GO:0160144 GDF15-GFRAL signaling pathway: Stress-Induced Metabolic Signaling, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0160144 defines the GDF15-GFRAL signaling pathway, a stress-responsive biological process initiated when GDF15 binds the GFRAL coreceptor, leading to RET autophosphorylation and activation.
• GFRAL is expressed in the area postrema and nucleus of the solitary tract of the hindbrain, where it mediates GDF15-dependent suppression of food intake and body weight regulation.
• The pathway is a major driver of cancer cachexia and anorexia, and antibody-mediated inhibition of GDF15-GFRAL activity reverses cachexia in preclinical models.
• GDF15-GFRAL signaling links adipose tissue lipolysis with anxiety-like behavior, revealing a metabolic-to-neurobehavioral axis.
• In amyotrophic lateral sclerosis models, GDF15-GFRAL signaling drives weight loss and lipid metabolism, suggesting a role in neurodegeneration-associated metabolic dysfunction.
• The pathway is being actively targeted by therapeutic modalities including bicyclic peptide tandems and GDF15 analogues that act as GFRAL ligands.
Description
The GDF15-GFRAL signaling pathway (GO:0160144) is a stress-induced biological process in which growth/differentiation factor 15 (GDF15) binds to the GDNF family receptor alpha-like (GFRAL) coreceptor, triggering RET autophosphorylation and downstream signal transduction. This pathway has emerged as a central regulator of energy homeostasis, food intake, and body weight, and it is now recognized as a key mediator of cachexia and anorexia in chronic disease. Because GFRAL expression is largely restricted to the hindbrain, the pathway provides a relatively selective pharmacological target for modulating appetite and metabolism without broad off-target effects. Researchers study GO:0160144 to understand how peripheral stress signals are translated into central nervous system responses, and to develop interventions for cancer cachexia, metabolic disease, and neurodegeneration. The pathway also intersects with lipid metabolism and anxiety-like behavior, expanding its relevance beyond classical energy balance. In cancer biology, expression of GDF15, GFRAL, and RET has clinical relevance in gastric cancer, underscoring the translational importance of this signaling axis.
GDF15-GFRAL signaling pathway At A Glance
| GO ID | GO:0160144 |
|---|---|
| GO term | GDF15-GFRAL signaling pathway |
| Ontology | biological_process |
| Synonym | None listed |
| Definition | The series of molecular signals initiated by GDF15 binding to GFRAL coreceptor, triggering RET autophosphorylation and activation, in response to stress. |
| Major function | Stress-induced regulation of food intake, body weight, and energy metabolism via hindbrain GFRAL-RET signaling. |
| Key ligands/receptors | GDF15 (ligand), GFRAL (coreceptor), RET (receptor tyrosine kinase). |
| Primary tissue context | Area postrema and nucleus of the solitary tract in the hindbrain. |
| Disease relevance | Cancer cachexia, anorexia, metabolic disease, amyotrophic lateral sclerosis, and solid tumors. |
What Is GO:0160144?
GO:0160144, the GDF15-GFRAL signaling pathway, is defined as the series of molecular signals initiated by GDF15 binding to the GFRAL coreceptor, which triggers RET autophosphorylation and activation in response to stress. In simpler terms, it is the process by which a stress-induced hormone (GDF15) engages a specific receptor (GFRAL) on hindbrain neurons, switching on an intracellular kinase (RET) that relays signals to reduce appetite and alter metabolism.
Why Is GDF15-GFRAL signaling pathway Important in Cell Biology?
GO:0160144 is important because it defines a conserved stress-response circuit that connects peripheral metabolic stress to central appetite suppression, and it is causally implicated in cancer cachexia, a debilitating condition with few effective treatments. The pathway is also a promising therapeutic node: blocking GDF15-GFRAL activity reverses cachexia in mice, while GDF15 analogues and bicyclic peptide tandems are being engineered to modulate GFRAL signaling. Its involvement in lipid metabolism, anxiety, and neurodegeneration further broadens its biomedical significance.
• Mediates stress-induced anorexia and weight loss through hindbrain GFRAL-RET signaling.
• Drives cancer cachexia; antibody-mediated inhibition reverses cachexia in preclinical models.
• Links adipose tissue lipolysis to anxiety-like behavior, revealing a metabolic-neurobehavioral axis.
• Contributes to weight loss and lipid metabolism dysregulation in amyotrophic lateral sclerosis models.
• Represents a druggable target with GDF15 analogues and bicyclic peptide tandems under development.
• Inhibition of GDF15/GFRAL is being explored as a novel opportunity for solid tumor treatment.
• Expression of GDF15, GFRAL, and RET has clinical relevance in gastric cancer.
• Provides a model for understanding how peripheral hormones access hindbrain circuits to control energy balance.
• Offers a selective pharmacological handle due to restricted GFRAL expression in the hindbrain.
• Connects metabolic stress to neurobehavioral outcomes, expanding therapeutic scope beyond appetite.
What Happens During GDF15-GFRAL signaling pathway?
GDF15 Secretion and Stress Sensing
In simple terms: When cells are under stress, they release a hormone called GDF15 into the bloodstream.
GDF15 is produced and secreted in response to cellular stress, including conditions associated with cancer, metabolic dysfunction, and tissue injury. Circulating GDF15 acts as a systemic signal that communicates peripheral stress status to the brain. The regulation of GDF15 secretion is a critical upstream step that determines the magnitude of pathway activation.
GDF15 Binding to GFRAL Coreceptor
In simple terms: The stress hormone GDF15 docks onto a specific receptor called GFRAL on brain cells.
GFRAL is a glial cell line-derived neurotrophic factor family receptor alpha-like protein that serves as the coreceptor for GDF15. GDF15 binding to GFRAL occurs primarily in the area postrema and nucleus of the solitary tract, where GFRAL expression is enriched. This binding event is the initiating step of GO:0160144 and is required for downstream RET activation.
RET Autophosphorylation and Activation
In simple terms: Once GDF15 binds GFRAL, it switches on a kinase enzyme called RET by adding phosphate groups to it.
The GDF15-GFRAL complex recruits and activates the RET receptor tyrosine kinase, leading to RET autophosphorylation. RET autophosphorylation is a defining molecular event in GO:0160144 and triggers downstream intracellular signaling cascades. This step is essential for transmitting the GDF15 signal into cellular responses.
Downstream Signaling and Appetite Suppression
In simple terms: The activated RET sends signals that tell the brain to reduce food intake and alter metabolism.
Activation of RET by the GDF15-GFRAL complex initiates downstream signaling that ultimately suppresses food intake and reduces body weight. This pathway is a major mediator of anorexia and weight loss in cancer cachexia, and its inhibition reverses these effects in mice. The signaling also influences lipid metabolism and energy expenditure.
Metabolic and Neurobehavioral Outputs
In simple terms: The pathway not only controls appetite but also affects fat breakdown and anxiety-like behavior.
GDF15-GFRAL signaling links adipose tissue lipolysis with anxiety-like behavior, demonstrating that the pathway coordinates metabolic and neurobehavioral outputs. In amyotrophic lateral sclerosis models, GDF15-GFRAL signaling drives weight loss and lipid metabolism alterations. These outputs highlight the pathway's broad physiological impact beyond simple appetite regulation.
Key Genes Involved in GO:0160144 GDF15-GFRAL signaling pathway
The GDF15-GFRAL signaling pathway involves a defined set of ligand, receptor, and kinase genes that together mediate stress-induced metabolic and neurobehavioral responses.
| Gene | Major Role | Research Relevance |
|---|---|---|
| GDF15 | Stress-induced ligand that initiates pathway activation | Biomarker and therapeutic target in cachexia and metabolic disease |
| GFRAL | Coreceptor for GDF15; expressed in hindbrain | Selective target for modulating appetite and body weight |
| RET | Receptor tyrosine kinase activated by GDF15-GFRAL complex | Central kinase mediating downstream signaling |
| GDNF | Related ligand in the GDNF family | Comparative studies of GFRAL family signaling |
| NTRN | Neurturin, a GDNF family ligand | Context for GFRAL receptor family biology |
| ARTN | Artemin, a GDNF family ligand | Context for GFRAL receptor family biology |
| PSPN | Persephin, a GDNF family ligand | Context for GFRAL receptor family biology |
| GFRA1 | GDNF family receptor alpha 1 | Comparative receptor biology |
| GFRA2 | GDNF family receptor alpha 2 | Comparative receptor biology |
| GFRA3 | GDNF family receptor alpha 3 | Comparative receptor biology |
| GFRA4 | GDNF family receptor alpha 4 | Comparative receptor biology |
| POMC | Pro-opiomelanocortin, downstream appetite regulator | Potential downstream mediator of GFRAL signaling |
| NPY | Neuropeptide Y, orexigenic signal | Potential downstream mediator of GFRAL signaling |
| AGRP | Agouti-related peptide, orexigenic signal | Potential downstream mediator of GFRAL signaling |
| MC4R | Melanocortin 4 receptor, energy balance regulator | Downstream energy balance pathway |
| LEP | Leptin, adiposity signal | Comparative energy balance signaling |
| INS | Insulin, metabolic hormone | Metabolic context for GDF15-GFRAL signaling |
How Is GDF15-GFRAL signaling pathway Regulated?
The GDF15-GFRAL signaling pathway is regulated at multiple levels. GDF15 secretion is induced by cellular stress, including cancer and metabolic dysfunction, which controls ligand availability. GFRAL expression is largely restricted to the hindbrain, limiting pathway activation to specific neuronal populations. Antibody-mediated inhibition of GDF15-GFRAL activity can reverse cancer cachexia, demonstrating that the pathway is pharmacologically tunable. Additionally, the pathway is modulated by metabolic states such as adipose tissue lipolysis, which influences anxiety-like behavior. In disease contexts such as amyotrophic lateral sclerosis, GDF15-GFRAL signaling is altered and contributes to weight loss and lipid metabolism changes.
GDF15-GFRAL signaling pathway and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| GDF15 | Cancer cachexia | Xenograft mouse models with GDF15-secreting tumors |
| GFRAL | Obesity and metabolic disease | GFRAL knockout mice |
| RET | Solid tumors and gastric cancer | RET mutant knock-in cell lines |
| GDF15 | Amyotrophic lateral sclerosis | SOD1 mutant mouse models |
| GDF15 | Anxiety and lipolysis | Adipose-specific GDF15 overexpression models |
Cancer Cachexia
Cancer cachexia is a severe metabolic wasting syndrome characterized by involuntary weight loss and anorexia. GDF15-GFRAL signaling is a major driver of cachexia, and antibody-mediated inhibition of this pathway reverses cachexia in mice. This makes GO:0160144 a high-priority target for therapeutic intervention in cancer-associated wasting.
Metabolic Disease and Obesity
The GDF15-GFRAL pathway regulates food intake and body weight, positioning it as a key node in metabolic disease. GDF15 analogues acting as GFRAL ligands are being developed to modulate this pathway for therapeutic benefit. Dysregulation of the pathway contributes to altered lipid metabolism and energy balance.
Neurodegeneration and Amyotrophic Lateral Sclerosis
In amyotrophic lateral sclerosis models, GDF15-GFRAL signaling drives weight loss and lipid metabolism alterations, linking neurodegeneration to metabolic dysfunction. This suggests that targeting the pathway could address metabolic comorbidities in neurodegenerative disease.
Solid Tumors and Gastric Cancer
Inhibition of GDF15/GFRAL is being explored as a novel opportunity for the treatment of solid tumors. Expression of GDF15, GFRAL, and RET has clinical relevance in gastric cancer, indicating potential prognostic and therapeutic implications.
From GDF15-GFRAL signaling pathway-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does GDF15-GFRAL signaling drive cachexia? | GDF15 knockout or GFRAL knockout mouse models |
| Can GFRAL ligand analogues modulate appetite? | GFRAL point-mutation knock-in models |
| What is the role of RET autophosphorylation? | RET kinase-dead knock-in cell lines |
| How does GDF15 affect lipid metabolism? | Adipose-specific GDF15 overexpression models |
| Is GDF15-GFRAL signaling involved in neurodegeneration? | ALS mouse models with GDF15 or GFRAL manipulation |
| Can GDF15-GFRAL inhibition treat solid tumors? | Tumor xenografts with GDF15/GFRAL blockade |
How to Study the GDF15-GFRAL signaling pathway Process
| Method | What It Measures | Typical Application |
|---|---|---|
| CRISPR knockout | Loss of gene function | Dissecting GDF15, GFRAL, or RET requirement |
| Point mutation knock-in | Specific amino acid changes | Studying RET autophosphorylation sites |
| Antibody inhibition | Pathway blockade | Reversing cancer cachexia in mice |
| Bicyclic peptide tandems | GDF15-GFRAL-RET complex inhibition | Developing therapeutic inhibitors |
| GDF15 analogues | GFRAL ligand activity | Modulating appetite and metabolism |
| Metabolic phenotyping | Food intake, body weight, lipid metabolism | Assessing pathway effects in vivo |
| Behavioral assays | Anxiety-like behavior | Linking lipolysis to neurobehavior |
| Expression profiling | GDF15, GFRAL, RET levels | Clinical correlation in gastric cancer |
Genetic Knockout and Knock-in Models
CRISPR-Cas9-mediated knockout of GDF15, GFRAL, or RET in cell lines and mouse models is used to dissect the pathway's role in appetite, metabolism, and cachexia. Knock-in models expressing point mutations in RET or GFRAL allow precise interrogation of signaling events such as autophosphorylation.
Antibody and Peptide-Based Inhibition
Antibody-mediated inhibition of GDF15-GFRAL activity is a validated approach to reverse cancer cachexia in mice. Bicyclic peptide tandems mimicking homodimeric GDF15 have been designed to inhibit GDF15-GFRAL-RET complex cell signaling. GDF15 analogues acting as GFRAL ligands provide additional tools for pathway modulation.
Metabolic and Behavioral Phenotyping
Food intake, body weight, and lipid metabolism are measured in animal models to assess pathway activity. Anxiety-like behavior is evaluated to capture neurobehavioral outputs of GDF15-GFRAL signaling. These phenotypic readouts are essential for linking molecular events to organismal outcomes.
Expression and Clinical Correlation Studies
Expression levels of GDF15, GFRAL, and RET are analyzed in patient samples to assess clinical relevance, as demonstrated in gastric cancer. Such studies help identify biomarkers and patient populations that may benefit from pathway-targeted therapies.
How CRISPR Can Be Used to Study GO:0160144 GDF15-GFRAL signaling pathway
Knockout
CRISPR knockout of GDF15, GFRAL, or RET is used to abolish pathway activity and determine its contribution to appetite suppression, cachexia, and metabolic regulation. GFRAL knockout mice are particularly valuable because GFRAL expression is restricted to the hindbrain, allowing selective pathway disruption.
Point Mutation
Point mutation knock-in models introduce specific amino acid substitutions in RET or GFRAL to dissect signaling events such as autophosphorylation and ligand binding. These models help distinguish between kinase-dependent and kinase-independent functions.
Knock-in
Knock-in of tagged or reporter constructs into the GDF15, GFRAL, or RET loci enables visualization and tracking of pathway components in vivo. Such models are useful for mapping the cellular sources and targets of GDF15-GFRAL signaling.
Overexpression
Overexpression of GDF15 or GFRAL in cell lines and animal models is used to amplify pathway activity and study downstream effects on metabolism and behavior. Adipose-specific GDF15 overexpression has been used to link lipolysis with anxiety-like behavior.
How EDITGENE Supports GDF15-GFRAL signaling pathway Research
Researchers studying GDF15-GFRAL signaling pathway-related genes often need to determine whether a candidate gene is causally involved in stress-induced metabolic and neurobehavioral responses. EDITGENE provides comprehensive CRISPR-based services to generate knockout, point-mutation, knock-in, and overexpression cell models, as well as CRISPR library screening and bioinformatics support, enabling rigorous functional interrogation of GO:0160144.
Contact EDITGENE today to design your custom CRISPR model for GDF15-GFRAL signaling pathway research.
Frequently Asked Questions About GDF15-GFRAL signaling pathway
What is the GDF15-GFRAL signaling pathway?
It is a stress-induced biological process (GO:0160144) in which GDF15 binds the GFRAL coreceptor, triggering RET autophosphorylation and activation, leading to appetite suppression and metabolic changes.
What genes are involved in the GDF15-GFRAL signaling pathway?
Key genes include GDF15 (ligand), GFRAL (coreceptor), and RET (receptor tyrosine kinase), along with downstream energy balance regulators.
Where is GFRAL expressed?
GFRAL is expressed primarily in the area postrema and nucleus of the solitary tract in the hindbrain.
What diseases are linked to GDF15-GFRAL signaling?
Cancer cachexia, metabolic disease, amyotrophic lateral sclerosis, and solid tumors including gastric cancer.
Can GDF15-GFRAL signaling be inhibited therapeutically?
Yes, antibody-mediated inhibition reverses cancer cachexia in mice, and peptide-based inhibitors are under development.
What is the role of RET in this pathway?
RET is a receptor tyrosine kinase that undergoes autophosphorylation upon GDF15-GFRAL binding, initiating downstream signaling.
How does GDF15-GFRAL signaling affect metabolism?
It suppresses food intake, reduces body weight, and influences lipid metabolism and adipose tissue lipolysis.
Is GDF15-GFRAL signaling involved in anxiety?
Yes, GDF15 links adipose tissue lipolysis with anxiety-like behavior, indicating a metabolic-neurobehavioral axis.
What research models are used to study GDF15-GFRAL signaling?
Knockout mice, point mutation knock-in cell lines, antibody inhibition, and GDF15 analogues are commonly used.
What is the clinical relevance of GDF15, GFRAL, and RET expression in cancer?
Expression of these genes has clinical relevance in gastric cancer, suggesting prognostic and therapeutic implications.
Conclusion
GO:0160144, the GDF15-GFRAL signaling pathway, is a stress-responsive biological process that connects peripheral metabolic stress to central appetite suppression and neurobehavioral changes through GDF15, GFRAL, and RET. Its causal role in cancer cachexia and its emerging links to metabolic disease, neurodegeneration, and solid tumors make it a high-value target for therapeutic development. Continued research using CRISPR-based models and pharmacological tools will further clarify how this pathway can be modulated for clinical benefit.
References
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- 2. Suriben R et al.. 2020. Antibody-mediated inhibition of GDF15-GFRAL activity reverses cancer cachexia in mice.. Nat Med 26(8):1264-1270 PMID: 32661391
- 3. Townsend LK et al.. 2025. GDF15 links adipose tissue lipolysis with anxiety.. Nat Metab 7(5):1004-1017 PMID: 40234625
- 4. Cocozza G et al.. 2025. GDF15-GFRAL signaling drives weight loss and lipid metabolism in mouse model of amyotrophic lateral sclerosis.. Brain Behav Immun 124:280-293 PMID: 39672239
- 5. Noisier AFM et al.. 2025. Design of Bicyclic Peptide Tandems Mimicking the Homodimeric GDF15 Protein to Inhibit GDF15-GFRaL-RET Complex Cell Signaling.. J Med Chem 68(20):21441-21457 PMID: 41066664
- 6. Di Santo A et al.. 2025. GDF15 Analogues Acting as GFRAL Ligands.. ChemMedChem 20(9):e202400961 PMID: 39907315
- 7. Zhang P et al.. 2026. Inhibition of GDF15/GFRAL: A novel opportunity for the treatment of solid tumors.. Int Immunopharmacol 170:116109 PMID: 41455368
- 8. Buchholz K et al.. 2021. Expression of the Body-Weight Signaling Players: GDF15, GFRAL and RET and their clinical relevance in Gastric Cancer.. J Cancer 12(15):4698-4709 PMID: 34149933
