Discrete Aspects of FGF21 In Vivo Pharmacology Do Not Require UCP1

Samms, Ricardo J.; Smith, Dennis P.; Cheng, Christine C.; Antonellis, Patrick P.; Perfield, James W.; Kharitonenkov, Alexei; Gimeno, Ruth E.; Adams, Andrew C.

doi:10.1016/j.celrep.2015.04.046

Cited by 154Fibroblast Growth Factor ResearchAdipose Tissue and MetabolismAdipokines, Inflammation, and Metabolic Diseases

Discrete Aspects of FGF21 In Vivo Pharmacology Do Not Require UCP1

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Samms, Ricardo J., Smith, Dennis P., Cheng, Christine C., Antonellis, Patrick P., Perfield, James W., Kharitonenkov, Alexei, Gimeno, Ruth E., Adams, Andrew C.·2015·Cell Reports

DOI 10.1016/j.celrep.2015.04.046

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Abstract

A primary target of the pleiotropic metabolic hormone FGF21 is adipose tissue, where it initiates a gene expression program to enhance energy expenditure, an effect presumed to be centered on augmented UCP1 expression and activity. In UCP1 null (UCP1KO) mice, we show that the effect of FGF21 to increase the metabolic rate is abolished. However, in contrast to prior expectations, we found that increased UCP1-dependent thermogenesis is only partially required to achieve the beneficial effects of FGF21 treatment. In UCP1KO mice, there appears to be an underlying reduction in food intake following FGF21 administration, facilitating weight loss equal to that observed in wild-type animals. Furthermore, we show that UCP1-dependent thermogenesis is not required for FGF21 to improve glycemic control or to reduce circulating cholesterol or free fatty acids. These data indicate that several important metabolic endpoints of FGF21 are UCP1 independent; however, the contribution of UCP1-dependent thermogenesis to other discrete aspects of FGF21 biology requires further study.

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Two independent studies revealed FGF21 significantly decreases body weight in the absence of UCP1.
“two independent studies have revealed that FGF21 significantly decreases body weight in the absence of UCP1 (refs. 102,103).”
From Metabolic messengers: FGF21 (2021) · cites this paper as [103]
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 [111]

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In Brief
Samms, R. J., Smith, D. P., Gimeno, R. E., & Adams, A. C. (2015)
Self-citation
FGF21-Mediated Improvements in Glucose Clearance Require Uncoupling Protein 1
Kwon, M. M., O’Dwyer, S. M., Baker, R. K., Covey, S. D., & Kieffer, T. J. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.10.021 · Cited by 77 · see citing works
A pyrexic effect of FGF21 independent of energy expenditure and UCP1
Zouhar, P., Janovská, P., Stanić, S., Bardová, K., Funda, J., Haberlova, B., Andersen, B., Rossmeisl, M., Cannon, B., Kopecký, J., et al. (2021) · Molecular Metabolism · doi:10.1016/j.molmet.2021.101324 · Cited by 24 · see citing works
Endogenous FGF21-signaling controls paradoxical obesity resistance of UCP1-deficient mice
Keipert, S., Lutter, D., Schroeder, B. O., Brandt, D., Ståhlman, M., Schwarzmayr, T., Graf, E., Fuchs, H., de Angelis, M. H., Tschöp, M. H., et al. (2020) · Nature Communications · doi:10.1038/s41467-019-14069-2 · Cited by 82 · see citing works

Authors: Samms, R. J., Smith, D. P., Cheng, C. C., Antonellis, P. P., Perfield, J. W., Kharitonenkov, A., Gimeno, R. E., & Adams, A. C.
Affiliations: Eli Lilly (United States) (US)
Corresponding author: Adams, Andrew C.
ORCID: Samms, Ricardo J.
Perfield, James W.
Kharitonenkov, Alexei
Adams, Andrew C.
Venue: Cell Reports
Publisher: Elsevier BV
Published: 2015-05
Volume: 11
Issue: 7
Pages: 991-999
ISSN: 2211-1247 (ISSN-L)
DOI: 10.1016/j.celrep.2015.04.046
OpenAlex: W1697181819
Cited by: 154
References: 37
Citations by year: 2026: 5 · 2025: 5 · 2024: 7 · 2023: 7 · 2022: 10 · 2021: 16 · 2020: 14 · 2019: 16 · 2018: 11 · 2017: 20 · 2016: 22 · 2015: 21
FWCI: 10.72
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by-nc-nd
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
creativecommons.org/licenses/by-nc-nd/4.0/ (vor)
Locations: Cell Reports (publishedVersion, cc-by-nc-nd)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
Keywords: FGF21, UCP1, thermogenesis, energy expenditure, UCP1 knockout mice, dietary intake, weight loss, glycemic control, cholesterol, free fatty acids, adipose tissue, metabolic hormones
MeSH terms: Uncoupling Protein 1, Animals, Adipose Tissue, Brown, Eating, Energy Metabolism, Fibroblast Growth Factors, Ion Channels, Male, Mice, Inbred C57BL, Blotting, Western, Mice, Knockout, Thermogenesis, Mitochondrial Proteins, Mice, Adipose Tissue, White, Real-Time Polymerase Chain Reaction

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Discrete Aspects of FGF21 In Vivo Pharmacology Do Not Require UCP1

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