The DOI matches its Crossref record; 45 of the 45 references it cites were found in a registry or an index.
FGF21 Acts Centrally to Induce Sympathetic Nerve Activity, Energy Expenditure, and Weight Loss
Open accessAbstract
The mechanism by which pharmacologic administration of the hormone FGF21 increases energy expenditure to cause weight loss in obese animals is unknown. Here we report that FGF21 acts centrally to exert its effects on energy expenditure and body weight in obese mice. Using tissue-specific knockout mice, we show that βKlotho, the obligate coreceptor for FGF21, is required in the nervous system for these effects. FGF21 stimulates sympathetic nerve activity to brown adipose tissue through a mechanism that depends on the neuropeptide corticotropin-releasing factor. Our findings provide an unexpected mechanistic explanation for the strong pharmacologic effects of FGF21 on energy expenditure and weight loss in obese animals.
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In the citing paper
“Weight loss likely occurs [163,165] at the expense of VAT, as evidenced by a 15% mean decrease in abdominal fat content, measured by DEXA, in obese monkeys [165].”
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 [163]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“FGF21 further augments BAT function indirectly, by increasing SNS output [163,165] (7)”
In the citing paper
“These effects of extended FGF21 signalling in promoting weight loss through increased energy expenditure are mediated through direct actions on the central nervous system67,80–84, not adipose tissues65,67,85”
From Metabolic messengers: FGF21 (2021) · cites this paper as [80]
In the citing paper
“Instead, FGF21 signals directly to the CNS (Fig. 3a), at least in rodents, and consequently regulates energy expenditure and improves glucose and lipid homeostasis80,82.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [80]
In the citing paper
“while it signals the CNS to increase energy expenditure and decrease body weight [169,171,172] (Figure 2).”
From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [172]
In the citing paper
“The chronic metabolic effects of FGF21 on body weight and glucose homeostasis are lost when β-klotho is deleted from the CNS (Klbfl/fl;Camk2a-Cre) (101, 126).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [101]
In the citing paper
“FGF21 administration increases sympathetic nerve activity to BAT (101) and WAT (28), and browning of WAT depots (28, 101).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [101]
In the citing paper
“The administration of a corticotropin-releasing hormone antagonist blocks FGF21-mediated increases in sympathetic nerve activity to BAT (101).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [101]
In the citing paper
“Interestingly, FGF21-mediated increases in sympathetic nerve activity to BAT appear to require hypothalamic corticotropin-releasing hormone.”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [101]
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Citations
Cites
Brown Adipose Tissue: Function and Physiological Significance
CANNON, B., & NEDERGAARD, J. (2004) · Physiological Reviews · doi:10.1152/physrev.00015.2003 · Cited by 6,433
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
FGF21 regulates PGC-1α and browning of white adipose tissues in adaptive thermogenesis
Fisher, F. M., Kleiner, S., Douris, N., Fox, E. C., Mepani, R. J., Verdeguer, F., Wu, J., Kharitonenkov, A., Flier, J. S., Maratos-Flier, E., et al. (2012) · Genes & Development · doi:10.1101/gad.177857.111 · Cited by 1,478 · cited 8×
“FGF21 also promotes the browning of scWAT (Fisher et al., 2012), an effect that in vivo involves bKlotho in the nervous system.”
InfluentialXu, 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
Fibroblast Growth Factor 21 Corrects Obesity in Mice
Coskun, T., Bina, H. A., Schneider, M. A., Dunbar, J. D., Hu, C. C., Chen, Y., Moller, D. E., & Kharitonenkov, A. (2008) · Endocrinology · doi:10.1210/en.2008-0816 · Cited by 1,031
The 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
The metabolic state of diabetic monkeys is regulated by fibroblast growth factor-21
Kharitonenkov, A., Wroblewski, V. J., Koester, A., Chen, Y.-F., Clutinger, C. K., Tigno, X. T., Hansen, B. C., Shanafelt, A. B., & Etgen, G. J. (2007) · Endocrinology · doi:10.1210/en.2006-1168 · Cited by 738
Fon Tacer, K., Bookout, A. L., Ding, X., Kurosu, H., John, G. B., Wang, L., Goetz, R., Mohammadi, M., Kuro-o, M., Mangelsdorf, D. J., et al. (2010) · Molecular Endocrinology · doi:10.1210/me.2010-0142 · Cited by 700
Self-citationLin, Z., Tian, H., Lam, K. S. L., Lin, S., Hoo, R. C. L., Konishi, M., Itoh, N., Wang, Y., Bornstein, S. R., Xu, A., et al. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.04.005 · Cited by 691
BMP8B Increases Brown Adipose Tissue Thermogenesis through Both Central and Peripheral Actions
Whittle, A. J., Carobbio, S., Martins, L., Slawik, M., Hondares, E., Vázquez, M. J., Morgan, D., Csikasz, R. I., Gallego, R., Rodriguez-Cuenca, S., et al. (2012) · Cell · doi:10.1016/j.cell.2012.02.066 · Cited by 573
Self-citation
Cited by
Sorted by citations
Understanding the Physiology of FGF21
Fisher, F. M., & Maratos-Flier, E. (2016) · Annual Review of Physiology · doi:10.1146/annurev-physiol-021115-105339 · Cited by 912
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
Nonalcoholic fatty liver disease as a nexus of metabolic and hepatic diseases
Samuel, V. T., & Shulman, G. I. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2017.08.002 · Cited by 745
“This effect appears to be mediated centrally via hypothalamic receptors and activation of the sympathetic nervous system (Owen et al., 2014).”
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
The 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
Metadata
- Authors
- Owen, B. M., Ding, X., Morgan, D. A., Coate, K. C., Bookout, A. L., Rahmouni, K., Kliewer, S. A., & Mangelsdorf, D. J.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- University of Iowa (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Kliewer, Steven A.
- Mangelsdorf, David J.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2014-10
- Volume
- 20
- Issue
- 4
- Pages
- 670-677
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC4192037
- OpenAlex
- W2158477352
- Cited by
- 523
- References
- 45
- Citations by year
- 2026: 35 · 2025: 39 · 2024: 40 · 2023: 43 · 2022: 49 · 2021: 38 · 2020: 49 · 2019: 46 · 2018: 50 · 2017: 44 · 2016: 39 · 2015: 47 · 2014: 3
- FWCI
- 18.17
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (1F32DK098908, GM007062, HL084207, R01DK067158)
- Howard Hughes Medical Institute
- Welch Foundation (I-1275, I-1558)
- American Heart Association (14EIA18860041)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Keywords
- FGF21, β-Klotho, central nervous system, sympathetic activity, brown adipose tissue, energy expenditure, weight loss, corticotropin-releasing factor, obesity, tissue-specific knockout mice
- MeSH terms
- Klotho Proteins, Animals, Adipose Tissue, Brown, Corticotropin-Releasing Hormone, Energy Metabolism, Fibroblast Growth Factors, Hypothalamus, Membrane Proteins, Mice, Inbred C57BL, Mice, Obese, Mice, Transgenic, RNA, Messenger, Sympathetic Nervous System, Weight Loss, Mice, Knockout, Thermogenesis, Mice
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