Affinage

GDF15

Growth/differentiation factor 15 · UniProt Q99988

Length
308 aa
Mass
34.1 kDa
Annotated
2026-06-10
100 papers in source corpus 41 papers cited in narrative 39 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GDF15 is a stress-induced, secreted dimeric cytokine that signals through a hindbrain receptor system to regulate feeding, energy balance, and stress responses (PMID:28846097, PMID:28846098, PMID:28846099, PMID:28953886). It is synthesized as a 62-kDa precursor that is furin-cleaved and secreted as a 25-kDa disulfide-linked dimer (PMID:9886240), with maturation depending on β-arrestin1 (ARRB1)-mediated trafficking of pro-GDF15 to the Golgi (PMID:31857195). Its canonical signaling axis requires the high-affinity receptor GFRAL, expressed exclusively in area postrema and nucleus tractus solitarius neurons that co-express the co-receptor RET, where GDF15 drives RET phosphorylation and activates a circuit reaching the parabrachial nucleus and central amygdala to suppress food intake and induce aversive responses (PMID:28846097, PMID:28846098, PMID:28846099, PMID:28953886, PMID:40555562, PMID:34942400). Through GFRAL this axis also activates the HPA stress axis (PMID:34187898), counteracts adaptive thermogenesis via a β-adrenergic pathway that sustains fatty acid oxidation in skeletal muscle (PMID:37380764), and drives an adipose sympathetic-lipolytic program linking lipolysis to anxiety-like behavior (PMID:32661391, PMID:40234625). The GDF15-GFRAL axis is the obligate mediator of metformin- and ketogenic-diet-induced weight loss, with GDF15 induced in kidney, intestine, and liver and its transcription controlled by the integrated stress response, AMPK, p53, and PPAR pathways (PMID:31875646, PMID:37060902, PMID:38056430, PMID:30639358, PMID:33337559, PMID:29967567). GDF15 expression is also tuned post-transcriptionally by the CNOT6L deadenylase (PMID:35385705). Beyond the CNS axis, GDF15 reprograms macrophage metabolism toward an anti-inflammatory oxidative state and stabilizes Treg FOXP3 by engaging CD48 on T cells, contributing to immune tolerance (PMID:37499753, PMID:34489334). Reported GFRAL-independent actions in peripheral fibroblasts and hepatocytes engage the ALK5/SMAD pathway (PMID:35993367, PMID:38176644).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1999 Medium

    Establishing how GDF15 becomes a secreted signal: it is produced as an intracellular precursor requiring proteolytic processing and dimerization before release.

    Evidence Biochemical characterization of precursor cleavage and secretion

    PMID:9886240

    Open questions at the time
    • Did not identify the trafficking machinery required for maturation
    • No receptor or downstream signaling defined
  2. 1997 Low

    First demonstration that GDF15 has direct biological activity, inhibiting hematopoietic progenitor proliferation.

    Evidence In vitro proliferation assay with hematopoietic progenitors

    PMID:9375789

    Open questions at the time
    • Single functional assay with no mechanistic detail
    • No receptor identified
  3. 2017 High

    Resolved the central question of how GDF15 signals: GFRAL is its high-affinity receptor, acting with RET co-receptor in restricted hindbrain neurons to mediate appetite and body weight suppression.

    Evidence Receptor binding, RET co-receptor identification, GFRAL knockout mice, in vivo pharmacology in mice and primates; replicated across four labs

    PMID:28846097 PMID:28846098 PMID:28846099 PMID:28953886

    Open questions at the time
    • Did not resolve peripheral GFRAL-independent actions
    • Structural basis of the GDF15-GFRAL-RET ternary complex not defined here
  4. 2017 High

    Mapped GFRAL signaling to a defined neural circuit and demonstrated its requirement for chemotherapy-induced anorexia, framing GDF15 as an 'emergency' stress-feeding regulator.

    Evidence Neuronal activation mapping, GFRAL knockout mice, chemotherapy-induced anorexia model; crystal structure and gastric emptying assays

    PMID:28953886 PMID:29046435

    Open questions at the time
    • Cell-type resolution of direct targets not yet defined
    • Downstream effector neurons of PBN/CeA circuit incompletely mapped
  5. 2019 Medium

    Established the trafficking step needed for maturation: ARRB1 binds pro-GDF15 and routes it to the Golgi, linking maturation defects to steatohepatitis.

    Evidence Co-IP, Arrb1 knockout mice, pro-GDF15 rescue experiments

    PMID:31857195

    Open questions at the time
    • Single Co-IP for the ARRB1-GDF15 interaction
    • Whether ARRB1 acts on all GDF15-producing tissues unknown
  6. 2019 High

    Connected GDF15 to clinical pharmacology by showing the GDF15-GFRAL axis is required for metformin-induced weight loss, and tied GDF15 induction to the integrated stress response.

    Evidence Human RCTs, GDF15 and GFRAL knockout mice, GFRAL-antagonist antibody, dietary models, conditioned taste aversion

    PMID:30639358 PMID:31875646

    Open questions at the time
    • Tissue source of metformin-induced GDF15 not fully resolved at this stage
    • Molecular link between ISR sensors and Gdf15 transcription not detailed
  7. 2021 High

    Extended GFRAL signaling beyond feeding to endocrine stress, showing GDF15 activates the HPA axis and is required for stress-toxin-induced corticosterone responses.

    Evidence GDF15 administration with GFRAL-blocking antibody, Gdf15 knockout mice, multiple stress models, corticosterone readout

    PMID:34187898

    Open questions at the time
    • Circuit linking GFRAL neurons to HPA axis not mapped
    • Physiological stressors driving endogenous response incompletely defined
  8. 2020 High

    Defined a peripheral effector branch: GFRAL activation drives a sympathetic-lipolytic axis in adipose tissue, and a GFRAL antagonist blocks GDF15-driven RET recruitment.

    Evidence Antagonistic antibody, chemical sympathectomy, ATGL knockout mice, adipose gene expression, tumor-bearing models

    PMID:32661391

    Open questions at the time
    • How a hindbrain receptor produces sympathetic output to adipose not fully mapped
  9. 2023 High

    Showed GDF15 maintains energy expenditure against caloric-restriction-induced adaptive thermogenesis via a GFRAL-β-adrenergic axis acting on skeletal muscle.

    Evidence Recombinant GDF15, caloric restriction, fatty acid oxidation and calcium futile cycling assays in muscle

    PMID:37380764

    Open questions at the time
    • Identity of intermediary neurons relaying GFRAL signal to muscle unclear
  10. 2023 High

    Refined the source of metformin-induced GDF15 to the kidney and confirmed dual-site (kidney GDF15, area postrema GFRAL) requirement for drug action.

    Evidence Tissue-specific AAV knockdown of GDF15 in kidney and GFRAL in area postrema in rats

    PMID:37060902

    Open questions at the time
    • Mechanism of metformin-driven renal GDF15 induction not detailed
  11. 2023 High

    Identified hepatic PPARγ as a direct transcriptional driver of Gdf15 mediating ketogenic-diet weight loss through GFRAL.

    Evidence PPARγ ChIP, hepatocyte-specific Gdf15 knockdown, GDF15/GFRAL/hepatic PPARγ knockouts, recombinant rescue

    PMID:38056430

    Open questions at the time
    • Interplay between PPARγ and other Gdf15 regulators (p53, AMPK) not integrated
  12. 2021 Medium

    Defined transcriptional and feedback control of GDF15 expression through p53, PPARβ/δ-AMPK, and energetic stress sensing.

    Evidence ChIP/luciferase for p53 (CRP-induced), PPARβ/δ epistasis, AMPKβ1 knockout mice with direct activators

    PMID:29967567 PMID:33337559 PMID:34380027

    Open questions at the time
    • Relative contribution of each pathway in vivo unclear
    • Direct AMPK-to-Gdf15 transcriptional link not fully defined
  13. 2022 Medium

    Revealed a positive feedback loop in which GDF15 is needed for full AMPK activation by metformin in liver and muscle independently of GFRAL, and uncovered CNOT6L as a post-transcriptional regulator.

    Evidence Gdf15 knockout/siRNA, AMPK assays, metformin; CNOT6L inhibition with mRNA stability assay

    PMID:35385705 PMID:36435271

    Open questions at the time
    • GFRAL-independent peripheral receptor for the AMPK feedback not identified
    • Direct CNOT6L target site on Gdf15 mRNA not mapped
  14. 2021 Medium

    Established GDF15 as an immunomodulator, stabilizing Treg FOXP3 by engaging CD48 on T cells and downregulating STUB1.

    Evidence Co-IP, mass spectrometry, ChIP, Gdf15 knockout, flow cytometry, RNA-seq in HCC

    PMID:34489334

    Open questions at the time
    • CD48 as a functional GDF15 receptor needs reciprocal validation
    • Relationship to canonical GFRAL signaling unclear
  15. 2022 Medium

    Demonstrated GDF15 reprograms macrophages toward an anti-inflammatory oxidative-phosphorylation state, attenuating liver fibrosis.

    Evidence Gdf15 knockout, AAV8 overexpression, recombinant GDF15, adoptive macrophage transfer, metabolic profiling

    PMID:37499753

    Open questions at the time
    • Receptor mediating macrophage effect not identified
    • Single-disease context
  16. 2023 High

    Linked peripheral lipolysis to behavior, showing adipose-macrophage-derived GDF15 mediates β-adrenergic-induced anxiety via GFRAL.

    Evidence ATGL, β-adrenergic receptor, and GFRAL knockout mice, restraint stress, anxiety assays, tissue GDF15 measurement

    PMID:40234625

    Open questions at the time
    • Circuit translating GFRAL activation into anxiety behavior not mapped
  17. 2021 Medium

    Resolved cell-type resolution of GDF15's central target as a single GFRAL/RET co-expressing excitatory AP neuron population.

    Evidence Single nuclei RNA sequencing of AP/NTS from GDF15-treated rats

    PMID:34942400

    Open questions at the time
    • Functional dissection of transcriptomic changes not performed
    • Secondary glial/neuronal effects not mechanistically resolved
  18. 2022 Medium

    Distinguished pharmacological from physiological GDF15 and from GLP-1 agonism: GDF15 induces malaise without altering feeding motivation, and physiological exercise-induced GDF15 does not affect appetite.

    Evidence Operant paradigms, CCK potentiation, pica/aversion tests, AgRP fibre photometry, human exercise studies

    PMID:33589633 PMID:35129264

    Open questions at the time
    • Why physiological and pharmacological GDF15 differ despite similar levels unresolved
    • Single lab group for the mechanistic comparison
  19. 2024 Medium

    Characterized GFRAL-independent peripheral actions through ALK5/SMAD signaling in fibroblasts and hepatocytes, with context-dependent pro- and anti-fibrotic outcomes.

    Evidence ALK5 inhibitor and SMAD3 inhibition, recombinant GDF15, Gdf15 knockout and bleomycin/SIC/PPP1R15A disease models

    PMID:35993367 PMID:38176644 PMID:39147013 PMID:39312445

    Open questions at the time
    • Direct ALK5/TGFβR binding contested due to possible TGF-β contamination
    • Reconciliation with GFRAL-restricted canonical model not achieved

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how GDF15 exerts its reported GFRAL-independent peripheral effects mechanistically, including the identity of any peripheral receptor and validation of CD48 and ALK5/TGFβR engagement.
  • No validated GFRAL-independent receptor
  • TGFβR/ALK5 claims confounded by contamination concerns
  • CD48 interaction lacks reciprocal validation

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 3 GO:0060089 molecular transducer activity 3
Localization
GO:0005576 extracellular region 2 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-1430728 Metabolism 4 R-HSA-162582 Signal Transduction 3 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-168256 Immune System 2
Partners
ARRB1CD48GFRALRET

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 MIC-1/GDF15 is synthesized as a 62-kDa intracellular precursor protein that is cleaved by a furin-like protease and secreted as a 25-kDa disulfide-linked dimeric protein. Protein expression analysis, biochemical characterization of cleavage and dimerization Journal of leukocyte biology Medium 9886240
1997 GDF15/PLAB inhibits the proliferation of primitive hematopoietic progenitors, demonstrating a direct biological activity. In vitro proliferation assay with hematopoietic progenitors Biochimica et biophysica acta Low 9375789
2017 GDNF family receptor α-like (GFRAL) is the high-affinity receptor for GDF15; GDF15 binds GFRAL with high affinity and requires GFRAL to elicit intracellular signaling through the co-receptor RET. GFRAL expression is restricted to neurons of the area postrema and nucleus of the solitary tract in the hindbrain. Genetic deletion of GFRAL abolishes GDF15-induced reductions in food intake and body weight in mice. Receptor binding assays, co-receptor identification (RET), GFRAL knockout mice, in vivo pharmacology in mice and nonhuman primates Nature medicine High 28846097 28846098 28846099 28953886
2017 GDF15 activates neurons in the area postrema and nucleus tractus solitarius via GFRAL, which then triggers activation of neurons in the parabrachial nucleus and central amygdala as part of an 'emergency circuit' regulating feeding responses under stress. GFRAL knockout mice are resistant to chemotherapy-induced anorexia and body weight loss. Neuronal activation mapping, GFRAL knockout mice, chemotherapy-induced anorexia model Nature High 28953886
2017 GDF15 delays gastric emptying and activates area postrema neurons, consistent with a gut-brain axis role in regulating energy intake. Crystal structure analysis of GDF15 informed structure-guided design of Fc fusion proteins with extended half-life. Gastric emptying assay, area postrema neuron activation imaging, GDF15 crystal structure analysis Science translational medicine Medium 29046435
2019 Metformin increases circulating GDF15 levels, with GDF15 expression increasing predominantly in the distal intestine and kidney. Metformin's effects on body weight and energy balance are absent in GDF15 knockout mice and GFRAL knockout mice, and are reversed by a GFRAL-antagonist antibody, demonstrating that the GDF15-GFRAL axis is required for metformin-induced weight loss. Randomized controlled trials (human), GDF15 and GFRAL knockout mice, GFRAL-antagonist antibody treatment, tissue-specific expression analysis Nature High 31875646
2019 GDF15 expression is regulated by the integrated stress response and is induced in selected tissues by sustained high-fat feeding or dietary amino acid imbalance. Pharmacological GDF15 administration triggers conditioned taste aversion in mice, indicating an aversive component to its anorectic action. Mouse dietary models, conditioned taste aversion assay, tissue expression analysis Cell metabolism Medium 30639358
2020 A GFRAL-antagonist monoclonal antibody (3P10) inhibits RET signaling by preventing the GDF15-driven interaction of RET with GFRAL on the cell surface. GDF15-GFRAL-RET pathway activation induces lipid metabolism gene expression in adipose tissue; peripheral chemical sympathectomy and loss of adipose triglyceride lipase protect mice from GDF15-induced weight loss, revealing a peripheral sympathetic-lipolytic axis downstream of GFRAL. Antagonistic antibody treatment, chemical sympathectomy, adipose triglyceride lipase knockout mice, gene expression analysis in adipose tissue, tumor-bearing mouse models Nature medicine High 32661391
2014 Transgenic overexpression of human NAG-1/GDF15 in mice increases thermogenic gene expression (UCP1, PGC1α, and others) in brown adipose tissue and lipolytic gene expression (Adrb3, ATGL, HSL) in white and brown adipose tissue, resulting in increased energy expenditure and resistance to diet-induced obesity without reducing food intake. Transgenic mouse overexpression model, high-fat diet challenge, gene expression analysis (thermogenic and lipolytic genes), xenograft model International journal of obesity Medium 24531647
2021 GDF15 potently activates the hypothalamic-pituitary-adrenal (HPA) axis in mice and rats via GFRAL; a blocking antibody to GFRAL completely prevented the corticosterone response to GDF15 administration. In wild-type mice, endogenous GDF15 is required for HPA axis activation in response to genotoxic or endoplasmic reticulum toxins (which do not provoke cytokine responses), as shown by the absence of this response in Gdf15-/- mice. GDF15 administration with GFRAL-blocking antibody, Gdf15 knockout mice, corticosterone measurement, multiple stress models (LPS, genotoxic, ER toxins) Proceedings of the National Academy of Sciences of the United States of America High 34187898
2021 PPARβ/δ activation increases GDF15 levels via an AMPK-p53 pathway, and GDF15 in turn sustains AMPK activation; the metabolic effects of PPARβ/δ activation (glucose tolerance improvement, fatty acid oxidation, ER stress reduction, AMPK activation) are abrogated by GDF15 neutralizing antibody or in Gdf15-/- mice. GDF15 neutralizing antibody, Gdf15 knockout mice, pharmacological PPARβ/δ activation, AMPK activity assays Cell reports Medium 34380027
2021 GDF15 combined with leptin causes greater weight and adiposity loss in obese mice than either treatment alone. GFRAL-expressing neurons in the hindbrain are extensively connected with leptin receptor (LepR)-expressing neurons; LepR knockdown in the NTS reduces GDF15-mediated AP neuronal activation, indicating that leptin signaling in the hindbrain potentiates GDF15's metabolic actions. Combined GDF15 and leptin infusion in obese mice, leptin receptor knockdown in NTS, hindbrain neuronal activation mapping, leptin-deficient ob/ob mice and competitive leptin antagonist Cell metabolism Medium 37433299
2023 GDF15 counteracts adaptive thermogenesis (compensatory reduction in energy expenditure during caloric restriction) by maintaining energy expenditure through a GFRAL-β-adrenergic-dependent signaling axis that increases fatty acid oxidation and calcium futile cycling in skeletal muscle of mice. Recombinant GDF15 treatment, caloric restriction models, β-adrenergic signaling analysis, fatty acid oxidation and calcium futile cycling assays in skeletal muscle Nature High 37380764
2023 Metformin increases plasma GDF15 levels by upregulating GDF15 synthesis specifically in the kidney. Kidney-specific knockdown of GDF15 expression, as well as area postrema-specific knockdown of GFRAL, negated the ability of metformin to lower food intake and body weight in rats. Tissue-specific AAV-mediated knockdown of GDF15 in kidney and GFRAL in area postrema, plasma GDF15 measurement, food intake and body weight assays Cell metabolism High 37060902
2023 Ketogenic diet activates hepatic PPARγ, which directly binds to the regulatory region of Gdf15, increasing its transcription in hepatocytes. Elevated circulating GDF15 is required for ketogenic diet-mediated weight loss via GFRAL signaling; GDF15- or GFRAL-deficient mice do not lose weight on KD. PPARγ chromatin immunoprecipitation, hepatocyte-specific AAV8 Gdf15 knockdown, GDF15 and GFRAL knockout mice, hepatic Pparγ knockout mice, recombinant GDF15 rescue experiments Cell metabolism High 38056430
2022 CNOT6L deadenylase regulates GDF15 expression post-transcriptionally; CNOT6L inhibition stabilizes hepatic Gdf15 mRNA, increasing circulating GDF15 levels which act on the hindbrain to suppress appetite. CNOT6L inhibition, mRNA stability assay, serum protein measurement, food intake assay Cell metabolism Medium 35385705
2019 β-Arrestin1 (ARRB1) interacts with GDF15 precursor (pro-GDF15) and facilitates transportation of pro-GDF15 to the Golgi apparatus for cleavage and maturation. ARRB1 deficiency impairs GDF15 maturation and accelerates steatohepatitis development. Co-immunoprecipitation (ARRB1-GDF15 interaction), Arrb1 knockout mice, pro-GDF15 overexpression rescue experiments, recombinant GDF15 treatment Journal of hepatology Medium 31857195
2021 GDF15 promotes generation of peripherally derived inducible Treg cells and enhances suppressive function of natural Treg cells by interacting with CD48 on T cells, which downregulates STUB1 (an E3 ligase that mediates FOXP3 protein degradation), thereby stabilizing FOXP3 and promoting immunosuppression in HCC. Co-immunoprecipitation (GDF15-CD48 interaction), mass spectrometry, chromatin immunoprecipitation, Gdf15 knockout mouse models, flow cytometry, RNA sequencing Journal for immunotherapy of cancer Medium 34489334
2020 GDF15 stimulates melanogenesis in melanocytes through MITF/tyrosinase upregulation via β-catenin signaling, as demonstrated by co-culture experiments with GDF15-overexpressing or GDF15-knockdown fibroblasts. Fibroblast-melanocyte co-culture, GDF15 lentiviral overexpression and shRNA knockdown, melanogenesis assay, ex vivo skin culture The Journal of investigative dermatology Low 32416083
2018 GDF15 promotes cervical cancer cell proliferation via the PI3K/AKT and MAPK/ERK signaling pathways, and GDF15 forms a protein complex with ErbB2 in cervical cancer cells as identified by immunoprecipitation. C-myc trans-activates GDF15 expression by binding E-box motifs in the GDF15 promoter. Immunoprecipitation (GDF15-ErbB2 complex), chromatin immunoprecipitation (C-myc binding to GDF15 promoter), western blotting, MTT assay, in vivo tumor formation Journal of experimental & clinical cancer research Low 29636108
2016 GDF15 promotes epithelial-mesenchymal transition (EMT) and metastasis in colorectal cancer by binding to TGF-β receptor and activating Smad2 and Smad3 signaling pathways. Recombinant GDF15 treatment, TGF-β receptor binding, Smad2/3 phosphorylation assay, in vitro metastasis assays, in vivo xenograft model Oncotarget Low 26497212
2018 GDF15 inhibits lung fibroblast growth and activation by inactivating the TGF-Smad pathway; GDF15 administration alleviates pulmonary fibrosis in mouse models. Primary fibroblast culture, epithelial cell-conditioned media fractionation, TGF-Smad pathway signaling analysis, mouse lung fibrosis model Cell death & disease Low 29724997
2022 Recombinant GDF15 stimulates α-smooth muscle actin (αSMA) expression in normal human lung fibroblasts, and this fibroblast activation is mediated through the ALK5 (activin receptor-like kinase 5) receptor, not GFRAL, suggesting a GFRAL-independent mechanism in peripheral fibrosis. Recombinant GDF15 treatment of lung fibroblasts, αSMA expression assay, ALK5 receptor inhibitor experiments, 3D spheroid assay, in vivo bleomycin fibrosis model with GDF15 neutralization JCI insight Medium 35993367
2021 AMPK mediates energetic stress-induced GDF15 expression in mouse liver; direct activation of AMPK β1-containing complexes by A769662 increases hepatic Gdf15 expression and circulating GDF15 independently of ER stress, an effect absent in AMPKβ1-/- mice. AMPKβ1 knockout mice, direct AMPK activators (AICAR, R419, A769662), CHOP knockout mice, hepatic Gdf15 expression and circulating GDF15 measurement FASEB journal Medium 33337559
2022 GDF15 upregulation by metformin is AMPK-dependent, and GDF15 in turn is required for full AMPK activation by metformin in liver and skeletal muscle independently of CNS/GFRAL signaling, revealing a positive feedback loop between AMPK and GDF15. Gdf15 knockout mice, Gdf15 siRNA knockdown in cultured hepatocytes and myotubes, AMPK activity assays, metformin treatment Pharmacological research Medium 36435271
2024 GDF15 activates AMPK and inhibits gluconeogenesis and fibrosis in the liver by attenuating the TGF-β1/SMAD3 pathway; Gdf15-/- mice show overactivated TGF-β1/SMAD3 signaling, reduced hepatic AMPK activity, elevated gluconeogenesis and fibrosis, and recombinant GDF15 reverses these effects in hepatocytes independently of GFRAL. Gdf15 knockout mice, recombinant GDF15 treatment, pharmacological SMAD3 inhibition, primary hepatocyte culture, AMPK and SMAD3 phosphorylation assays Metabolism: clinical and experimental Medium 38176644
2022 GDF15 knockdown in cancer cells decreases SLC7A11 (system Xc- component) expression, promotes erastin-induced ferroptosis, and reduces extracellular glutamate, intracellular GSH, while increasing lipid ROS levels, indicating GDF15 promotes ferroptosis resistance through SLC7A11 upregulation. GDF15 siRNA knockdown, erastin-induced ferroptosis assay, SLC7A11 expression analysis, lipid ROS measurement, GSH quantification Biochemical and biophysical research communications Low 32209255
2021 In the asthma context, Wnt pathway activation downstream of Notch4 in Treg cells induces GDF15 expression, and GDF15 produced by Treg cells activates group 2 innate lymphoid cells (ILC2s), creating a feed-forward mechanism for aggravated airway inflammation. Notch4 conditional knockout, Wnt pathway inhibition, GDF15 expression analysis in Treg cells, ILC2 activation assay Nature immunology Medium 32929274
2019 GDF15 apoptotic and cytotoxic effects in A549 lung cancer cells depend on TGFBR2 expression; TGFBR2 silencing blocks GDF15-induced cytotoxicity, apoptosis, caspase-9 and caspase-3 activation, and ERK1/2/p38 MAPK modulation. TGFBR2 siRNA knockdown, GDF15 overexpression, caspase activation assay, annexin V/PI flow cytometry, ERK/p38 phosphorylation Cell biochemistry and function Low 31172564
2022 Pharmacological GDF15 suppresses voluntary wheel running activity (exercise motivation) and feeding via GFRAL-dependent mechanisms, but physiologically induced GDF15 by exercise does not affect appetite or exercise motivation despite reaching similar circulating levels. Recombinant GDF15 administration, GFRAL antagonism, voluntary wheel running assay, exercise intervention in mice and humans, food intake measurement Nature communications Medium 33589633
2022 GDF15 and semaglutide reduce food intake and body weight through largely distinct mechanisms: semaglutide amplifies satiation signals (CCK, ingested food) and inhibits AgRP neurons, while GDF15 induces visceral malaise but does not affect feeding motivation or CCK signal processing; combined treatment produces additive weight loss without enhanced malaise. Progressive ratio operant paradigm, CCK potentiation assay, pica/kaolin intake assay, conditioned food aversion test, fibre photometry of AgRP neurons in vivo Diabetes, obesity & metabolism Medium 35129264
2023 GDF15 produced in white adipose tissue macrophages (M2-like) mediates adrenaline/β-adrenergic-induced anxiety-like behavior; genetic deletion of adipose triglyceride lipase or β-adrenergic receptors blocks β-adrenergic-induced GDF15 increases; anxiety-like behavior elicited by adrenaline or restraint stress is eliminated in GFRAL-deficient mice, identifying GDF15-GFRAL as a link between lipolysis and anxiety behavior. ATGL knockout, β-adrenergic receptor knockout, GFRAL knockout mice, restraint stress model, GDF15 measurement in adipose tissue and plasma, anxiety behavioral assays Nature metabolism High 40234625
2022 GDF15 promotes liver fibrosis amelioration by reprogramming macrophage metabolism to an oxidative phosphorylation-dependent anti-inflammatory state; adoptive transfer of GDF15-preprogrammed macrophages to fibrotic mice attenuates inflammation and fibrosis. Gdf15 knockout mice, AAV8-mediated GDF15 overexpression, recombinant GDF15 treatment, adoptive macrophage transfer, metabolic pathway analysis in macrophages Cellular and molecular gastroenterology and hepatology Medium 37499753
2024 In sepsis-induced cardiomyopathy, GDF15 activates the ALK5-SMAD2/3 pathway, which inhibits SOCS1 expression, thereby activating the JAK2/STAT3 pathway, promoting GPX4 transcription and inhibiting ferroptosis in cardiomyocytes. Transcriptomic analysis, ALK5-SMAD2/3 signaling pathway assay, SOCS1 expression, JAK2/STAT3 and GPX4 measurements, mouse SIC model with GDF15 antagonism European journal of pharmacology Low 39147013
2024 GDF15 blockade prevents cachexia and slows the progression of heart failure in a mouse model where PPP1R15A deficiency leads to increased cardiac Gdf15 expression and elevated circulating GDF15, indicating that cardiac stress drives a GDF15-dependent pathway promoting weight loss and worsening cardiac function. GDF15-blocking antibody treatment, PPP1R15A knockout bone marrow reconstitution mouse model, cardiac function assessment, Gdf15 expression analysis Cardiovascular research Medium 39312445
2018 GDF15 in colorectal cancer cells promotes EMT and metastasis via TGFβR/Smad2/Smad3 pathway activation. GDF15 silencing by shRNA suppresses GDF15-induced cell invasion and migration in LoVo cells. GDF15 overexpression and shRNA knockdown, western blotting for EMT markers (N-cadherin, vimentin, Twist1, E-cadherin), cell invasion/migration assays Artificial cells, nanomedicine, and biotechnology Low 29771147
2018 C-reactive protein (CRP) stimulates GDF15 expression in endothelial cells through p53; CRP treatment of endothelial cells recruits p53 to binding sites in the GDF15 promoter, inducing GDF15 transcription. CRP treatment of human aortic endothelial cells, dual-luciferase reporter assay, chromatin immunoprecipitation (p53 binding to GDF15 promoter), CRP plasmid transfection Mediators of inflammation Medium 29967567
2022 GDF15 in cancer-associated fibroblasts binds GFRAL on melanoma cells, promoting RET phosphorylation, triggering downstream signaling that induces tumor cell stemness and secretion of CCL18 and TGF-β, leading to M2 macrophage polarization and immunosuppressive microenvironment. Co-immunoprecipitation, chromatin immunoprecipitation, luciferase reporter assay, recombinant protein rescue experiments, CRISPR knockout mice, Cre-loxP system mice, cell co-culture Journal for immunotherapy of cancer Medium 40555562
2021 Single nuclei RNA sequencing identified a single population of GFRAL and RET co-expressing excitatory neurons in the area postrema as the primary direct cellular target of GDF15 in the hindbrain; GDF15 treatment induced cell-type-specific transcriptomic changes in these neurons and secondary changes in other neuronal and glial subtypes of the AP/NTS. Single nuclei RNA sequencing of AP and NTS micropunches from GDF15-treated vs. saline-treated rats Molecular metabolism Medium 34942400

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates. Nature medicine 626 28846097
2017 The metabolic effects of GDF15 are mediated by the orphan receptor GFRAL. Nature medicine 552 28846098
2017 GFRAL is the receptor for GDF15 and is required for the anti-obesity effects of the ligand. Nature medicine 543 28846099
2017 Non-homeostatic body weight regulation through a brainstem-restricted receptor for GDF15. Nature 508 28953886
2019 GDF15 mediates the effects of metformin on body weight and energy balance. Nature 447 31875646
2021 GDF15: emerging biology and therapeutic applications for obesity and cardiometabolic disease. Nature reviews. Endocrinology 409 34381196
2020 Growth/Differentiation Factor-15 (GDF-15): From Biomarker to Novel Targetable Immune Checkpoint. Frontiers in immunology 404 32508832
2019 GDF15 Provides an Endocrine Signal of Nutritional Stress in Mice and Humans. Cell metabolism 403 30639358
2018 The MIC-1/GDF15-GFRAL Pathway in Energy Homeostasis: Implications for Obesity, Cachexia, and Other Associated Diseases. Cell metabolism 336 30184485
2020 Antibody-mediated inhibition of GDF15-GFRAL activity reverses cancer cachexia in mice. Nature medicine 258 32661391
1999 MIC-1 is a novel TGF-beta superfamily cytokine associated with macrophage activation. Journal of leukocyte biology 235 9886240
1997 PLAB, a novel placental bone morphogenetic protein. Biochimica et biophysica acta 218 9375789
2020 GDF15: A Hormone Conveying Somatic Distress to the Brain. Endocrine reviews 209 32310257
2014 NAG-1/GDF-15 prevents obesity by increasing thermogenesis, lipolysis and oxidative metabolism. International journal of obesity (2005) 209 24531647
2017 Long-acting MIC-1/GDF15 molecules to treat obesity: Evidence from mice to monkeys. Science translational medicine 196 29046435
2023 GDF15 promotes weight loss by enhancing energy expenditure in muscle. Nature 192 37380764
2020 The GDF15-GFRAL Pathway in Health and Metabolic Disease: Friend or Foe? Annual review of physiology 179 33228454
2018 GDF15 promotes the proliferation of cervical cancer cells by phosphorylating AKT1 and Erk1/2 through the receptor ErbB2. Journal of experimental & clinical cancer research : CR 172 29636108
2019 Growth differentiation factor 15 (GDF15): A survival protein with therapeutic potential in metabolic diseases. Pharmacology & therapeutics 153 30790643
2018 GDF15 and Growth Control. Frontiers in physiology 147 30542297
2022 GDF15, an emerging key player in human aging. Ageing research reviews 141 35051643
2012 The diverse roles of nonsteroidal anti-inflammatory drug activated gene (NAG-1/GDF15) in cancer. Biochemical pharmacology 139 23220538
2021 Pathophysiological role of growth differentiation factor 15 (GDF15) in obesity, cancer, and cachexia. Cytokine & growth factor reviews 138 34836750
2016 GDF15 promotes EMT and metastasis in colorectal cancer. Oncotarget 138 26497212
2021 GDF15 induces immunosuppression via CD48 on regulatory T cells in hepatocellular carcinoma. Journal for immunotherapy of cancer 137 34489334
2020 Insights Into Mechanisms of GDF15 and Receptor GFRAL: Therapeutic Targets. Trends in endocrinology and metabolism: TEM 136 33172749
2021 GDF15 and Cardiac Cells: Current Concepts and New Insights. International journal of molecular sciences 118 34445593
2020 GDF15, an update of the physiological and pathological roles it plays: a review. Pflugers Archiv : European journal of physiology 113 32936319
2021 Pharmacological but not physiological GDF15 suppresses feeding and the motivation to exercise. Nature communications 109 33589633
2022 Overexpression of NAG-1/GDF15 prevents hepatic steatosis through inhibiting oxidative stress-mediated dsDNA release and AIM2 inflammasome activation. Redox biology 107 35504134
2020 A regulatory T cell Notch4-GDF15 axis licenses tissue inflammation in asthma. Nature immunology 106 32929274
2018 Uniting GDF15 and GFRAL: Therapeutic Opportunities in Obesity and Beyond. Trends in endocrinology and metabolism: TEM 102 29866502
2021 The Role of GDF15 as a Myomitokine. Cells 100 34831213
2011 Macrophage inhibitory cytokine-1 (MIC-1/GDF15) and mortality in end-stage renal disease. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 98 21940482
2021 GDF15 mediates the metabolic effects of PPARβ/δ by activating AMPK. Cell reports 89 34380027
2021 GDF15 as a biomarker of ageing. Experimental gerontology 87 33421539
2021 Activation of the hypothalamic-pituitary-adrenal axis by exogenous and endogenous GDF15. Proceedings of the National Academy of Sciences of the United States of America 82 34187898
2022 GDF15 promotes prostate cancer bone metastasis and colonization through osteoblastic CCL2 and RANKL activation. Bone research 76 35058441
2017 TGF-β contamination of purified recombinant GDF15. PloS one 76 29161287
2000 GDF-15/MIC-1 a novel member of the TGF-beta superfamily. Journal of neural transmission. Supplementum 71 11205146
2020 GDF15 knockdown promotes erastin-induced ferroptosis by decreasing SLC7A11 expression. Biochemical and biophysical research communications 69 32209255
2017 Targeting Obesity and Cachexia: Identification of the GFRAL Receptor-MIC-1/GDF15 Pathway. Trends in molecular medicine 67 29129392
2023 Metformin triggers a kidney GDF15-dependent area postrema axis to regulate food intake and body weight. Cell metabolism 66 37060902
2019 ARRB1 inhibits non-alcoholic steatohepatitis progression by promoting GDF15 maturation. Journal of hepatology 64 31857195
2021 GDF15/GFRAL Pathway as a Metabolic Signature for Cachexia in Patients with Cancer. Journal of Cancer 61 33442410
2022 NAG-1/GDF15 inhibits diabetic nephropathy via inhibiting AGE/RAGE-mediated inflammation signaling pathways in C57BL/6 mice and HK-2 cells. Life sciences 60 36367498
2003 Dysregulated expression of MIC-1/PDF in human prostate tumor cells. Biochemical and biophysical research communications 60 12763036
2023 GDF15 Ameliorates Liver Fibrosis by Metabolic Reprogramming of Macrophages to Acquire Anti-Inflammatory Properties. Cellular and molecular gastroenterology and hepatology 58 37499753
2022 Increased expression and accumulation of GDF15 in IPF extracellular matrix contribute to fibrosis. JCI insight 56 35993367
2004 Cloning and characterization of the gene encoding the major cell-associated phospholipase A of Legionella pneumophila, plaB, exhibiting hemolytic activity. Infection and immunity 47 15102773
2022 GDF15 in Appetite and Exercise: Essential Player or Coincidental Bystander? Endocrinology 46 34849709
2020 Growth differentiation factor 15 (GDF15) in cancer cell metastasis: from the cells to the patients. Clinical & experimental metastasis 46 32504264
2022 Growth differentiation factor 15 (GDF15) and semaglutide inhibit food intake and body weight through largely distinct, additive mechanisms. Diabetes, obesity & metabolism 45 35129264
2023 GDF15 is a major determinant of ketogenic diet-induced weight loss. Cell metabolism 44 38056430
2022 Deadenylase-dependent mRNA decay of GDF15 and FGF21 orchestrates food intake and energy expenditure. Cell metabolism 43 35385705
2022 Metformin and growth differentiation factor 15 (GDF15) in type 2 diabetes mellitus: A hidden treasure. Journal of diabetes 43 36444166
2024 Overview of growth differentiation factor 15 (GDF15) in metabolic diseases. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 42 38810400
2023 GDF15 Promotes Cell Growth, Migration, and Invasion in Gastric Cancer by Inducing STAT3 Activation. International journal of molecular sciences 42 36769245
2018 CST3 and GDF15 ameliorate renal fibrosis by inhibiting fibroblast growth and activation. Biochemical and biophysical research communications 42 29653105
2021 AMPK mediates energetic stress-induced liver GDF15. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 41 33337559
2020 Senescent Fibroblast-Derived GDF15 Induces Skin Pigmentation. The Journal of investigative dermatology 40 32416083
2018 CRP Stimulates GDF15 Expression in Endothelial Cells through p53. Mediators of inflammation 39 29967567
2022 Knocking on GDF15's door for the treatment of type 2 diabetes mellitus. Trends in endocrinology and metabolism: TEM 38 36151002
2021 The anti-diabetic effects of NAG-1/GDF15 on HFD/STZ-induced mice. Scientific reports 38 34294853
2024 GDF15 activates AMPK and inhibits gluconeogenesis and fibrosis in the liver by attenuating the TGF-β1/SMAD3 pathway. Metabolism: clinical and experimental 37 38176644
2023 GDF15 as a key disease target and biomarker: linking chronic lung diseases and ageing. Molecular and cellular biochemistry 37 37093513
2022 The GDF15-GFRAL pathway is dispensable for the effects of metformin on energy balance. Cell reports 37 36001956
2023 GDF15 enhances body weight and adiposity reduction in obese mice by leveraging the leptin pathway. Cell metabolism 36 37433299
2018 Epithelial cell-derived cytokines CST3 and GDF15 as potential therapeutics for pulmonary fibrosis. Cell death & disease 36 29724997
2023 Growth differentiation factor 15 (GDF-15) in endocrinology. Endocrine 35 37129758
2022 A positive feedback loop between AMPK and GDF15 promotes metformin antidiabetic effects. Pharmacological research 35 36435271
2020 Mitochondrial stress and GDF15 in the pathophysiology of sepsis. Archives of biochemistry and biophysics 34 33188737
2022 NCAM1 and GDF15 are biomarkers of Charcot-Marie-Tooth disease in patients and mice. Brain : a journal of neurology 33 35148379
2020 Functional roles of GDF15 in modulating microenvironment to promote carcinogenesis. Biochimica et biophysica acta. Molecular basis of disease 33 32304740
2024 GDF15 is still a mystery hormone. Trends in endocrinology and metabolism: TEM 32 39472228
2022 Camptothecin effectively treats obesity in mice through GDF15 induction. PLoS biology 32 35202387
2021 The Clinical Value of GDF15 and Its Prospective Mechanism in Sepsis. Frontiers in immunology 32 34566964
2019 GDF-15: A Multifunctional Modulator and Potential Therapeutic Target in Cancer. Current pharmaceutical design 31 30947652
2024 Artesunate treats obesity in male mice and non-human primates through GDF15/GFRAL signalling axis. Nature communications 30 38310105
2024 GDF15 antagonism limits severe heart failure and prevents cardiac cachexia. Cardiovascular research 30 39312445
2019 GDF15 induced apoptosis and cytotoxicity in A549 cells depends on TGFBR2 expression. Cell biochemistry and function 30 31172564
2010 Phospholipase PlaB is a new virulence factor of Legionella pneumophila. International journal of medical microbiology : IJMM 28 20153694
2024 Macrophages as a Source and Target of GDF-15. International journal of molecular sciences 27 39000420
2024 GDF15 attenuates sepsis-induced myocardial dysfunction by inhibiting cardiomyocytes ferroptosis via the SOCS1/GPX4 signaling pathway. European journal of pharmacology 27 39147013
2009 Phospholipase PlaB of Legionella pneumophila represents a novel lipase family: protein residues essential for lipolytic activity, substrate specificity, and hemolysis. The Journal of biological chemistry 26 19640837
2018 GDF15 promotes epithelial-to-mesenchymal transition in colorectal [corrected]. Artificial cells, nanomedicine, and biotechnology 25 29771147
2022 The GDF15-GFRAL axis mediates chemotherapy-induced fatigue in mice. Brain, behavior, and immunity 24 36427806
2024 GDF15, an Emerging Player in Renal Physiology and Pathophysiology. International journal of molecular sciences 23 38892145
2022 GDF15: a potential therapeutic target for type 1 diabetes. Expert opinion on therapeutic targets 23 35138971
2022 Hepatocyte-derived GDF15 suppresses feeding and improves insulin sensitivity in obese mice. iScience 22 36465107
2025 GDF15 links adipose tissue lipolysis with anxiety. Nature metabolism 21 40234625
2025 Ectopic expression of GDF15 in cancer-associated fibroblasts enhances melanoma immunosuppression via the GFRAL/RET cascade. Journal for immunotherapy of cancer 21 40555562
2024 GDF15/MIC-1: a stress-induced immunosuppressive factor which promotes the aging process. Biogerontology 20 39643709
2022 Growth and differentiation factor 15 (GDF15) levels predict adverse respiratory outcomes in premature neonates. Pediatric pulmonology 20 36205439
2021 Single nuclei RNA sequencing of the rat AP and NTS following GDF15 treatment. Molecular metabolism 20 34942400
2019 GDF15 promotes osteosarcoma cell migration and invasion by regulating the TGF‑β signaling pathway. Molecular medicine reports 20 31545486
2019 Competitive inhibition by NAG-1/GDF-15 NLS peptide enhances its anti-cancer activity. Biochemical and biophysical research communications 19 31474335
2018 Targeting the divergent TGFβ superfamily cytokine MIC-1/GDF15 for therapy of anorexia/cachexia syndromes. Current opinion in supportive and palliative care 19 30382947
2023 Cross-species comparison of pregnancy-induced GDF15. American journal of physiology. Endocrinology and metabolism 18 37584611
2015 MIC-1/GDF15 in Barrett's oesophagus and oesophageal adenocarcinoma. British journal of cancer 17 25867265

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