The DOI matches its Crossref record; 54 of the 54 references it cites were found in a registry or an index.
Growth and differentiation factor 15 is secreted by skeletal muscle during exercise and promotes lipolysis in humans
Open accessAbstract
We hypothesized that skeletal muscle contraction produces a cellular stress signal, triggering adipose tissue lipolysis to sustain fuel availability during exercise. The present study aimed at identifying exercise-regulated myokines, also known as exerkines, able to promote lipolysis. Human primary myotubes from lean healthy volunteers were submitted to electrical pulse stimulation (EPS) to mimic either acute intense or chronic moderate exercise. Conditioned media (CM) experiments with human adipocytes were performed. CM and human plasma samples were analyzed using unbiased proteomic screening and/or ELISA. Real-time qPCR was performed in cultured myotubes and muscle biopsy samples. CM from both acute intense and chronic moderate exercise increased basal lipolysis in human adipocytes. Growth and differentiation factor 15 (GDF15) gene expression and secretion increased rapidly upon skeletal muscle contraction. GDF15 protein was upregulated in CM from both acute and chronic exercise–stimulated myotubes. We further showed that physiological concentrations of recombinant GDF15 protein increased lipolysis in human adipose tissue, while blocking GDF15 with a neutralizing antibody abrogated EPS CM-mediated lipolysis. We herein provide the first evidence to our knowledge that GDF15 is a potentially novel exerkine produced by skeletal muscle contraction and able to target human adipose tissue to promote lipolysis.
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“acute exercise in humans also releases additional molecules79, such as growth and differentiation factor 15 (GDF15)80 and IL-6 (REF.81), which also affect lipolysis”
From Exerkines in health, resilience and disease (2022) · cites this paper as [80]
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The metabolic effects of GDF15 are mediated by the orphan receptor GFRAL
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GFRAL is the receptor for GDF15 and is required for the anti-obesity effects of the ligand
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“55,56 These differential effects under varying lipid environments suggest context-dependent metabolic regulation by GDF15, highlighting its sophisticated role in hepatic lipid homeostasis.”
Yassuda, V., Sequeira, B., & Sousa‐Coelho, A. L. D. (2026) · Journal of Physiology and Biochemistry · doi:10.1007/s13105-026-01160-8 · Cited by 2
“…reduction of fat mass and hepatic steatosis in diet-induced obesity mouse models [18 ], to the increase in the adipose tissue lipolysis in humans [19 ], and to maintaining energy expenditure in skeletal muscle during caloric restriction [20 ], extending its impact beyond its anorexic affect, and…”
Wang, C., Chen, H., Shen, L., Xu, S., Xu, J., Huang, Q., Zhang, W., Lin, C. K. S., Chang, J., Liu, X., et al. (2026) · Journal of Cachexia Sarcopenia and Muscle · doi:10.1002/jcsm.70315 · Cited by 2
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“Constitutively GDF15 expression in skeletal muscle and myocardium is lower than other organs [107].”
BackgroundGabrišová, K., Kurdiová, T., Barkova, D., Pálešová, N., Babulicová, J., Tyčiaková, S., Novotová, M., Balážová, M., Sabo, M., Pustka, V., et al. (2025) · FEBS Open Bio · doi:10.1002/2211-5463.70114 · Cited by 1
“While some studies reported increased uptake [12] and oxidation of oleic [7,12,18] and palmitic acid [27,28] after low frequency (0.1 or 1 Hz, 10 V, 2 ms) 24 h or 48 h EPS, others found no change in oleate and palmitate oxidation (1 Hz, 11.5 V or 30 V, 2 ms; 24 h) [7,8] in primary human muscle…”
InfluentialAn integrative approach to detecting potential blood-based biomarkers of cognitive frailty
Furutani, M., Suganuma, M., Hosoyama, T., Mitsumori, R., Takemura, M., Matsui, Y., Nakano, Y., Niida, S., Ozaki, K., Satake, S., et al. (2025) · The journal of nutrition health & aging · doi:10.1016/j.jnha.2025.100726 · Cited by 1
“In healthy humans, circulating levels of GDF15 transiently increase following aerobic and resistance exercise, with particularly intense and prolonged exercise eliciting elevations comparable to those observed in disease states [35,36].”
Marques, S. S., Liebaug, A., Maurer, S., Rothenbacher, D., Brenner, R. E., & Riegger, J. (2025) · MedComm · doi:10.1002/mco2.70484 · Cited by 1
“Although it has been initially hypothesized that GFRAL expression was restricted to the central nervous system [40], more recent studies report the presence of GFRAL in peripheral tissues, such as adipose, pancreatic ductal adenocarcinoma, and gastric cancer tissue [41–43].”
Rahimi, R., Morton, A. B., Golpasandi, H., & Salih, S. H. (2025) · BMC Sports Science Medicine and Rehabilitation · doi:10.1186/s13102-025-01456-0 · Cited by 1
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“…hormone ⎯ catecholamines, inflamma - tory cytokines ⎯ tumor necrosis factor (TNF) & interleukin 6 (IL-6) [19 ], and different mediators of cachexia, includ - ing leukemia inhibitory factor (LIF) [ 20], ZAG [21], and growth differentiation factor 15 (GDF15) [ 22], to induce adipocyte lipolysis.”
Ker, C.-R., Chen, Y.-L., Feng, C., Wang, S.-H., Lee, C., & Chan, T. (2026) · Taiwanese Journal of Obstetrics and Gynecology · doi:10.1016/j.tjog.2025.04.027 · Cited by 1
Kim, M. Y., Harriot, A. D., & Kim, D. (2026) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2026.115896 · Cited by 1
Stern, S., Crisamore, K., Patton, J., Schuck, R. N., & Pacanowski, M. A. (2026) · Clinical and Translational Science · doi:10.1111/cts.70634 · Cited by 1
Alghamdi, N. A., Dorling, J. L., Alreshidi, A., Gerasimidis, K., & Malkova, D. (2025) · European Journal of Clinical Nutrition · doi:10.1038/s41430-025-01629-7 · Cited by 1
“Training studies are needed in PKU patients, but these fi ndings indicate that exercise could bene fi t appetite regulation, thus preventing overconsumption and assisting weight management in PKU patients.”
GDF15 in Vascular and Liver Metabolic Disorders: A Novel Therapeutic Target
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Early adipose tissue wasting in a novel preclinical model of human lung cancer cachexiaPreprint
Snoke, D. B., van der Velden, J. L. J., Bellafleur, E. R., Dearborn, J. S., Lenahan, S. M., Beal, A. E., Aboushousha, R., Heininger, S. C. J., Ather, J. L., Mank, M. M., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.09.27.615385 · Cited by 1
(2021) · Actualité et dossier en santé publique · doi:10.3917/aedesp.114.0047
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Yan, C., Wen, B., Tang, R., Tang, S., Sun, Y., Xu, J., Zhao, D., & Wang, T. (2022) · Research Square · doi:10.21203/rs.3.rs-2314639/v1
GDF15 mediates renal cell plasticity in response to potassium depletionPreprint
Lasaad, S., Walter, C., Rafael, C., Morla, L., Doucet, A., Picard, N., Blanchard, A., Fromes, Y., Matot, B., Crambert, G., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.12.27.521983
“There are also many examples showing that muscle produces GDF15 in different contexts such as exercise (49) or cachexia (33).”
BackgroundEXERCINAS: NOVOS HORIZONTES NA BIOLOGIA DO EXERCÍCIO FÍSICO
Yamada, A. K. (2023) · Revista Brasileira de Ciência e Movimento · doi:10.31501/rbcm.v30i3.12682
Abubaker, J. A., Abu‐Farha, M., Abdalla, M. A., Albatineh, A. N., Al‐Khairi, I., Cherian, P., Qaddoumi, M. G., Abdul‐Ghani, M. A., & Al‐Mulla, F. (2024) · Research Square · doi:10.21203/rs.3.rs-4055454/v1
Eduardo, M. B., Islam, A. B. M. M. K., McCloskey, C. W., Zappia, M. P., Frolov, M. V., Khokha, R., Benevolenskaya, E. V., Khan, S. A., & Clare, S. E. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.10.01.679891
Exercise Intensity Modulates the Human Plasma Secretome and Interorgan CommunicationPreprint
Olsen, L., Botella, J., Barrows, D., Romero, E., Baird, K., Katayama, M., Kilic, E., Peralta, C., Sanford, H., Farrell, L. A., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.10.22.683699
“Similarly, many soluble proteins, such as interleukin-6 (IL6) and growth differentiation factor 15 (GDF15), are also secreted in an intensity-dependent manner, resulting in broad and context-dependent metabolic changes 13,14,15 .”
Murphy, E. E., Laurens, C., Frances, L., Marqués, M.-A., Crampes, F., de Glisezinski, I., Monedero, J., Kenny, H., McCaffrey, N., Finucane, F. M., et al. (2026) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00548.2025
Self-citationSon, Y. H., Sheng, C. Y., Jeong, J., Choi, Y., Jung, H., Won, J., Atinsky, A., Park, J., Kim, J., Lee, K. Y., et al. (2026) · BioChip Journal · doi:10.1007/s13206-026-00268-9
“Engineered skeletal muscle tissues provide a tunable platform to model disease progression and evaluate therapeutic responses under controlled biomechanical and bio-chemical conditions [27– 38 ].”
Wu, C., Zhao, Y., & Zhao, Y. (2026) · Frontiers in Physiology · doi:10.3389/fphys.2026.1868998 · Cited by 1
Yin, R., Sun, R., Gong, B., Shan, Z., & Zhao, D. (2026) · Frontiers in Medicine · doi:10.3389/fmed.2026.1854594
“GDF15 functions as a stress-responsive protein that is induced by both exercise and metformin (32–34).”
Olsen, L., Botella, J., Barrows, D., Romero, E., Baird, K., Katayama, M., Kilic, E., Peralta, C., Zanou, N., Sanford, H., et al. (2026) · Cell Reports Medicine · doi:10.1016/j.xcrm.2026.102988
“11,12 13–15 Characterizing intensity-dependent secretory responses may uncover how SIE—often lasting less than 5 min of total work—results in similar, if not superior, whole-body metabolic adaptations compared with longer-duration, low-intensity exercise or MIE.”
Exerkine-Mediated Inter-Organ Crosstalk and Translational Perspectives in Metabolic Diseases
Zhou, B., Zhang, S., Zhang, Z., Ran, S., Guo, H., Wang, S., & Meng, H. (2026) · Current Obesity Reports · doi:10.1007/s13679-026-00752-1
“GFRAL is primarily expressed in the hindbrain and mediates the well-established effects of GDF15 on appetite suppression and energy balance regulation, highlighting that exercise-associated GDF15 may exert additional peripheral actions beyond its canonical central pathway [46– 49 ].”
The Myokine Landscape: Sources, Signaling, and Context-Dependent Actions
Casadevall, C., Ramírez-Sarmiento, A., Camps-Ubach, R., Barreiro, E., Orozco‐Levi, M., & Gea, J. (2026) · Cells · doi:10.3390/cells15181682
“However, because GFRAL is not expressed in adipose tissue, this proposed peripheral action would require a GFRAL-independent mechanism that has not yet been fully characterized [120,121].”
Sumi, K., Masuda, T., Mochizuki, S., Kondo, H., Takahashi, N., & Kimura, N. (2026) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2026.126199
Biological functions and emerging interplay of FGF21 and GDF15 in metabolic diseases and aging
Salmón‐Gómez, L., Keipert, S., Catalán, V., Rodrı́guez, A., Becerril, S., Frühbeck, G., & Gómez‐Ambrosi, J. (2026) · Molecular Biomedicine · doi:10.1186/s43556-026-00627-w
Metadata
- Authors
- Laurens, C., Parmar, A., Murphy, E., Carper, D., Lair, B., Maes, P., Vion, J., Boulet, N., Fontaine, C., Marquès, M., Larrouy, D., Harant, I., Thalamas, C., Montastier, E., Caspar-Bauguil, S., Bourlier, V., Tavernier, G., Grolleau, J.-L., Bouloumié, A., Langin, D., Viguerie, N., Bertile, F., Blanc, S., de Glisezinski, I., O’Gorman, D., & Moro, C.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Université Toulouse III - Paul Sabatier (FR)
- Dublin City University (IE)
- Inserm, UMR1048, Institute of Metabolic and Cardiovascular Diseases, Toulouse, France.
- Inserm (FR)
- Centre d’Investigation Clinique 1436 (FR)
- ORCID
- Laurens, Claire
- Murphy, Enda
- Carper, Deborah
- Lair, Benjamin
- Vion, Julie
- Boulet, Nathalie
- Fontaine, Coralie
- Larrouy, Dominique
- Harant, Isabelle
- Thalamas, Claire
- Montastier, Emilie
- Caspar-Bauguil, Sylvie
- Bourlier, Virginie
- Tavernier, Geneviève
- Bouloumié, Anne
- Langin, Dominique
- Viguerie, Nathalie
- Bertile, Fabrice
- de Glisezinski, Isabelle
- O’Gorman, Donal
- Moro, Cedric
- Venue
- JCI Insight
- Published
- 2020-03-26
- Volume
- 5
- Issue
- 6
- Pages
- e131870
- ISSN
- 2379-3708 (ISSN-L)
- PMC
- PMC7213799
- OpenAlex
- W3008261843
- Cited by
- 135
- References
- 54
- Citations by year
- 2026: 16 · 2025: 24 · 2024: 25 · 2023: 13 · 2022: 20 · 2021: 27 · 2020: 10
- FWCI
- 13.17
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- JCI Insight (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- Funders
- Agence Nationale de la Recherche (ANR-10-INBS-0008, ANR-10-INSB-08, ANR-10-INSB-08–03, ANR-10)
- Institut National de la Santé et de la Recherche Médicale
- Centre National d’Etudes Spatiales
- Centre National de la Recherche Scientifique
- Institut Universitaire de France
- Société Française de Nutrition
- Région Occitanie Pyrénées-Méditerranée
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › GDF15 and Related Biomarkers
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Health Sciences › Medicine › Physiology (medical) › Exercise and Physiological Responses
- Keywords
- growth and differentiation factor 15, GDF15, myokines, exerkines, skeletal muscle contraction, physical activity, lipolysis, adipose tissue, myotubes, electrical pulse stimulation
- MeSH terms
- Adult, Humans, Lipolysis, Male, Exercise, Muscle, Skeletal, Growth Differentiation Factor 15
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