine · doi:10.1084/jem.20201203 · Cited by 72
“Feeding also increased the adipose expression of fibroblast growth factor 21 (Fgf21; Fisher et al., 2012), which promoted browning in an autocrine/paracrine manner.”
BackgroundMethodInfluentialSpotlight on the Mechanism of Action of Semaglutide
Papakonstantinou, I. P., Tsioufis, K. P., & Katsi, V. K. (2024) · Current Issues in Molecular Biology · doi:10.3390/cimb46120872 · Cited by 89
Implication of hepatokines in metabolic disorders and cardiovascular diseases
Jung, T. W., Yoo, H. J., & Choi, K. M. (2016) · BBA Clinical · doi:10.1016/j.bbacli.2016.03.002 · Cited by 71
“Moreover, FGF21 modulates PGC1α and induces browning in white adipose tissue as a defense mechanism against hypothermia [58].”
BackgroundNie, T., Zhao, S., Mao, L., Yang, Y., Sun, W., Lin, X., Liu, S., Li, K., Sun, Y., Li, P., et al. (2018) · British Journal of Pharmacology · doi:10.1111/bph.14139 · Cited by 69
“…demonstrated to treat obesity by increasing adipocyte thermogenesis, but a critical problem is that few people like to regard obesity as an illness and treat it medicinally (Buemann et al., 2000; Fisher et al., 2012; Bi et al., 2014; Zhang et al., 2014; Wang et al., 2015; Baskaran et al., 2016).”
BackgroundBabaknejad, N., Nayeri, H., Hemmati, R., Bahrami, S., & Esmaillzadeh, A. (2018) · Hormone and Metabolic Research · doi:10.1055/a-0623-2909 · Cited by 70
Brown and Brite: The Fat Soldiers in the Anti-obesity Fight
Srivastava, S., & Veech, R. L. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.00038 · Cited by 74
“FGF21 can also lead to browning of WAT through increased PPAR-γ (Dutchak et al., 2012) and PGC1-α activity (Fisher et al., 2012).”
BackgroundSpann, R. A., Morrison, C. D., & den Hartigh, L. J. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.802541 · Cited by 76
Zeng, X., Wang, H., Bai, F., Zhou, X., Li, S., Ren, L., Sun, R., Xue, C. C., Jiang, H., Hu, L., et al. (2015) · British Journal of Pharmacology · doi:10.1111/bph.13209 · Cited by 70
“However, further studies are required to determine whether the observed up-regulation of UCP1 results from matrine’s direct effect at HSP90 of adipose tissue or a secondary effect of hepatokines such as FGF21 (Fisher et al., 2012).”
BackgroundFibroblast Growth Factor 21 Analogs for Treating Metabolic Disorders
Zhang, J., & Li, Y. (2015) · Frontiers in Endocrinology · doi:10.3389/fendo.2015.00168 · Cited by 70
“The avimer fusion molecule, FGF21 (1-171)-WD22, indeed has improved properties and decreased susceptibility to modifications compared to wild-type FGF21 (78), providing a novel framework for further engineering that is not possible with the wild-type protein.”
BackgroundRegulation of brown and beige fat by microRNAs
Chen, Y., Pan, R., & Pfeifer, A. (2016) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2016.10.004 · Cited by 73
Goto, T., Hirata, M., Aoki, Y., Iwase, M., Takahashi, H., Kim, M., Li, Y., Jheng, H., Nomura, W., Takahashi, N., et al. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.767590 · Cited by 72
“Moreover, although differences in cold-induced thermogenic gene expression were not apparent in the interscapular BAT of FGF21-KO mice, the expression of browning marker genes, such as Ucp1, Pgc1a, Cidea, was significantly reduced in the iWAT of the cold-exposed FGF21-KO mice (20).”
BackgroundInfluential
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
