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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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BackgroundChREBP Reciprocally Regulates Liver and Plasma Triacylglycerol Levels in Different Manners
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“FGF21 has been shown to stimulate hepatic fatty acid oxidation (24, 25), adipose tissue glucose uptake (1), adipose thermogenic gene expression, and browning of white adipose tissue (26).”
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“Quantification of gene transcripts for cholesterol 7 alpha-hydroxylase (CYP7A1), CYP7B1, CYP27A1, CYP8B1, bile salt export pump (BSEP), β-klotho, fibroblast growth factor receptor 1c (FGFR1c), FGFR4, G protein-coupled bile acid receptor (TGR5), farnesoid X receptor (FXR), FGF15, HMG-CoA reductase (HMGCR), HMG-CoA synt…”
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“For instance, FGF21 and bone morphogenetic protein 4 (BMP4) that are produced in response to adrenergic signaling can promote WAT browning (Fisher et al., 2012; Grefhorst et al., 2015).”
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BackgroundBiology of Beige Adipocyte and Possible Therapy for Type 2 Diabetes and Obesity
Lizcano, F., & Vargas, D. (2016) · International Journal of Endocrinology · doi:10.1155/2016/9542061 · Cited by 38
Epigenetic Regulation of the Thermogenic Adipose Program
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“FGF21 activates thermogenic genes and thus FGF21 KO mice exhibit impaired cold tolerance and reduced browning of WAT [34,36].”
Zinc-α2-Glycoprotein Is Associated with Obesity in Chinese People and HFD-Induced Obese Mice
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“Interestingly, a third type of adipocyte in WAT, named “beige” or “brite” cells, was discovered recently, and studies have demonstrated that those cells can be activated upon pharmacological activation of β3-AR and that they highly express uncoupling protein 1 (UCP1), then dissipate energy (Fisher et al., 2012; Harms…”
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“Intriguingly, Fgf21 mRNA expression in iBAT, which has been shown to be upregulated by cold exposure and adrenergic stimulation to induce PGC1 (29, 44), increased 27-fold (P = 0.”
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“Fisher et al. (2012) found that FGF21 can also increase thermogenic gene expression in specific WAT depots (IWAT and PRWAT), and FGF21 appeared to induce the expression of many genes associated with the function of the brown/beige adipocytes.”
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Adipocyte-Specific Transgenic and Knockout Models
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“The upregulation of Cpt1, Pck1, PPARα and Ucp1 in addition to adiponectin in breast tissue is consistent with previous studies in the independent adipose tissue and adipocytes, which showed that FGF21 activates the adipose FGFR1-KLB complex leading to significant changes in the expression of these metabolic genes and…”
ResultBioengineering Beige Adipose Tissue Therapeutics
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Izaguirre, M., Gil, M. J., Monreal, I., Montecucco, F., Frühbeck, G., & Catalán, V. (2017) · Current Diabetes Reports · doi:10.1007/s11892-017-0866-3 · Cited by 41
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Morita, M., Siddiqui, N., Katsumura, S., Rouya, C., Larsson, O. S., Nagashima, T., Hekmatnejad, B., Takahashi, A., Kiyonari, H., Zang, M., et al. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1816023116 · Cited by 37
mTOR signaling in Brown and Beige adipocytes: implications for thermogenesis and obesity
Ye, Y., Liu, H., Zhang, F., & Hu, F. (2019) · Nutrition & Metabolism · doi:10.1186/s12986-019-0404-1 · Cited by 39
“For example, under cold stimulation, adipose-derived fibroblast growth factor 21 (FGF21) can act in an autocrine/paracrine manner to increase the expression of Ucp1 and other thermogenic genes in fat tissues, which is independent of the β3-adrenergic signaling pathway [94, 95].”
BackgroundStudying Brown Adipose Tissue in a Human in vitro Context
Samuelson, I., & Vidal‐Puig, A. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.00629 · Cited by 38
“These include fibroblast growth factor 21 (FGF21), which may regulate browning of scWAT through activation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) (36), as well as through UCP1-independent mechanisms (37).”
BackgroundBrowning of White Adipose Tissue as a Therapeutic Tool in the Fight against Atherosclerosis
Roth, C. L., Molica, F., & Kwak, B. R. (2021) · Metabolites · doi:10.3390/metabo11050319 · Cited by 37
“It stimulates PPAR-γ activity and PGC1-α expression, and enhances UCP1 production, increasing the thermogenic activity in beige and brown cells [42,44,45].”
BackgroundXiao, F., Jiang, H., Li, Z., Jiang, X., Chen, S., Niu, Y., Yin, H., Shu, Y., Peng, B., Lu, W., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-38141-0 · Cited by 36
Yi, X., Yang, Y., Li, T., Li, M., Yao, T., Hu, G., Wan, G., & Chang, B. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1192458 · Cited by 36
“Glucose uptake by tissues can occur through both insulin-dependent and insulin-independent pathways (40), and BAIBA has been speculated to regulate blood glucose levels in IR or T2DM in an insulin-independent manner.”
BackgroundLi, S., Zou, T., Chen, J., Li, J., & You, J. (2023) · Genes & Diseases · doi:10.1016/j.gendis.2023.06.033 · Cited by 37
Acute effect of exercise intensity on circulating FGF-21, FSTL-1, cathepsin B, and BDNF in young men
Ji, M., Cho, C., & Lee, S. (2023) · Journal of Exercise Science & Fitness · doi:10.1016/j.jesf.2023.11.002 · Cited by 36
“15,17 Another exerkine, follistatin-like protein 1 (FSTL-1), predominantly secreted in skeletal muscle and heart, amelio-rates endothelial cell function and stimulates revascularization in ischemic tissue via activation of the endothelial nitric oxide synthase (eNOS) signaling mechanism.”
BackgroundLi, X., Zhao, Y., Qi, X., Cui, J., Zhou, Y., Tan, Y., Huang, X., & Ye, H. (2024) · Current Research in Food Science · doi:10.1016/j.crfs.2024.100683 · Cited by 38
“Our data showed the naringin treatment significantly increased the expression of such biomarkers in the process of “ browning ” of iWAT as UCP1 and PGC-1 α (Fm et al., 2012; X et al., 2016).”
BackgroundInfluentialJohnson, C. L., Mehmood, R., Laing, S. W., Stepniak, C. V., Kharitonenkov, A., & Pin, C. L. (2014) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00559.2013 · Cited by 36
“Mice containing a deletion of Mist1 (Mist1 / ) or Fgf21 (Fgf21 / ) or overexpressing the human FGF21 from the ApoE promoter (ApoEFGF21) have been described (14, 25, 42) and were all on a C57/Bl6 background.”
BackgroundRizk, F. H., Elshweikh, S. A. R., & El-Naby, A. Y. A. (2015) · Canadian Journal of Physiology and Pharmacology · doi:10.1139/cjpp-2015-0371 · Cited by 36
“The conversion of white adipocytes to brown adipocytes leads to an increase in energy expenditure and thermogenesis with subsequent improvement in insulin sensitivity, reductions in body weight, and improved glucose tolerance in mice (Fisher et al. 2012).”
BackgroundMartinez-Perez, B., Ejarque, M., Gutiérrez, C., Núñez‐Roa, C., Roche, K., Vila‐Bedmar, R., Ballesteros, M., Redondo‐Angulo, I., Planavila, A., Villarroya, F., et al. (2016) · Translational research · doi:10.1016/j.trsl.2016.06.012 · Cited by 34
Tamucci, K. A., Namwanje, M., Fan, L., & Qiang, L. (2017) · Protein & Cell · doi:10.1007/s13238-017-0434-2 · Cited by 39
“The browning capacity of FGF21 is mediated through stabilization of Pgc-1α (Chau et al. 2010; Fisher et al. 2012) or a positive-feedback on PPARγ activation (Dutchak et al. 2012).”
BackgroundInfluentialChoi, J. H., Song, N., Lee, A. R., Lee, D. H., Seo, M.-J., Kim, S., Chang, S., Yang, D. K., Hwang, Y.-J., Hwang, K., et al. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms20010026 · Cited by 36
“In addition, the liver has been shown to participate in the thermogenic effects during cold exposure in mice [41].”
BackgroundTherapeutic Approaches to Alzheimer’s Type of Dementia: A Focus on FGF21 Mediated Neuroprotection
Taliyan, R., Chandran, S. K., & Kakoty, V. (2019) · Current Pharmaceutical Design · doi:10.2174/1381612825666190716101411 · Cited by 35
Cooke, D., Mattocks, D. A. L., Nichenametla, S. N., Anunciado‐Koza, R. P., Koza, R. A., & Ables, G. P. (2020) · Obesity · doi:10.1002/oby.22763 · Cited by 36
Elevated Serum Fibroblast Growth Factor 21 in Humans with Acute Pancreatitis
Shenoy, V. K., Beaver, K. M., Fisher, F. M., Singhal, G., Dushay, J. R., Maratos–Flier, E., & Flier, S. N. (2016) · PLoS ONE · doi:10.1371/journal.pone.0164351 · Cited by 36
FGF21, energy expenditure and weight loss – How much brown fat do you need?
Straub, L. G., & Wolfrum, C. (2015) · Molecular Metabolism · doi:10.1016/j.molmet.2015.06.008 · Cited by 35
“In addition to its endocrine function, FGF21 may have paracrine or autocrine functions, as fat-specific knockout of FGF21 inhibits browning of white adipose tissue in adaptive thermogenesis [44].”
BackgroundResultThe Nuclear Receptor Rev-erbα Regulates Adipose Tissue-specific FGF21 Signaling
Jager, J., Wang, F., Fang, B., Lim, H., Peed, L. C., Steger, D. J., Won, K., Kharitonenkov, A., Adams, A. C., & Lazar, M. A. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.719120 · Cited by 35
Chiba, A., Watanabe‐Takano, H., Miyazaki, T., & Mochizuki, N. (2017) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-017-2723-6 · Cited by 37
Merlin, J., Sato, M., Chia, L. Y., Fahey, R. P., Pakzad, M., Nowell, C. J., Summers, R. J., Bengtsson, T., Evans, B. A., & Hutchinson, D. S. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00249 · Cited by 36
Loss of glucagon signaling alters white adipose tissue browning
Townsend, L. K., Medak, K. D., Knuth, C. M., Peppier, W. T., Charron, M. J., & Wright, D. C. (2019) · The FASEB Journal · doi:10.1096/fj.201802048rr · Cited by 35
The emerging roles of lactate as a redox substrate and signaling molecule in adipose tissues
Carrière, A., Lagarde, D., Jeanson, Y., Portais, J., Galinier, A., Ader, I., & Casteilla, L. (2020) · Journal of Physiology and Biochemistry · doi:10.1007/s13105-019-00723-2 · Cited by 35
“It also contributes to the browning remodeling of white adipocytes [22, 28].”
BackgroundQueen, N. J., Bates, R., Huang, W., Xiao, R., Appana, B., & Cao, L. (2020) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2020.12.011 · Cited by 38
“In white adipose tissue (WAT), FGF21 stimulates glucose uptake in an insulin-independent manner,(6) modulates lipolysis,(3) regulates mitochondrial activity,(7) and regulates adaptive thermogenesis.(8) Furthermore, the antidiabetic actions of FGF21—resulting in improvements in obesity-induced hyperglycemia, hypertrigl…”
BackgroundLow Protein Diets and Energy Balance: Mechanisms of Action on Energy Intake and Expenditure
Pezeshki, A., & Chelikani, P. K. (2021) · Frontiers in Nutrition · doi:10.3389/fnut.2021.655833 · Cited by 36
“The thermogenic effects of low protein diets have been associated with (i) increased sympathetic flux to brown adipose tissue (BAT) via β-adrenergic receptor (β-AR) signaling (50, 51, 55–57, 72, 73), as well as stimulation of thermogenesis in white adipose tissue (74) and muscle (27), (ii) FGF21 and mitochondrial unco…”
BackgroundCan Brown Fat Win the Battle Against White Fat?
Elattar, S., & Ande, S. (2015) · Journal of Cellular Physiology · doi:10.1002/jcp.24986 · Cited by 37
“Although WAT consists of a small fraction of immune and stromal cell populations (Gimble et al., 2011; Lolmede et al., 2011), it is predominantly composed of white adipocytes.”
BackgroundMetabolic actions of FGF21: molecular mechanisms and therapeutic implications
Ge, X., Wang, Y., Lam, K. S., & Xu, A. (2012) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2012.06.011 · Cited by 35
Thermogenesis and Energy Metabolism in Brown Adipose Tissue in Animals Experiencing Cold Stress
Zhang, X., Jin, X., Jiang, M., Phillips, C. J. C., & Shi, B. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26073233 · Cited by 42
“Fisher et al. [61] showed that thermogenesis in both differentiated brown and inguinal adipocytes necessitates the presence of PGC-1 α , as evidenced by their findings in a PGC-1 α KO model. p38 MAPK activates PGC-1 α , which enhances its activity of PGC-1 α as a gene transcriptional coactivator.…”
Recently Discovered Adipokines and Cardio-Metabolic Comorbidities in Childhood Obesity
Barraco, G. M., Luciano, R., Semeraro, M., Prieto-Hontoria, P. L., & Manco, M. (2014) · International Journal of Molecular Sciences · doi:10.3390/ijms151119760 · Cited by 33
Akyol, M., Alacacıoğlu, A., Demir, L., Küçükzeybek, Y., Yıldız, Y., Gumus, Z., Kara, M., Salman, T., Varol, U., Taşkaynatan, H., et al. (2017) · Cancer Biomarkers · doi:10.3233/cbm-161507 · Cited by 34
“FGF-21 exerts hormone-like effects, and it has been demonstrated to be linked to thermogenesis hyperglycemia, hyper-lipidemia, obesity, hepatic steatosis and metabolic syndrome [15–18].”
Regulation of thermogenic adipocytes during fasting and cold
Reinisch, I., Schreiber, R., & Prokesch, A. (2020) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2020.110869 · Cited by 36
Glucagon receptor signaling regulates weight loss via central KLB receptor complexes
Nason, S. R., Antipenko, J., Presedo, N., Cunningham, S. E., Pierre, T. H., Kim, T., Paul, J. R., Holleman, C., Young, M. E., Gamble, K. L., et al. (2021) · JCI Insight · doi:10.1172/jci.insight.141323 · Cited by 34
“In the last decade, FGF21 has emerged as an appealing therapeutic for obesity and the metabolic syndrome (15-20) with pleotropic effects on thermogenesis (19, 20), fatty acid oxidation (21), glucose metabolism (24-26), and body weight (25).”
Self-citationFGF10 and Lipofibroblasts in Lung Homeostasis and Disease: Insights Gained From the Adipocytes
Lv, Y., Dhlamini, Q., Chen, C., Li, X., Bellusci, S., & Zhang, J. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.645400 · Cited by 36
“Moreover, in obese lungs, LIFs, and AT2 cells alike, extensively accumulate lipid droplets (Foster et al., 2010), which in turn may lead to lipotoxicity, and lipotoxicity-mediated outcomes, such as cell cycle arrest and apoptosis, often observed in IPF among other lung pathologies.”
BackgroundInfluentialModulation of energy balance by fibroblast growth factor 21
Ramos, D. C., & Aguilar-Salinas, C. A. (2016) · Hormone Molecular Biology and Clinical Investigation · doi:10.1515/hmbci-2016-0023 · Cited by 36
“Patients with pheochromocytoma and very high adrenergic action occasioned by high catecholamine release by tumor showed higher proportion of beige cells in omental WAT with higher expression of FGF21 and UCP1 [23].”
BackgroundInfluentialCharacterization of the central neural projections to brown, white, and beige adipose tissue
Wiedmann, N. M., Stefanidis, A., & Oldfield, B. J. (2017) · The FASEB Journal · doi:10.1096/fj.201700433r · Cited by 33
Igfbp2 Deletion in Ovariectomized Mice Enhances Energy Expenditure but Accelerates Bone Loss
DeMambro, V., Le, P. T., Guntur, A. R., Maridas, D. E., CANALIS, E. M., Nagano, K., Baron, R., Clemmons, D. R., & Rosen, C. J. (2015) · Endocrinology · doi:10.1210/en.2014-1452 · Cited by 33
Plasma FGF21 levels are increased in patients with hypothyroidism independently of lipid profile
Lee, Y., Park, Y. J., Ahn, H. Y., Lim, J., Park, K. U., Choi, S. H., Park, D. J., Oh, B., Jang, H. C., & Yi, K. H. (2013) · Endocrine Journal · doi:10.1507/endocrj.ej12-0427 · Cited by 33
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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