GFRAL is the receptor for GDF15 and is required for the anti-obesity effects of the ligand
Abstract
Growth differentiation factor 15 (GDF15; also known as MIC-1) is a divergent member of the TGF-β superfamily and is associated with body-weight regulation in humans and rodents. However, the cognate receptor of GDF15 is unknown. Here we show that GDF15 binds specifically to GDNF family receptor α-like (GFRAL) with high affinity, and that GFRAL requires association with the coreceptor RET to elicit intracellular signaling in response to GDF15 stimulation. We also found that GDF15-mediated reductions in food intake and body weight of mice with obesity were abolished in GFRAL-knockout mice. We further found that GFRAL expression was limited to hindbrain neurons and not present in peripheral tissues, which suggests that GDF15-GFRAL-mediated regulation of food intake is by a central mechanism. Lastly, given that GDF15 did not increase energy expenditure in treated mice with obesity, the anti-obesity actions of the cytokine are likely driven primarily by a reduction in food intake.
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GDF-15 regulates food intake, energy expenditure and body weight in response to metabolic and toxin-induced stress.
“which regulates food intake, energy expenditure and body weight in response to metabolic and toxin-induced stress79–81.”
From Genetic determinants of plasma protein levels in the Estonian population (2024) · cites this paper as [81]
GDF-15 is a key mediator of metformin-induced weight loss.
“Recently, the growth differentiation factor 15 (GDF-15), a member of the transforming growth factor beta superfamily, has been identified as a key mediator of metformin-induced weight loss.”
From GDF-15 as a Weight Watcher for Diabetic and Non-Diabetic People Treated With Metformin (2020) · cites this paper as [26]
Exogenous administration of recombinant murine or human GDF-15 induces weight loss in different animal models.
“In line with these studies, exogenous administration of recombinant murine or human GDF-15 induced weight loss in different animal models (26, 32, 40, 41, 107).”
From GDF-15 as a Weight Watcher for Diabetic and Non-Diabetic People Treated With Metformin (2020) · cites this paper as [26]
GFRAL solely binds to GDF-15, but not to GDNF and its homologs neurturin, artemin, and persephin.
“Flow cytometry analyses showed that GFRAL solely bound to GDF-15, but not to GDNF and its homologs neurturin, artemin, and persephin (26).”
From GDF-15 as a Weight Watcher for Diabetic and Non-Diabetic People Treated With Metformin (2020) · cites this paper as [26]
Administration of hGDF15 to GFRAL-deficient mice has no effect on body weight, energy expenditure, serum leptin and insulin levels, and food intake compared to wild-type mice given hGDF15.
“Administration of hGDF15 to GFRAL-deficient mice had no effect on body weight, energy expenditure, serum leptin and insulin levels, and food intake compared to wild-type mice given hGDF15 [213].”
From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [213]
GDF15 binds with high affinity to GFRAL and its co-receptor RET, inducing phosphorylation of RET and downstream signaling through AKT, ERK1/2, and PLCγ pathways.
“GDF15 binds with high affinity to GFRAL and its co-receptor RET, which induces phosphorylation of RET, leading to downstream signaling through the AKT, ERK1/2, and phospholipase C (PLCγ) pathways [201,213,215].”
From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [213]
Administration of GDF15 to wild-type mice produced responses similar to transgenic mice, but these mice exhibited consistent reduction in food intake.
“Conversely, administration of GDF15 to wild-type mice produced responses similar to those in transgenic mice; however, these mice exhibited consistent reduction in food intake [201,213].”
From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [213]
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- Authors
- Yang, L., Chang, C.-C., Sun, Z., Madsen, D., Zhu, H., Padkjær, S. B., Wu, X., Huang, T., Hultman, K., Paulsen, S. J., Wang, J., Bugge, A., Frantzen, J. B., Nørgaard, P., Jeppesen, J. F., Yang, Z., Secher, A., Chen, H., Li, X., John, L. M., Shan, B., He, Z., Gao, X., Su, J., Hansen, K. T., Yang, W., & Jørgensen, S. B.
- Affiliations
- Novo Nordisk (Denmark) (DK)
- Corresponding author
- Jørgensen, Sebastian Beck
- ORCID
- Venue
- Nature Medicine
- Published
- 2017-08-28
- Volume
- 23
- Issue
- 10
- Pages
- 1158-1166
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2746853643
- Cited by
- 668
- References
- 36
- Citations by year
- 2026: 69 · 2025: 83 · 2024: 102 · 2023: 71 · 2022: 81 · 2021: 78 · 2020: 79 · 2019: 53 · 2018: 39 · 2017: 13
- FWCI
- 43.98
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Rheumatology › GDF15 and Related Biomarkers
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Keywords
- GDF15, GFRAL, growth differentiation factor 15, receptor identification, TGF-beta superfamily, obesity, food intake regulation, body weight regulation, hindbrain neurons, energy expenditure
- MeSH terms
- Animals, Eating, Energy Metabolism, Flow Cytometry, Humans, Obesity, Weight Loss, Rats, Sprague-Dawley, Mice, Knockout, Surface Plasmon Resonance, Glial Cell Line-Derived Neurotrophic Factor Receptors, Mice, Rats, Growth Differentiation Factor 15, HEK293 Cells, In Vitro Techniques
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