The metabolic effects of GDF15 are mediated by the orphan receptor GFRAL
Abstract
Growth/differentiation factor 15 (GDF15), also known as MIC-1, is a distant member of the transforming growth factor-β (TGF-β) superfamily and has been implicated in various biological functions, including cancer cachexia, renal and heart failure, atherosclerosis and metabolism. A connection between GDF15 and body-weight regulation was initially suggested on the basis of an observation that increasing GDF15 levels in serum correlated with weight loss in individuals with advanced prostate cancer. In animal models, overexpression of GDF15 leads to a lean phenotype, hypophagia and other improvements in metabolic parameters, suggesting that recombinant GDF15 protein could potentially be used in the treatment of obesity and type 2 diabetes. However, the signaling and mechanism of action of GDF15 are poorly understood owing to the absence of a clearly identified cognate receptor. Here we report that GDNF-family receptor α-like (GFRAL), an orphan member of the GFR-α family, is a high-affinity receptor for GDF15. GFRAL binds to GDF15 in vitro and is required for the metabolic actions of GDF15 with respect to body weight and food intake in vivo in mice. Gfral-/- mice were refractory to the effects of recombinant human GDF15 on body-weight, food-intake and glucose parameters. Blocking the interaction between GDF15 and GFRAL with a monoclonal antibody prevented the metabolic effects of GDF15 in rats. Gfral mRNA is highly expressed in the area postrema of mouse, rat and monkey, in accordance with previous reports implicating this region of the brain in the metabolic actions of GDF15 (refs. 4,5,6). Together, our data demonstrate that GFRAL is a receptor for GDF15 that mediates the metabolic effects of GDF15.
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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 [79]
GDF-15 binds exclusively to GFRAL and not to other TGF-β receptors or other GDNF family receptors.
“Metformin increases the secretion of GDF-15, which binds exclusively to glial cell-derived neurotrophic factor family receptor alpha-like (GFRAL).”
From GDF-15 as a Weight Watcher for Diabetic and Non-Diabetic People Treated With Metformin (2020) · cites this paper as [39]
The effect of GDF-15 on body weight and food intake reduction in wild-type mice is completely lost in Gfral knockout mice.
“Moreover, the effect of GDF-15 on body weight and food intake reduction in wild-type mice was completely lost in Gfral knockout mice (39).”
From GDF-15 as a Weight Watcher for Diabetic and Non-Diabetic People Treated With Metformin (2020) · cites this paper as [39]
GDF-15-induced cell signaling requires the interaction of GFRAL with the coreceptor RET.
“Additionally, GDF-15-induced cell signaling requires the interaction of GFRAL with the coreceptor RET (39).”
From GDF-15 as a Weight Watcher for Diabetic and Non-Diabetic People Treated With Metformin (2020) · cites this paper as [39]
GFRAL antibody blocks GDF-15-induced body weight and food-intake suppression in rats.
“GFRAL antibody blocked GDF-15-induced body weight and food-intake suppression in rats (39).”
From GDF-15 as a Weight Watcher for Diabetic and Non-Diabetic People Treated With Metformin (2020) · cites this paper as [39]
GFRAL expression is limited to the brainstem and Gfral mRNA is highly expressed in the area postrema of mouse, rat, monkey and human.
“Unlike Gdf-15 which is expressed in diverse tissues, including kidney, liver, gut, muscle, adipose, and placenta, GFRAL expression is limited to the brainstem and Gfral mRNA is highly expressed in the area postrema of mouse, rat, monkey and human (39–41).”
From GDF-15 as a Weight Watcher for Diabetic and Non-Diabetic People Treated With Metformin (2020) · cites this paper as [39]
GDF-15 and GFRAL have emerged as regulators of energy balance and body weight.
“In addition to these functions, GDF-15 and its tissue-specific brainstem receptor, the glial cell-derived neurotrophic factor (GDNF) family receptor alpha-like (GFRAL), have emerged as regulators of energy balance and body weight (39–41).”
From GDF-15 as a Weight Watcher for Diabetic and Non-Diabetic People Treated With Metformin (2020) · cites this paper as [39]
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- Authors
- Emmerson, P. J., Wang, F., Du, Y., Liu, Q., Pickard, R. T., Gonciarz, M. D., Coskun, T., Hamang, M. J., Sindelar, D. K., Ballman, K. K., Foltz, L. A., Muppidi, A., Alsina-Fernandez, J., Barnard, G. C., Tang, J. X., Liu, X., Mao, X., Siegel, R., Sloan, J. H., Mitchell, P. J., Zhang, B. B., Gimeno, R. E., Shan, B., & Wu, X.
- Affiliations
- Eli Lilly (United States) (US)
- Lilly (China) (CN)
- Corresponding author
- Wu, Xinle
- ORCID
- Venue
- Nature Medicine
- Published
- 2017-08-28
- Volume
- 23
- Issue
- 10
- Pages
- 1215-1219
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2750180661
- Cited by
- 675
- References
- 20
- Citations by year
- 2026: 80 · 2025: 81 · 2024: 102 · 2023: 79 · 2022: 73 · 2021: 75 · 2020: 78 · 2019: 53 · 2018: 40 · 2017: 13
- FWCI
- 43.98
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Shanghai Ocean University
- 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, MIC-1, GFRAL, orphan receptors, body weight regulation, dietary intake, glucose metabolism, area postrema, type 2 diabetes, TGF-beta superfamily
- MeSH terms
- Animals, Brain, Eating, Flow Cytometry, Humans, Macaca fascicularis, Male, Obesity, RNA, Messenger, Immunoblotting, Weight Loss, Rats, Sprague-Dawley, Mice, Knockout, Surface Plasmon Resonance, Area Postrema, Glial Cell Line-Derived Neurotrophic Factor Receptors, Mice, Rats, Growth Differentiation Factor 15, HEK293 Cells, Real-Time Polymerase Chain Reaction
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