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FGF21 regulates PGC-1α and browning of white adipose tissues in adaptive thermogenesis
Open accessAbstract
Certain white adipose tissue (WAT) depots are readily able to convert to a "brown-like" state with prolonged cold exposure or exposure to β-adrenergic compounds. This process is characterized by the appearance of pockets of uncoupling protein 1 (UCP1)-positive, multilocular adipocytes and serves to increase the thermogenic capacity of the organism. We show here that fibroblast growth factor 21 (FGF21) plays a physiologic role in this thermogenic recruitment of WATs. In fact, mice deficient in FGF21 display an impaired ability to adapt to chronic cold exposure, with diminished browning of WAT. Adipose-derived FGF21 acts in an autocrine/paracrine manner to increase expression of UCP1 and other thermogenic genes in fat tissues. FGF21 regulates this process, at least in part, by enhancing adipose tissue PGC-1α protein levels independently of mRNA expression. We conclude that FGF21 acts to activate and expand the thermogenic machinery in vivo to provide a robust defense against hypothermia.
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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]
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In the citing paper
“In WAT, it induces lipolysis [166] and browning [43], likely via upregulation of PGC-1α [192].”
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In the citing paper
“the exercise-induced hepatokines FGF21 [43] and follistatin [185], both upregulated by glucagon (5)”
From The Role of Exercise in the Interplay between Myokines, Hepatokines, Osteokines, Adipokines, and Modulation of Inflammation for Energy Substrate Redistribution and Fat Mass Loss: A Review (2020) · cites this paper as [43]
Experimental — accuracy not yet measuredIn the citing paper
“The direct effect of Fgf21 on adipocyte browning has also been demonstrated by others [284].”
From Mitochondrial Uncoupling: A Key Controller of Biological Processes in Physiology and Diseases (2019) · cites this paper as [284]
In the citing paper
“Consistent with a functional role for FGF21 during cold, both Fgf21 total knockout mice (36) and adipose-specific Fgf21 knockout mice (52) exhibit reduced body temperature in response to acute cold exposure.”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [36]
In the citing paper
“However, while an increase in circulating levels of FGF21 has been reported in response to cold in mice (49), this has not been observed in other studies (36, 52).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [36]
In the citing paper
“Fgf21 mRNA expression is upregulated in both WAT (36, 52) and BAT (15, 36, 49, 52) in response to cold.”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [36]
In the citing paper
“Consistent with its role in regulating thermogenesis, FGF21 treatment is sufficient to increase thermogenic gene expression in mouse primary white adipocytes (36).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [36]
In the citing paper
“Some teams have reported that FGF21 knockout mice have impaired adaptation to chronic cold exposure and decreased browning of WAT 92.”
From Inter‐organ communication: a gatekeeper for metabolic health (2019) · cites this paper as [92]
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Citations
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“Enhanced expression levels of Bmp8b, Fgf21, and Kng2 were found in iWAT in association with cold-induced browning, also as previously reported (Fisher et al., 2012; Peyrou et al., 2020).”
ResultGene expression of peripheral blood mononuclear cells is affected by cold exposure
Reynés, B., García-Ruiz, E., Oliver, P., & Palou, A. (2015) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00221.2015 · Cited by 19
“Fgf21 codes for a hormone involved in Pgc1 and Ucp1 expression, and thus it has an important role in adaptive thermogenesis (19, 34, 36).”
BackgroundTranscriptional control and hormonal response of thermogenic fat
Emont, M. P., Yu, H. M., & Wu, J. (2015) · Journal of Endocrinology · doi:10.1530/joe-15-0026 · Cited by 19
“FGF21 is mostly produced in and released from the liver; however, thermogenic activation also increases FGF21 expression in subcutaneous and brown adipose tissue (Hondares et al. 2011, Fisher et al. 2012).”
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“278,279 Hepatic expression of FGF21 and its circulating levels are markedly elevated in patients with MASLD 280,281 and in livers under carcinogenic stress.”
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FGF21 is required for the metabolic benefits of IKKε/TBK1 inhibition
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“We have previously shown that IKKε inhibits cAMP signaling by activating PDE-3, and that inhibition of IKKε with amlexanox adipocyte thermogenesis (35, 36), we wondered whether FGF21 might play a role in amlexanox-induced energy expenditure.”
Fish Oil Increases Diet-Induced Thermogenesis in Mice
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β-arrestin-1 contributes to brown fat function and directly interacts with PPARα and PPARγ
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MiR‐21‐3p Inhibits Adipose Browning by Targeting FGFR1 and Aggravates Atrial Fibrosis in Diabetes
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“These effects were recapitulated in vitro, using mouse (12) and human (13) primary adipocytes, suggesting FGF21 has a direct browning effect on adipocytes.”
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“Furthermore, FGF21 regulates the browning of adipose tissue and metabolism by regulating uncoupling protein (UCP)1 and peroxisome proliferator-activated receptor (PPAR) coactivator (PGC)1α expression, which are important for mitochondrial function and energy expenditure [20].”
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“of metabolic processes, particularly for WAT browning.(38) A more recent report indicated that the FGF21induced energy dissipation might not be related to UCP1, because it occurred in UCP1-/- mice.”
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Compound dark tea ameliorates obesity and hepatic steatosis and modulates the gut microbiota in mice
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“Additionally, fat browning is driven by Fgf-21 (54).”
BackgroundInfluentialSkeletal muscles and gut microbiota-derived metabolites: novel modulators of adipocyte thermogenesis
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ESRRG and PERM1 Govern Mitochondrial Conversion in Brite/Beige Adipocyte Formation
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“Since PGC1α is highly regulated post-transcriptionally (43, 44), the transcript level alone is of limited informational value.”
BackgroundThe Leukodystrophies HBSL and LBSL—Correlates and Distinctions
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“Additionally, FGF21 ensures the stability of the transcription factor Peroxisome proliferator-activated receptor-Gamma Coactivator 1-alpha (PGC-1α) (Fisher et al., 2012).”
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“Various stimulus/factors can induce browning of WAT/white adipocyte such as cold exposure (Dempersmier et al., 2015), exercise (Norheim et al., 2014), high energy diet (HED) (García-Ruiz et al., 2015), irisin (Boström et al., 2012), agonists of β-adrenergic receptor or PPARγ (Kleiner et al., 2012; Petrovic et al., 201…”
BackgroundInfluentialLifestyle and Food Habits Impact on Chronic Diseases: Roles of PPARs
d’Angelo, M., Castelli, V., Tupone, M. G., Catanesi, M., Antonosante, A., Dominguez-Benot, R., Ippoliti, R., Cimini, A., & Benedetti, E. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20215422 · Cited by 17
“The first option proposes that one of the PPARα capabilities is to increase the expression of a particular hepatokine, the fibroblast growth factor 21 (FGF21) [42], a cytokine able to increase the energy consumptions in white adipose tissue (WAT) via the enhancement of the brown adipose tissue (BAT) activity (generall…”
BackgroundMaeng, H. J., Lee, G. Y., Bae, J. H., & Lim, S. K. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21186836 · Cited by 16
“FGF21 has also been implicated in the “browning” of WAT as it stimulates the expression of mitochondrial brown fat UCP1 in WAT adipocytes, via enhancement of proliferator-activated receptor gamma coactivator-1 α activity and promotes thermogenesis [20].”
BackgroundRecruitment of Thermogenic Fat: Trigger of Fat Burning
Wang, Z., Yu, X., & Chen, Y. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.696505 · Cited by 16
“Specifically, FGF21 plays a physiologic role in recruiting beige fat cells in WAT depots by increasing transcription factor PGC1a level (86).”
BackgroundConstitutively active receptor ADGRA3 signaling induces adipose thermogenesisPreprint
Zhao, Z., Hu, L., Song, B., Jiang, T., Wu, Q., Lin, J., Li, X., Cai, Y., Li, J., Qian, B., et al. (2024) · eLife · doi:10.7554/elife.100205 · Cited by 16
Hope, D. C. D., & Tan, T. M.-M. (2023) · Peptides · doi:10.1016/j.peptides.2023.170962 · Cited by 16
Aja, P. M., Awoke, J. N., Agu, P. C., Adegboyega, A. E., Ezeh, E. M., Igwenyi, I. O., Orji, O. U., Ani, O. G., Ale, B. A., & Ibiam, U. A. (2022) · Journal of Genetic Engineering and Biotechnology · doi:10.1186/s43141-022-00370-z · Cited by 15
Zhao, Z., Liu, S., Qian, B., Zhou, L., Shi, J., Liu, J., Xu, L., & Yang, Z. (2022) · Fundamental Research · doi:10.1016/j.fmre.2022.06.014 · Cited by 15
“While the 𝛽 3-adrenoceptor agonist effectively promoted thermogenesis in brown and beige adipocytes in rodents, the clinical implications seem unfeasible due to the low ef-ficacy of 𝛽 3-adrenoceptor agonists in humans [ 29 , 30 ].”
BackgroundWarrier, M., Paules, E. M., Silva-Gómez, J. A., Friday, W. B., Bramlett, F., Kim, H., Zhang, K., & Trujillo‐Gonzalez, I. (2023) · Heliyon · doi:10.1016/j.heliyon.2023.e13216 · Cited by 15
van Beek, S. M. M., Hashim, D., Bengtsson, T., & Hoeks, J. (2023) · International Journal of Obesity · doi:10.1038/s41366-023-01270-z · Cited by 16
Tang, M., Cheng, S., Wang, L., Tang, H., Liu, T., Zhao, T., & Dang, R. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1165443 · Cited by 16
“FGF21 was shown previously to induce hepatic expression of PGC-1α, suggested as a mechanism for its metabolic actions (Fisher et al., 2012).”
BackgroundWang, R., Wang, J., Zhang, Z., Ma, B., Sun, S., Gao, L., & Gao, G. (2023) · Molecular Medicine · doi:10.1186/s10020-023-00755-x · Cited by 17
“In addition, FGF21 has been claimed to have beneficial regulatory effects on lipid metabolism and thermogenesis, especially in mice undergoing serious stresses such as starvation, cold exposure and hepatic steatosis (Mai et al. 2009; Inagaki et al. 2008; Fisher et al. 2012; Zhang et al. 2015).”
BackgroundMetabolic liability for weight gain in early adulthood
Murthy, V. L., Mosley, J. D., Perry, A., Jacobs, D. R., Tanrıverdi, K., Zhao, S., Sawicki, K. T., Carnethon, M. R., Wilkins, J. T., Nayor, M. G., et al. (2024) · Cell Reports Medicine · doi:10.1016/j.xcrm.2024.101548 · Cited by 14
Mäkelä, A. M., Hohtola, E., Miinalainen, I., Autio, J. A., Schmitz, W., Niemi, K. J., Hiltunen, J. K., & Autio, K. J. (2019) · Scientific Reports · doi:10.1038/s41598-019-48562-x · Cited by 15
Satoh, A., Han, S., Araki, M., Nakagawa, Y., Ohno, H., Mizunoe, Y., Kumagai, K., Murayama, Y., Osaki, Y., IWASAKI, H. O., et al. (2020) · iScience · doi:10.1016/j.isci.2020.100930 · Cited by 15
“FGF21 directly activates PGC-1a and in turn increases Ucp1 expression in adipocytes, leading to an increase in thermogenesis in these cells (Fisher et al., 2012).”
BackgroundInfluentialDOT1L Regulates Thermogenic Adipocyte Differentiation and Function via Modulating H3K79 Methylation
Shuai, L., Li, B., Jiang, H., Duan, Y.-N., Yang, L., Li, J., & Li, J. (2020) · Diabetes · doi:10.2337/db20-1110 · Cited by 15
Haque, N., & Tischkau, S. A. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23147679 · Cited by 18
Role of Distinct Fat Depots in Metabolic Regulation and Pathological Implications
Sahu, B., Tikoo, O., Pati, B., Senapati, U., & Bal, N. C. (2022) · Reviews of physiology, biochemistry and pharmacology · doi:10.1007/112_2022_73 · Cited by 15
MicroRNAs as Mediators of Adipose Thermogenesis and Potential Therapeutic Targets for Obesity
Ma, L., Gilani, A., Yi, Q., & Tang, L. (2022) · Biology · doi:10.3390/biology11111657 · Cited by 16
“Fibroblast growth factor 21 (FGF21) is an endocrine molecule normally produced by the liver with multiple metabolic effects, including enhanced browning of inguinal white adipose tissue (iWAT) [35].”
BackgroundXu, S., Mao, L., Ding, P., Zhuang, X., Zhou, Y., Yu, L., Liu, Y., Nie, T., Xu, T., Xu, Y., et al. (2015) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2015.03.082 · Cited by 15
Photoperiodic regulation of FGF21 production in the Siberian hamster
Samms, R. J., Fowler, M. J., Cooper, S., Emmerson, P. J., Coşkun, T., Adams, A. C., Kharitonenkov, A., Tsintzas, K., & Ebling, F. J. P. (2014) · Hormones and Behavior · doi:10.1016/j.yhbeh.2014.03.013 · Cited by 15
“For example, cold-exposure increases FGF21 production in BAT (Chartoumpekis et al., 2011; Hondares et al., 2011) where it stimulates the expression of several thermogenic genes (Fisher et al., 2012).”
Adipose Tissue, at the Core of the Action of Incretin and Glucagon-Based Anti-Obesity Drugs
Villarroya, F., Peyrou, M., & Giralt, M. (2025) · Current Obesity Reports · doi:10.1007/s13679-025-00660-w · Cited by 14
“FGF21 is a powerful inducer of thermogenic acti - vation in adipose tissues [159 , 160 ], and results obtained from FGF21-null mice showed that FGF21 critically medi - ates the effects of GCG on BAT activity and WAT brown - ing [103 , 104].”
Zuccaro, A., Zapatería, B., Sánchez‐Alonso, M. G., Haro, M., Limones, M., Terrados, G., Izquierdo, A., Corrales, P., Medina‐Gómez, G., Herradón, G., et al. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22179261 · Cited by 14
“Moreover, in the last decade, several studies have highlighted the emergence of brown adipocytes in the white adipose depots in response to exercise [9], cold exposure [10], dietary factors [11] and cytokines or pharmaceuticals [12,13]; these brown cells within white adipose tissue can also contribute to increase ener…”
BackgroundNederveen, J. P., Manta, K., Bujak, A. L., Simone, A. C., Fuda, M. R., Nilsson, M. I., Hettinga, B. P., Hughes, M. C., Perry, C. G. R., & Tarnopolsky, M. A. (2021) · Nutrients · doi:10.3390/nu13113726 · Cited by 14
Hepatic function of glucagon-like peptide-1 and its based diabetes drugs
Feng, J. N., & Jin, T. (2024) · Medical Review · doi:10.1515/mr-2024-0018 · Cited by 17
Ketogenic diet with aerobic exercise can induce fat browning: potential roles of β-hydroxybutyrate
Kim, S., Park, D., Moon, S., Gu, B., Mantik, K. E. K., Kwak, H., Ryu, J.-K., & Kang, J.-H. (2024) · Frontiers in Nutrition · doi:10.3389/fnut.2024.1443483 · Cited by 14
“It has been reported that adipose-derived FGF21 increases the expression of thermogenic genes like UCP1 in thermogenically competent WAT of mice, which is dependent on PGC-1 α activation and does not alter adipose differentiation (11).”
BackgroundYuan, X., Huang, H., Huang, Y., Wang, J., Yan, J., Ding, L., Zhang, C., & Zhang, L. (2017) · Experimental Biology and Medicine · doi:10.1177/1535370217694435 · Cited by 14
Physiological regulation and metabolic role of browning in white adipose tissue
Janković, A., Otašević, V., Stančić, A., Buzadžić, B., Korać, A., & Korać, B. (2017) · Hormone Molecular Biology and Clinical Investigation · doi:10.1515/hmbci-2017-0034 · Cited by 14
“Moreover, FGF21 plays an essential physiological role in thermogenic recruitment of WAT during cold exposure [80] and after dietary methionine restriction [81] via translational upregulation of PGC-1α protein [80].”
BackgroundOxidative Phosphorylation Dysfunction Modifies the Cell Secretome
Garrido-Pérez, N., Vela‐Sebastián, A., López‐Gallardo, E., Emperador, S., Iglesias, E., Meade, P., Jimenez-Mallebrera, C., Montoya, J., Bayona‐Bafaluy, M. P., & Ruiz‐Pesini, E. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21093374 · Cited by 14
“FGF21 has been associated with anti-inflammatory properties in various tissues [51].”
BackgroundTangseefa, P., Martin, S. K., Chin, P. Y., Breen, J., Mah, C. Y., Baldock, P. A. J., Wittert, G., Page, A. J., Proud, C. G., Fitter, S., et al. (2021) · Bone Research · doi:10.1038/s41413-020-00123-z · Cited by 15
Pancreatic Tumorigenesis: Oncogenic KRAS and the Vulnerability of the Pancreas to Obesity
Luo, Y., Li, X., Ma, J., Abbruzzese, J. L., & Lu, W. (2021) · Cancers · doi:10.3390/cancers13040778 · Cited by 14
Ketone body and FGF21 coordinately regulate fasting-induced oxidative stress response in the heart
Kawakami, R., Sunaga, H., Iso, T., Kaneko, R., Koitabashi, N., Obokata, M., Harada, T., Matsui, H., Yokoyama, T., & Kurabayashi, M. (2022) · Scientific Reports · doi:10.1038/s41598-022-10993-4 · Cited by 14
Chuang, H.-C., Huang, C.-F., Chang, Y.-C., Lin, Y., & Chao, P. (2013) · Journal of Nutrition · doi:10.3945/jn.112.168948 · Cited by 14
Cre Recombinase Strains Used for the Study of Adipose Tissues and Adipocyte Progenitors
Liu, J., Xu, Z., Wu, W.-C., Wang, Y., & Shan, T. (2016) · Journal of Cellular Physiology · doi:10.1002/jcp.25675 · Cited by 14
“…type of adipocyte called beige or brite adipocyte has been identified in subcutaneous WAT (sWAT) after cold exposure, hormones or chemical stimulation, or key genes mutation (Cao et al., 2011; Bostrom et al., 2012; Fisher et al., 2012; Walden et al., 2012; Bi et al., 2014; Cohen et al., 2014).”
BackgroundChen, S., Bastarrachea, R. A., Shen, J.-S., Laviada-Nagel, A., Rodríguez-Ayala, E., Nava‐González, E. J., Huang, P., DeFronzo, R. A., Kent, J. W., & Grayburn, P. A. (2018) · Gene Therapy · doi:10.1038/s41434-018-0036-5 · Cited by 14
Even, P. C., Gehring, J., & Tomé, D. (2021) · Obesity Reviews · doi:10.1111/obr.13194 · Cited by 17
Liu, R., Liu, J., & Zhang, H. (2021) · Journal of Oceanology and Limnology · doi:10.1007/s00343-020-0241-0 · Cited by 14
Oxidative phosphorylation and fatty acid oxidation in slow-aging mice
Elmansi, A. M., & Miller, R. A. (2024) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2024.08.018 · Cited by 14
Murray, S. A., Dalbøge, L. S., Baquero, K., Sanford, C. A., Misquith, A., Mercer, A. J., Meek, T. H., Guldbrandt, M., Andersen, B., Kievit, P., et al. (2020) · Scientific Reports · doi:10.1038/s41598-020-64170-6 · Cited by 12
Convergent molecular evolution of thermogenesis and circadian rhythm in Arctic ruminants
Li, M., Li, X., Wu, Z., Zhang, G., Wang, N., Dou, M., Liu, S., Yang, C., Meng, G., Sun, H., et al. (2023) · Proceedings of the Royal Society B: Biological Sciences · doi:10.1098/rspb.2023.0538 · Cited by 12
“Notably, the REG FGF21 in muskox, the metabolic hormone fibroblast growth factor 21 gene, works in an autocrine/paracrine manner to increase UCP1 expression, hence stimulating sympathetic nerves to increase the abundance of brite/beige cells in WAT (‘browning’) and thereby induce thermogenesis [55,56].”
BackgroundThe role of FGF21 in the metabolic adjustments required for exercise capacity
Abe, L., & Dantzer, R. (2025) · Life Sciences · doi:10.1016/j.lfs.2025.123940 · Cited by 5
Metadata
- Authors
- Fisher, F. M., Kleiner, S., Douris, N., Fox, E. C., Mepani, R. J., Verdeguer, F., Wu, J., Kharitonenkov, A., Flier, J. S., Maratos-Flier, E., & Spiegelman, B. M.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Harvard University (US)
- Eli Lilly (United States) (US)
- ORCID
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2012-02-01
- Volume
- 26
- Issue
- 3
- Pages
- 271-281
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC3278894
- OpenAlex
- W2145142659
- Cited by
- 1,478
- References
- 38
- Citations by year
- 2026: 44 · 2025: 58 · 2024: 90 · 2023: 82 · 2022: 100 · 2021: 122 · 2020: 112 · 2019: 121 · 2018: 128 · 2017: 126 · 2016: 131 · 2015: 127 · 2014: 101 · 2013: 94 · 2012: 40
- Type
- posted content
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (DK028082, DK31405)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK028082, R01DK031405, DK-31405, R01DK028082, R37DK028082, R37DK031405)
- Topics
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Keywords
- FGF21, PGC-1α, white adipose tissue browning, adaptive thermogenesis, UCP1, cold exposure, thermogenic gene expression, autocrine and paracrine signaling
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Adaptation, Physiological, Animals, Adipose Tissue, Brown, Cell Differentiation, Cells, Cultured, Cold Temperature, Fibroblast Growth Factors, Gene Expression Regulation, Male, Mice, Inbred C57BL, RNA Processing, Post-Transcriptional, Transcription Factors, Trans-Activators, Thermogenesis, Mice, Adipose Tissue, White
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