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Skeletal muscle mitochondrial uncoupling drives endocrine cross-talk through the induction of FGF21 as a myokine
Open accessAbstract
UCP1-Tg mice with ectopic expression of uncoupling protein 1 (UCP1) in skeletal muscle (SM) are a model of improved substrate metabolism and increased longevity. Analysis of myokine expression showed an induction of fibroblast growth factor 21 (FGF21) in SM, resulting in approximately fivefold elevated circulating FGF21 in UCP1-Tg mice. Despite a reduced muscle mass, UCP1-Tg mice showed no evidence for a myopathy or muscle autophagy deficiency but an activation of integrated stress response (ISR; eIF2α/ATF4) in SM. Targeting mitochondrial function in vitro by treating C 2 C 12 myoblasts with the uncoupler FCCP resulted in a dose-dependent activation of ISR, which was associated with increased expression of FGF21, which was also observed by treatment with respiratory chain inhibitors antimycin A and myxothiazol. The cofactor required for FGF21 action, β-klotho, was expressed in white adipose tissue (WAT) of UCP1-Tg mice, which showed an increased browning of WAT similar to what occurred in altered adipocyte morphology, increased brown adipocyte markers (UCP1, CIDEA), lipolysis (HSL phosphorylation), and respiratory capacity. Importantly, treatment of primary white adipocytes with serum of transgenic mice resulted in increased UCP1 expression. Additionally, UCP1-Tg mice showed reduced body length through the suppressed IGF-I-GH axis and decreased bone mass. We conclude that the induction of FGF21 as a myokine is coupled to disturbance of mitochondrial function and ISR activation in SM. FGF21 released from SM has endocrine effects leading to increased browning of WAT and can explain the healthy metabolic phenotype of UCP1-Tg mice. These results confirm muscle as an important endocrine regulator of whole body metabolism.
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“the other hand, FGF21 expression in the muscle is reportedly elevated during mitochondrial dysfunction, and protects against obesity and insulin resistance [40, 41].”
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“…the transcriptional co-activator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1a, gene name Ppargc1a) as markers for brown adipocyte were not induced in either F1 or N2-tg mice which is in contrast to findings in UCP1-tg mice on a Bl6 background (Keipert et al. 2014).”
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“The decrease in BAT mRNA levels of Ucp1 (molecular marker of energy expenditure for thermogenesis) detected in late adult mice (as compared to younger mice) could also contribute to obesity (Keipert et al. 2014).”
BackgroundHepatic Fgf21 Expression Is Repressed after Simvastatin Treatment in Mice
Ziros, P. G., Zagoriti, Z., Lagoumintzis, G., Kyriazopoulou, V. E., Iskrenova, R. P., Habeos, E. E., Sykiotis, G. P., Chartoumpekis, D. V., & Habeos, I. G. (2016) · PLoS ONE · doi:10.1371/journal.pone.0162024 · Cited by 11
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Molecular Mechanisms Mediating Adaptation to Exercise
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Pseudo-Starvation Driven Energy Expenditure Negatively Affects Ovarian Follicle Development
Li, M., Coleman, V., Zhao, Y., Ost, M., Voigt, A., Bunschoten, A., Keijer, J., Teerds, K. J., & Klaus, S. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22073557 · Cited by 10
“UCP1-TG mice also display alterations in several other plasma hormones, including strongly increased levels of fibroblast growth factor 21 (FGF21) [37].”
BackgroundResultInfluentialSelf-citationLarson, K., Bundy, A. N., Lance, E. B., Darland, D. C., Casperson, S. L., & Roemmich, J. N. (2021) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2021.108853 · Cited by 10
“FGF21 is associated with regulation of adiposity by modulating energy expenditure and lipid metabolism [18– 20], including greater thermogenesis and beiging of white adipocytes [21].”
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“However, muscle FGF-21 release is elevated under conditions like fasting, exercise, and mitochondrial myopathy [128].”
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Lactate induces expression and secretion of fibroblast growth factor-21 by muscle cells
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“Although the source of elevated FGF21 in patients with mitochondrial diseases that manifest in muscle is not fully known, mitochondrial DNA mutations or experimental mitochondrial perturbations in muscle lead to enhanced expression and release of FGF21 by skeletal muscle [4, 5], a tissue not considered to be a substan…”
BackgroundGil, C. I., Löser, A., Lossow, K., Schwarz, M., Weber, D., Grune, T., Kipp, A. P., Klaus, S., & Ost, M. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1277866 · Cited by 11
“We have previously demonstrated the induction of FGF21 and GDF15 as non-cell-autonomous, systemic effects of muscle mitochondrial uncoupling (12, 23).”
BackgroundInfluentialSelf-citationStreeter, J., Persaud, L., Gao, J., Manika, D., Fairman, W., García-Peña, L. M., Marti, A., Manika, C., Gaddi, S., Schickling, B., et al. (2024) · Frontiers in Endocrinology · doi:10.3389/fendo.2024.1325286 · Cited by 8
Skeletal muscle growth to combat diabetes and obesity: the potential role of muscle‐secreted factors
Sammut, M. J., Thorne, B. R., & Melling, C. W. J. (2025) · Obesity · doi:10.1002/oby.24223 · Cited by 8
“Unlike constitutive Akt1, the transgenic mTORC1 and mitochondrial uncoupling rodent models exhibit reductions in muscle mass without myopathy, likely resulting from the enhanced whole-body energy expenditure and largely mediated by FGF21 [14, 35].”
Effect of myokines on bone tissue metabolism: a systematic review
Jaśkiewicz, Ł., Romaszko-Wojtowicz, A. M., Chmielewski, G., Kuna, J., & Krajewska–Włodarczyk, M. (2025) · Bone · doi:10.1016/j.bone.2025.117654 · Cited by 11
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Masania, J., Wijten, P., Keipert, S., Ost, M., Klaus, S., Rabbani, N., & Thornalley, P. J. (2022) · Redox Biology · doi:10.1016/j.redox.2022.102574 · Cited by 7
Self-citationThe emerging role of fibroblast growth factor 21 in diabetic nephropathy
Mao, S., Ren, X., & Zhang, J. (2016) · Journal of Receptors and Signal Transduction · doi:10.3109/10799893.2016.1147582 · Cited by 7
“Skeletal muscle mitochondrial uncoupling drives endocrine cross-talk through the induction of FGF21 as a myokine (65).”
BackgroundEditorial: Role of mitochondrial stress response in metabolic health
Pereira, R. O., & Keipert, S. (2024) · Frontiers in Endocrinology · doi:10.3389/fendo.2024.1504718 · Cited by 7
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Exerkines: Benign adaptation for exercise and benefits for non-alcoholic fatty liver disease
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Direct activation of the fibroblast growth factor-21 pathway in overweight and obese cats
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FOXO1 represses PPARα-Mediated induction of FGF21 gene expression
Sousa‐Coelho, A. L. D., Gacias, M., O'Neill, B. T., Relat, J., Link, W., Haro, D., & Marrero, P. F. (2023) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2023.01.012 · Cited by 5
UPRmt-regulated mitokines: novel strategies for myocardial injury repair
Gao, W., Liu, J., Zhang, W., Liu, B., & Shen, L. (2025) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2025.1652353 · Cited by 4
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Potential role of Akt in the regulation of fibroblast growth factor 21 by berberine
Hirai, T., Wang, W., Murono, N., Iwasa, K., & Inoue, M. (2023) · Journal of Natural Medicines · doi:10.1007/s11418-023-01755-1 · Cited by 4
“The regulation of FGF21 expression is associated with different signaling molecules in skeletal muscle cells [22–25, 32, 33].”
Bibliometric analysis of fibroblast growth factor 21 research over the period 2000 to 2021
She, Q.-Y., Li, L., Liu, M.-H., Tan, R.-Y., Zhong, Y.-W., Bao, J., & Xie, J.-D. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.1011008 · Cited by 9
“Notably, in addition to traditional topics, such as the metabolic effects of FGF-21 on peripheral tissues (Adams et al., 2013b; De Sousa-Coelho et al., 2013; Holland et al., 2013; Kim et al., 2013; Lin et al., 2013; Emanuelli et al., 2014; Fisher et al., 2014; Jiang et al., 2014; Keipert et al., 2014; Markan et al., 2…”
BackgroundCircadian Regulation of Endocrine Fibroblast Growth Factors on Systemic Energy Metabolism
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“Also, we find that FGF21 and GDF15 mRNA expression were higher in muscle of mKO mice compared to WT controls, and for GDF15 also plasma levels were elevated (Fig.”
InfluentialZhang, X., Li, Z., Wang, S., & Chen, Y. (2025) · Nutrients · doi:10.3390/nu17071179 · Cited by 2
“It interacts with adipose tissue to regulate its browning [29], and autophagy deficiency in skeletal muscle protects mice from obesity and insulin resistance by stimulating the production of this myokine [30].”
Role of ChREBP–PPARα–FGF21 Axis in Metabolic Dysfunction of MASLD
Girón, K. M. P., Nazará, Z., Maldonado‐González, M., Martínez‐López, E., Sánchez-Muñoz, M. P., Bautista-López, C. A., Aldana-Aguiñaga, M. S., Domínguez-Rosales, J. A., Vargas‐Guerrero, B., & Ruiz‐Madrigal, B. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms262311425 · Cited by 3
“FGF21 has been suggested as a marker of mitochondrial adaptive flexibility [115], mitochondrial dysfunction [116,117], autophagy deficiency [118], and endoplasmic reticulum stress.”
Muscle-to-CNS signaling in physiological homeostasis, aging, and disease
Chuang, C.-L., Rai, M., & Demontis, F. (2026) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2026.03.006 · Cited by 2
Effect of exercise on Fibroblast Growth Factor 21 levels in healthy males and females
Peterson, M. N., Richardson, K. A., & Funderburk, L. (2025) · PLoS ONE · doi:10.1371/journal.pone.0321738 · Cited by 2
“While FGF21 may act as a myokine in some situations [30,31], circulating levels of FGF21 are believed to be of hepatic origin [32], particularly after exercise [7,9].”
Kiyama, G., Nakashima, K., Shimada, K., Murono, N., Kakihana, W., Imai, H., Inoue, M., & Hirai, T. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2021.112078 · Cited by 2
Metadata
- Authors
- Keipert, S., Ost, M., Johann, K., Imber, F., Jastroch, M., van Schothorst, E. M., Keijer, J., & Klaus, S.
- Affiliations
- Helmholtz Munich (DE)
- German Institute of Human Nutrition (DE)
- Department of Human and Animal Physiology, Wageningen University, Wageningen, The Netherlands; and
- Wageningen University & Research (NL)
- Corresponding author
- Keipert, Susanne
- Venue
- American Journal of Physiology-Endocrinology and Metabolism
- Publisher
- American Physiological Society
- Published
- 2014-03-01
- Volume
- 306
- Issue
- 5
- Pages
- E469-E482
- ISSN
- 0193-1849 (ISSN-L)
- 1522-1555
- OpenAlex
- W2169091672
- Cited by
- 221
- References
- 64
- Citations by year
- 2026: 10 · 2025: 15 · 2024: 13 · 2023: 19 · 2022: 21 · 2021: 24 · 2020: 14 · 2019: 16 · 2018: 16 · 2017: 19 · 2016: 20 · 2015: 22 · 2014: 11
- FWCI
- 7.91
- Type
- journal article
- Language
- en
- Open access
- green
- research.wur.nl
- Locations
- American Journal of Physiology-Endocrinology and Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Socio-Environmental Systems Modeling (acceptedVersion)
- Site cant be reached (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Keywords
- skeletal muscle, mitochondrial uncoupling, UCP1, FGF21, myokines, integrated stress response, β-Klotho, white adipose tissue browning, brown adipocytes, lipolysis, bone mass, longevity, FCCP, antimycin A, myxothiazol
- MeSH terms
- Uncoupling Protein 1, Animals, Body Composition, Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone, Cell Line, Energy Metabolism, Fibroblast Growth Factors, Ion Channels, Mice, Transgenic, Mitochondria, Phosphorylation, Uncoupling Agents, Bone Density, Muscle, Skeletal, Mitochondrial Proteins, Myoblasts, Mice, Adipose Tissue, White
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