FGF21 mimetic antibody stimulates UCP1-independent brown fat thermogenesis via FGFR1/βKlotho complex in non-adipocytes
Open accessAbstract
OBJECTIVE: Fibroblast Growth Factor 21 (FGF21) is a potent stimulator of brown fat thermogenesis that improves insulin sensitivity, ameliorates hepatosteatosis, and induces weight loss by engaging the receptor complex comprised of Fibroblast Growth Factor Receptor 1 (FGFR1) and the requisite coreceptor βKlotho. Previously, recombinant antibody proteins that activate the FGFR1/βKlotho complex were proposed to act as an FGF21-mimetic; however, in vivo action of these engineered proteins has not been well studied. METHODS: We investigated the mechanism by which anti-FGFR1/βKlotho bispecific antibody (bFKB1) stimulates thermogenesis in UCP1-expressing brown adipocytes using genetically engineered mice. Anti-FGFR1 agonist antibody was also used to achieve brown adipose tissue restricted activation in transgenic mice. RESULTS: Studies with global Ucp1-deficient mice and adipose-specific Fgfr1 deficient mice demonstrated that bFKB1 acts on targets distal to adipocytes and indirectly stimulates brown adipose thermogenesis in a UCP1-independent manner. Using a newly developed transgenic system, we also show that brown adipose tissue restricted activation of a transgenic FGFR1 expressed under the control of Ucp1 promoter does not stimulate energy expenditure. Finally, consistent with its action as a FGF21 mimetic, bFBK1 suppresses intake of saccharin-containing food and alcohol containing water in mice. CONCLUSIONS: Collectively, we propose that FGFR1/βKlotho targeted therapy indeed mimics the action of FGF21 in vivo and stimulates UCP1-independent brown fat thermogenesis through receptors outside of adipocytes and likely in the nervous system.
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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 [85]
UCP1 is dispensable for FGF21-mediated increases in energy expenditure.
“However, while adipose tissues are critical for these metabolic effects, UCP1 is dispensable for FGF21-mediated increases in energy expenditure (17, 85, 111, 132).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [17]
Neither the inducible expression of a constitutively active FGFR1 protein specifically in adipose tissue nor antibody-mediated activation of a chimeric human FGFR1 receptor in brown adipocytes is sufficient to increase energy expenditure or affect body weight in vivo.
“Neither the inducible expression of a constitutively active FGFR1 protein specifically in adipose tissue (11) nor antibody-mediated activation of a chimeric human FGFR1 receptor in brown adipocytes (17) is sufficient to increase energy expenditure or affect body weight in vivo.”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [17]
Activation of FGFR1-dependent signaling specifically in adipose tissues is not sufficient to induce the beneficial metabolic effects of FGF21 in vivo.
“In addition to the loss-of-function studies, independent groups also found that the activation of FGFR1-dependent signaling specifically in adipose tissues is not sufficient to induce the beneficial metabolic effects of FGF21 in vivo (11, 17).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [17]
Adipose-specific Fgfr1 knockout mice (Fgfr1fl/fl;Adiponectin-Cre) respond to chronic FGF21 administration similarly to control mice.
“Consistent with these results, adipose-specific Fgfr1 knockout mice (Fgfr1fl/fl;Adiponectin-Cre) were also recently shown to respond to chronic FGF21 administration similarly to control mice (17) in contrast to the results obtained with Fgfr1fl/fl;ap2-Cre mice (4).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [17]
The core effect of FGF21 to suppress sweet and alcohol intake has been replicated by additional studies.
“this core effect of FGF21 to suppress sweet and alcohol intake has since been replicated by additional studies”
From FGF21 and the physiological regulation of macronutrient preference (2020) · cites this paper as [180]
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- Authors
- Chen, M. Z., Chang, J. C., Zavala-Solorio, J., Kates, L., Thai, M., Ogasawara, A., Bai, X., Flanagan, S., Nunez, V., Phamluong, K., Ziai, J., Newman, R., Warming, S., Kolumam, G., & Sonoda, J.
- Affiliations
- Genentech (US)
- Corresponding author
- Sonoda, Junichiro
- ORCID
- Venue
- Molecular Metabolism
- Publisher
- Elsevier BV
- Published
- 2017-11
- Volume
- 6
- Issue
- 11
- Pages
- 1454-1467
- ISSN
- 2212-8778 (ISSN-L)
- PMC
- PMC5681280
- OpenAlex
- W2755264179
- Cited by
- 58
- References
- 70
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 6 · 2023: 4 · 2022: 8 · 2021: 7 · 2020: 9 · 2019: 6 · 2018: 5
- FWCI
- 2.23
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Molecular Metabolism (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Genentech
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Keywords
- FGF21, FGFR1, β-Klotho, brown adipose tissue thermogenesis, energy expenditure, alcohol consumption, saccharin intake, nervous system
- MeSH terms
- Uncoupling Protein 1, Klotho Proteins, Animals, Antibodies, Adipose Tissue, Brown, Energy Metabolism, Fibroblast Growth Factors, Membrane Proteins, Mice, Transgenic, Obesity, Weight Loss, Mice, Knockout, Thermogenesis, Mitochondrial Proteins, Mice, Receptor, Fibroblast Growth Factor, Type 1, Adipose Tissue, White, Adipocytes, Brown
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