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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Weight loss likely occurs at the expense of VAT, as evidenced by a 15% mean decrease in abdominal fat content, measured by DEXA, in obese monkeys.
“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]
The Results and Discussion section (“FGF21 acts on the hypothalamus”; page not provided) reports reduced body weight and percent body fat after FGF21 treatment in obese mice. It does not report a 15% decrease in abdominal fat, a VAT measurement, or DEXA results in obese monkeys; the Mouse studies section says body composition was measured by EchoMRI. (LLM, conf=0.86)
Experimental — accuracy not yet measuredFGF21 augments BAT function indirectly by increasing SNS output.
“FGF21 further augments BAT function indirectly, by increasing SNS output [163,165] (7)”
Effects of extended FGF21 signalling in promoting weight loss through increased energy expenditure are mediated through direct actions on the CNS, not adipose tissues.
“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]
FGF21 signals directly to the CNS, at least in rodents, and consequently regulates energy expenditure and improves glucose and lipid homeostasis.
“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]
FGF21 signals the CNS to increase energy expenditure and decrease body weight.
“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]
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).
“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]
FGF21 administration increases sympathetic nerve activity to BAT and WAT, and browning of WAT depots.
“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]
Administration of a corticotropin-releasing hormone antagonist blocks FGF21-mediated increases in sympathetic nerve activity to BAT.
“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]
FGF21-mediated increases in sympathetic nerve activity to BAT appear to require hypothalamic corticotropin-releasing hormone.
“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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- 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 › 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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