Affinage

GDF15

Growth/differentiation factor 15 · UniProt Q99988

Round 2 corrected
Length
308 aa
Mass
34.1 kDa
Annotated
2026-04-28
130 papers in source corpus 37 papers cited in narrative 35 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GDF15 is a stress-responsive, secreted TGF-β superfamily cytokine that functions as a central regulator of energy balance, appetite, and tissue-protective responses across multiple organ systems. It is synthesized as a propeptide, undergoes proteolytic maturation facilitated by ARRB1-mediated Golgi transport, and is secreted as a disulfide-linked dimer whose transcription is driven by p53, ATF4/CHOP (integrated stress response), and AMPKβ1 (PMID:9326641, PMID:10777512, PMID:32694673, PMID:33337559, PMID:31857195). Circulating GDF15 signals through the brainstem-restricted GFRAL–RET receptor tyrosine kinase complex in area postrema/nucleus tractus solitarius neurons to suppress food intake via conditioned aversion, activate sympathetic outflow that drives peripheral lipolysis through ATGL, and counteract adaptive thermogenesis via β-adrenergic–skeletal muscle fatty acid oxidation and calcium futile cycling (PMID:28846097, PMID:28953886, PMID:32661391, PMID:37380764, PMID:30639358). Beyond its central metabolic actions, GDF15 exerts GFRAL-independent peripheral effects including cardioprotection via PI3K-Akt1 signaling, suppression of hepatic gluconeogenesis and fibrosis through SMAD3 pathway attenuation, macrophage metabolic reprogramming toward oxidative phosphorylation, hepcidin suppression contributing to iron overload in β-thalassemia, and pro-fibrotic ALK5-dependent signaling in lung fibroblasts (PMID:16397141, PMID:38176644, PMID:37499753, PMID:17721544, PMID:35993367).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1997 High

    Identifying GDF15 as a new TGF-β superfamily member secreted as a disulfide-linked dimer from macrophages established its biochemical identity and initial autocrine anti-inflammatory function.

    Evidence Subtraction cloning from activated macrophages, recombinant protein purification from CHO cells, and functional TNF-α inhibition assay

    PMID:9326641

    Open questions at the time
    • Receptor identity unknown
    • In vivo relevance of macrophage regulation not tested
    • Signaling pathway downstream of GDF15 not identified
  2. 2000 High

    Demonstrating that p53 directly binds and transactivates the GDF15 promoter linked GDF15 to the tumor suppressor network and explained its stress-inducible expression pattern.

    Evidence EMSA with recombinant p53, promoter-luciferase reporters, and adenoviral overexpression causing G1 arrest and apoptosis in breast cancer cells

    PMID:10777512

    Open questions at the time
    • Other stress-responsive transcription factors not yet mapped
    • Whether p53-GDF15 axis operates in non-cancer contexts unclear
  3. 2006 High

    The finding that Gdf15-knockout mice develop larger infarcts and that recombinant GDF15 rescues cardiomyocyte survival via PI3K-Akt1 established GDF15 as a cardioprotective cytokine with a defined survival signaling pathway.

    Evidence Gdf15-KO mice with coronary ligation, recombinant GDF15 rescue, PI3K inhibitor and dominant-negative Akt1 blockade

    PMID:16397141

    Open questions at the time
    • Receptor mediating cardiac PI3K-Akt1 activation unknown
    • Whether cardioprotection is paracrine or autocrine not resolved
  4. 2007 High

    Discovery that tumor-derived GDF15 causes cancer-associated anorexia reversible by neutralizing antibody, and that erythroid GDF15 suppresses hepatic hepcidin in β-thalassemia, revealed two major systemic endocrine functions.

    Evidence Prostate cancer xenograft models with anti-MIC-1 antibody reversal; β-thalassemia patient serum immunodepletion restoring hepcidin in primary hepatocytes

    PMID:17721544 PMID:17982462

    Open questions at the time
    • Central receptor not identified
    • Receptor mediating hepcidin suppression unknown
    • Relative contribution of GDF15 vs. other erythroid factors to iron overload not quantified
  5. 2017 High

    Four independent groups simultaneously identified GFRAL as the high-affinity receptor for GDF15, restricted to area postrema and NTS neurons and requiring RET as a co-receptor, resolving the two-decade-old receptor question and defining the neural circuit for appetite suppression.

    Evidence Receptor binding assays, Gfral-KO mice refractory to GDF15-induced anorexia, GFRAL monoclonal antibody blockade, ISH/IHC localization, RET co-receptor signaling studies, c-Fos neuronal activation mapping

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

    Open questions at the time
    • Peripheral receptor(s) mediating GFRAL-independent effects remain unidentified
    • Downstream intracellular signaling in GFRAL+ neurons incompletely mapped
    • Whether GFRAL has additional ligands unknown
  6. 2019 High

    Integrated stress response transcription factors ATF4/CHOP and dietary/pharmacological stressors were shown to drive GDF15 expression, and GDF15 was established as the required mediator of metformin's anorectic and weight-lowering effects in mice and humans, while conditioned taste aversion experiments revealed an aversive rather than classical satiety mechanism.

    Evidence GDF15-null mice unresponsive to metformin weight loss, two independent RCTs showing metformin increases circulating GDF15, ISR pathway analysis, GFRAL antagonist antibody, conditioned taste aversion behavioral assay

    PMID:30639358 PMID:31875646 PMID:32694673

    Open questions at the time
    • Whether metformin-GDF15 axis is relevant in lean individuals unknown
    • Precise neural mechanism translating GFRAL activation to malaise not defined
    • Tissue source hierarchy for metformin-induced GDF15 not fully resolved
  7. 2019 Medium

    ARRB1 was identified as a direct interactor of pro-GDF15 required for its Golgi transport and proteolytic maturation, revealing a previously unknown step in GDF15 secretory processing.

    Evidence Co-IP of ARRB1 with pro-GDF15, Arrb1-KO mice with impaired GDF15 maturation and steatohepatitis rescued by recombinant GDF15, subcellular fractionation

    PMID:31857195

    Open questions at the time
    • Protease responsible for pro-GDF15 cleavage not identified
    • Whether ARRB1 role is specific to GDF15 or shared with other TGF-β family members unknown
    • Single-lab finding awaiting independent replication
  8. 2020 High

    Mapping the peripheral effector arm showed that GDF15-GFRAL signaling activates sympathetic outflow requiring ATGL for adipose lipolysis, and that GDF15 induces visceral malaise distinct from GLP-1 receptor agonist mechanisms.

    Evidence GFRAL antagonist antibody, chemical sympathectomy, ATGL-KO mice in cachexia models; rat behavioral paradigms with fiber photometry comparing GDF15 vs. semaglutide

    PMID:32661391 PMID:35129264

    Open questions at the time
    • Whether sympathetic axis mediates GDF15's effects on muscle wasting not resolved
    • Neural pathway from AP/NTS to sympathetic outflow not fully traced
  9. 2021 High

    AMPKβ1 was identified as a stress-responsive transcriptional inducer of hepatic GDF15 independent of ER stress/CHOP, expanding the regulatory inputs beyond the canonical ISR.

    Evidence AMPKβ1-KO and CHOP-KO mice treated with three pharmacological AMPK activators, hepatic Gdf15 expression and serum measurements

    PMID:33337559

    Open questions at the time
    • Transcription factor downstream of AMPK that directly drives GDF15 promoter not identified
    • Whether AMPKβ1 and ATF4/CHOP pathways converge or are fully independent in vivo unclear
  10. 2022 Medium

    Post-transcriptional control of GDF15 was revealed through CNOT6L deadenylase regulation of Gdf15 mRNA stability, and peripheral anti-inflammatory mechanisms were expanded to include AIM2 inflammasome suppression and AGE/RAGE-NF-κB inhibition in liver and kidney disease models.

    Evidence CNOT6L genetic inhibition stabilizing Gdf15 mRNA; GDF15-transgenic mice showing reduced AIM2 activation in NASH and reduced TLR4/NF-κB in diabetic nephropathy

    PMID:35385705 PMID:35504134 PMID:36367498

    Open questions at the time
    • Whether CNOT6L regulation is tissue-specific not established
    • Receptor mediating GDF15's peripheral anti-inflammatory effects unknown
    • No structural basis for GDF15-mRNA deadenylase interaction
  11. 2022 Medium

    GDF15 was shown to signal through ALK5 (TGF-β type I receptor) in lung fibroblasts to drive α-SMA expression, and GDF15 neutralization reduced bleomycin-induced lung fibrosis, revealing a pro-fibrotic peripheral signaling axis.

    Evidence Recombinant GDF15 with ALK5 inhibitor in fibroblasts, IPF ECM proteomics, bleomycin mouse model with GDF15 neutralizing antibody

    PMID:35993367

    Open questions at the time
    • Whether ALK5 is a direct GDF15 receptor or requires a co-receptor not determined
    • Relationship between ALK5 signaling and GFRAL-independent effects in other tissues unknown
  12. 2023 High

    GDF15 was found to counteract adaptive thermogenesis during caloric restriction through a GFRAL–β-adrenergic–skeletal muscle axis driving fatty acid oxidation and calcium futile cycling, providing a mechanism for sustained energy expenditure during weight loss beyond appetite suppression.

    Evidence GFRAL-KO mice under caloric restriction, β-blocker pharmacology, skeletal muscle fatty acid oxidation and calcium cycling assays

    PMID:37380764

    Open questions at the time
    • Whether this anti-thermogenic-adaptation pathway operates in humans not tested
    • Molecular identity of muscle calcium cycling targets downstream of β-adrenergic signaling not specified
  13. 2023 Medium

    GDF15 was shown to reprogram macrophages toward oxidative phosphorylation and an anti-inflammatory phenotype, and adoptive transfer of GDF15-conditioned macrophages attenuated liver fibrosis, while leptin receptor signaling in NTS was found to potentiate GDF15's central metabolic effects.

    Evidence Gdf15-KO mice in CCl4/DDC fibrosis models, adoptive macrophage transfer, CyTOF immune profiling, metabolic flux analysis; combined GDF15-leptin infusion with AAV-LepR knockdown in NTS

    PMID:37433299 PMID:37499753

    Open questions at the time
    • Receptor mediating GDF15's macrophage reprogramming not identified
    • Whether leptin-GDF15 synergy occurs in humans unknown
    • Degree to which macrophage reprogramming vs. direct hepatocyte effects drive anti-fibrotic action not resolved
  14. 2024 Medium

    Hepatic GFRAL-independent GDF15 signaling was mapped to SMAD3 pathway attenuation that restores AMPK activity and suppresses gluconeogenesis and fibrosis, while cardiac ISR-driven GDF15 was identified as a mediator of cardiac cachexia blockable by GDF15 antibody.

    Evidence Gdf15-KO mice with elevated pSMAD3 and gluconeogenesis rescued by SMAD3 inhibitor; PPP1R15A-KO dilated cardiomyopathy model with GDF15 blocking antibody preventing cachexia

    PMID:38176644 PMID:39312445

    Open questions at the time
    • Peripheral hepatic receptor for GDF15 that mediates SMAD3 attenuation not identified
    • Whether cardiac GDF15 blockade is therapeutically viable without compromising stress-protective functions unknown
    • Structural basis for GDF15-SMAD3 pathway interaction not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • The identity of peripheral receptor(s) mediating GDF15's GFRAL-independent effects on macrophages, hepatocytes, and fibroblasts remains the central unresolved question; proposed interactors (ErbB2, CD48, ALK5) each derive from single laboratories and await independent validation and structural characterization.
  • No consensus peripheral receptor identified
  • No crystal structure of full-length GDF15-GFRAL-RET ternary complex
  • Therapeutic window between beneficial metabolic effects and detrimental cachexia/aversion not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 6 GO:0098772 molecular function regulator activity 4
Localization
GO:0005576 extracellular region 7 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-1430728 Metabolism 6 R-HSA-162582 Signal Transduction 6 R-HSA-168256 Immune System 4 R-HSA-5357801 Programmed Cell Death 3
Partners
ARRB1ATF4DDIT3GFRALPRKAB1RETTP53

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 GDF15 (then called MIC-1) is a divergent member of the TGF-β superfamily. It is synthesized as a propeptide, undergoes proteolytic cleavage, and is secreted as a cysteine-rich disulfide-linked 25 kDa dimer. In macrophages, its expression is upregulated by IL-1β, TNF-α, IL-2, M-CSF, and TGF-β, and purified recombinant MIC-1 inhibits LPS-induced macrophage TNF-α production, indicating an autocrine regulatory role in limiting macrophage activation. Subtraction cloning, CHO-cell expression with propeptide cleavage verification, purification of recombinant protein, functional TNF-α inhibition assay Proceedings of the National Academy of Sciences of the United States of America High 9326641
2000 GDF15 (PTGF-β) is a direct transcriptional target of p53; the GDF15 promoter contains two p53-binding site motifs, one of which is essential for p53-mediated induction and specifically binds recombinant p53 in gel-shift assays. GDF15 overexpression induces both G1 cell-cycle arrest and apoptosis in breast cancer cells, establishing it as a downstream mediator of p53-dependent growth arrest. Promoter-luciferase reporter assay, electrophoretic mobility shift assay (EMSA) with recombinant p53, adenoviral overexpression, flow cytometry for cell-cycle and apoptosis The Journal of biological chemistry High 10777512
2001 GDF15 (NAG-1) expression is induced by NSAID treatment (cyclooxygenase inhibitors) through COX-independent mechanisms in colorectal cancer cells, and forced GDF15 overexpression increases basal apoptosis and reduces tumorigenicity in nude mice, demonstrating a proapoptotic and antitumorigenic function. Subtractive hybridization, stable transfection, soft-agar colony assay, xenograft tumor model in nude mice Molecular pharmacology High 11259636
2006 GDF15 is induced in cardiomyocytes under ischemia/reperfusion (I/R) via NO-peroxynitrite-dependent signaling. Gdf15-knockout mice develop larger infarct sizes and more cardiomyocyte apoptosis after I/R than wild-type littermates. Recombinant GDF15 protects cultured cardiomyocytes from apoptosis during simulated I/R, and this protective effect is abolished by PI3K inhibitors and dominant-negative Akt1, placing GDF15 upstream of PI3K-Akt1 survival signaling. Gdf15 gene-targeted (knockout) mice with coronary artery ligation model, recombinant GDF15 treatment, histone ELISA/TUNEL/annexin-V FACS for apoptosis, PI3K inhibitor pharmacology, adenoviral dominant-negative Akt1 Circulation research High 16397141
2007 Elevated circulating MIC-1/GDF15 produced by tumors causes anorexia and weight loss by acting centrally; in xenograft models, antibody neutralization of MIC-1 reverses weight loss. GDF15 mediates its effects via hypothalamic TGF-β receptor II, and downstream activation of ERK1/2, STAT3, and modulation of NPY and POMC neuropeptides. Prostate cancer xenograft mouse model, anti-MIC-1 antibody neutralization, hypothalamic signaling analysis (ERK1/2, STAT3), neuropeptide measurement Nature medicine High 17982462
2007 During erythroblast maturation, GDF15 expression and secretion increase substantially. In β-thalassemia patients, markedly elevated serum GDF15 suppresses hepcidin mRNA expression in primary human hepatocytes; depletion of GDF15 from thalassemia patient serum reverses hepcidin suppression, demonstrating that GDF15 is a key erythroid regulator that suppresses hepcidin and contributes to iron overload. Erythroblast transcriptome profiling, GDF15 ELISA in patient serum, primary hepatocyte culture with patient serum, GDF15 immunodepletion with functional rescue Nature medicine High 17721544
2014 In transgenic mice ubiquitously expressing human GDF15 (NAG-1), GDF15 prevents obesity by increasing expression of thermogenic genes (UCP1, PGC1α, Dio2, Cox8b) in brown adipose tissue and lipolytic genes (Adrb3, ATGL, HSL) in both white and brown adipose tissue, leading to higher energy expenditure without reducing food intake. Transgenic mouse model, xenograft model (melanoma cells secreting GDF15), thermogenic and lipolytic gene expression analysis, metabolic phenotyping (glucose tolerance, insulin levels, energy expenditure) International journal of obesity High 24531647
2016 GDF15 produced in skeletal muscle with mitochondrial dysfunction (due to Crif1 deficiency activating UPRmt) acts as a myomitokine to regulate systemic energy homeostasis; elevated GDF15 secretion in muscle-specific Crif1-KO mice protects against obesity and improves insulin sensitivity. Recombinant GDF15 in ob/ob mice reduces body weight through elevated oxidative metabolism and lipid mobilization in liver, muscle, and adipose tissue. Muscle-specific Crif1-KO mouse model, recombinant GDF15 administration in ob/ob mice, metabolic phenotyping, oxidative metabolism assays The Journal of cell biology High 27986797
2017 GFRAL (GDNF family receptor α-like) is the cognate receptor for GDF15 in the hindbrain. GDF15 binds GFRAL with high affinity; Gfral-knockout mice are refractory to GDF15-induced reductions in food intake, body weight, and glucose parameters. GFRAL mRNA is expressed exclusively in neurons of the area postrema and nucleus of the solitary tract. GDF15-induced cell signaling requires interaction of GFRAL with the co-receptor RET tyrosine kinase. Receptor binding assay (high-affinity binding), Gfral-knockout mice with recombinant GDF15 treatment, GFRAL monoclonal antibody blockade in rats, immunohistochemistry/in situ hybridization for receptor localization, RET co-receptor signaling studies Nature medicine High 28846097 28846098 28846099 28953886
2017 GDF15 activates GFRAL-expressing neurons exclusively in the area postrema and nucleus tractus solitarius of the brainstem, which then activate neurons in the parabrachial nucleus and central amygdala (the 'emergency circuit'). Gfral-knockout mice are hyperphagic under stress conditions and resistant to chemotherapy-induced anorexia and weight loss, establishing this as a non-homeostatic neural circuit. Gfral-knockout mouse model with chemotherapy-induced anorexia model, neuronal activation mapping (c-Fos), circuit tracing, metabolic phenotyping Nature High 28953886
2018 GDF15 promotes proliferation of cervical cancer cells by binding to ErbB2 (HER2) in a protein complex, leading to phosphorylation of AKT1 and Erk1/2 and upregulation of CyclinD1 and CyclinE1 while downregulating p21. C-myc trans-activates GDF15 expression by binding E-box motifs in the GDF15 promoter, creating a positive feedback loop. Immunoprecipitation to show GDF15-ErbB2 complex, western blotting for phospho-AKT1 and phospho-Erk1/2, chromatin immunoprecipitation (ChIP) for C-myc binding to GDF15 promoter, flow cytometry for cell cycle, xenograft tumor formation assay Journal of experimental & clinical cancer research Medium 29636108
2019 ARRB1 (β-Arrestin1) interacts directly with pro-GDF15 and facilitates its transport to the Golgi apparatus for proteolytic cleavage and maturation into secreted GDF15. Arrb1-deficient mice have impaired GDF15 maturation and develop accelerated steatohepatitis; re-expression of Arrb1 or supplementation with recombinant GDF15 rescues the phenotype. Co-immunoprecipitation of ARRB1 with pro-GDF15, Arrb1-knockout mouse models (HFD and MCD diet), recombinant GDF15 rescue experiment, subcellular fractionation/Golgi localization Journal of hepatology Medium 31857195
2019 Metformin induces GDF15 expression and secretion from hepatocytes by activating ATF4 and CHOP (DDIT3) transcription factors as part of the integrated stress response. In wild-type mice on high-fat diet, oral metformin increases serum GDF15 and reduces food intake and body mass; these effects are absent in GDF15-null mice, demonstrating that GDF15 is required for metformin's effects on appetite and body weight. Unbiased hepatocyte transcriptomics, human serum proteomics, primary mouse hepatocyte culture, GDF15-null mice with metformin treatment, ATF4/CHOP mechanistic studies Nature metabolism High 32694673
2019 GDF15 expression is regulated by the integrated stress response (ISR) in selected tissues during sustained high-fat feeding or dietary amino acid imbalance. Pharmacological GDF15 administration to mice triggers conditioned taste aversion, suggesting that GDF15 induces aversive/nausea-like responses rather than classical satiety signaling. Mouse dietary stress models (high-fat and amino acid imbalance diets), ISR pathway analysis in tissues, conditioned taste aversion behavioral assay Cell metabolism High 30639358
2019 GDF15 mediates the weight loss effects of metformin in vivo; in two independent randomized controlled clinical trials, metformin increases circulating GDF15. In mice, GDF15 is expressed predominantly in the distal intestine and kidney in response to metformin, and Gdf15-knockout or GFRAL-antagonist antibody-treated mice fail to show metformin-induced body-weight reduction, while glucose-lowering effects are preserved. Randomized controlled clinical trials (two independent), Gdf15-knockout mice, GFRAL antagonist antibody in obese mice, tissue-specific GDF15 expression analysis Nature High 31875646
2019 Brown adipocytes release GDF15 in response to thermogenic activation via norepinephrine/cAMP through protein kinase A (PKA)-mediated mechanisms, and this release requires the active FGF21-β-klotho signaling pathway. GDF15 released by brown adipocytes targets macrophages and downregulates proinflammatory gene expression. Cold exposure of mice, norepinephrine/cAMP treatment of brown adipocyte cultures, PKA inhibitor experiments, FGF21/β-klotho invalidation cell models, RAW264.7 macrophage co-culture/conditioned medium experiments Obesity (Silver Spring) Medium 31411815
2020 Antibody-mediated inhibition of GFRAL (monoclonal antibody 3P10) blocks GDF15-driven RET co-receptor recruitment and signaling on brainstem neurons. GDF15-GFRAL-RET pathway activation induces lipid oxidation genes in adipose tissue, and peripheral sympathetic nervous system and adipose triglyceride lipase (ATGL) are required for GDF15-induced lipolysis and adipose/muscle mass loss, establishing a peripheral sympathetic-lipolytic axis downstream of GFRAL-RET. GFRAL antagonist monoclonal antibody (3P10) in tumor-bearing mice, chemical sympathectomy, ATGL-knockout mice, adipose tissue gene expression analysis, cancer cachexia mouse models Nature medicine High 32661391
2020 GDF15 promotes immunosuppression in hepatocellular carcinoma by interacting with CD48 on T cells (identified as a GDF15 receptor in the immune system). This interaction downregulates STUB1, an E3 ubiquitin ligase that mediates FOXP3 degradation, thereby stabilizing FOXP3 and enhancing generation and suppressive function of regulatory T cells. Co-immunoprecipitation of GDF15 with CD48, mass spectrometry, CyTOF immune profiling, Gdf15-knockout mouse orthotopic HCC models, RNA sequencing, ChIP, OT-I transgenic mice, flow cytometry for FOXP3 and Treg function Journal for immunotherapy of cancer Medium 34489334
2020 GDF15 induces visceral malaise (conditioned taste aversion, kaolin intake) but does not reduce feeding motivation or amplify gastrointestinal satiation signals (CCK or ingested food), in contrast to semaglutide. GDF15 does not modulate AgRP neuron calcium signaling, while semaglutide does; the two agents act through largely distinct, additive neural mechanisms to reduce food intake. Rat pharmaco-behavioral experiments (CCK potentiation, progressive ratio operant paradigm, kaolin intake, conditioned affective food aversion), fibre photometry in AgRP-Cre mice Diabetes, obesity & metabolism Medium 35129264
2020 CRP induces GDF15 transcription in human aortic endothelial cells via p53 recruitment to two p53-binding sites in the GDF15 promoter, as confirmed by ChIP and dual-luciferase reporter assays, linking inflammatory CRP signaling to p53-dependent GDF15 expression. CRP treatment of human aortic endothelial cells, dual-luciferase reporter assay, chromatin immunoprecipitation (ChIP) for p53 at GDF15 promoter Mediators of inflammation Medium 29967567
2021 AMPK (specifically β1-containing complexes) mediates energetic stress-induced hepatic GDF15 expression. Direct AMPK β1 activation (A769662) increases hepatic Gdf15 expression and circulating GDF15 independently of ER stress. Effects of AICAR, R419, and A769662 on GDF15 are all attenuated in AMPKβ1-knockout mice, while CHOP (downstream of ER stress) is not required for A769662-induced GDF15. AMPKβ1-knockout and CHOP-knockout mice, three pharmacological AMPK activators (AICAR, R419, A769662), hepatic adenine nucleotide and GDF15 measurements, food intake assay FASEB journal High 33337559
2021 GDF15 acts via the GFRAL-RET receptor complex in area postrema/NTS excitatory neurons; single-nuclei RNA sequencing identified ~600 cell-type-specific transcriptomic changes in AP/NTS neurons and glia after systemic GDF15 treatment, mapping downstream signaling pathways specifically in Gfral/Ret-positive excitatory neurons. Single-nuclei RNA sequencing (snRNAseq) of rat AP/NTS micropunches after GDF15 injection, Seurat-based cell-type clustering, differential gene expression Molecular metabolism Medium 34942400
2021 Notch4 signaling on lung Treg cells upregulates GDF15 expression (via Wnt pathway), and this Treg-derived GDF15 activates group 2 innate lymphoid cells (ILC2s) to create a feed-forward loop promoting airway inflammation in asthma. Notch4-conditional mouse models, Wnt pathway inhibitor experiments, ILC2 activation assays, human asthma patient Treg analysis Nature immunology Medium 32929274
2022 CNOT6L deadenylase controls the stability of hepatic Gdf15 mRNA; CNOT6L inhibition stabilizes Gdf15 mRNA, increasing serum GDF15 protein levels, which then suppresses appetite via hindbrain activation. CNOT6L genetic inhibition models, mRNA stability assays, serum GDF15 ELISA, food intake measurement, small-molecule CNOT6L inhibitor screening Cell metabolism Medium 35385705
2022 A positive feedback loop exists between AMPK and GDF15 in the context of metformin action: metformin activates AMPK, which increases GDF15; GDF15 in turn sustains full AMPK activation in liver and skeletal muscle independently of the CNS/GFRAL. Gdf15-knockout mice show blunted AMPK activation in response to metformin, and Gdf15 knockdown in cultured hepatocytes and myotubes reduces metformin-induced AMPK activation. Gdf15-knockout mice, Gdf15 siRNA knockdown in hepatocytes/myotubes, metformin treatment, AMPK phosphorylation western blotting, glucose tolerance testing Pharmacological research Medium 36435271
2022 GDF15 knockdown decreases SLC7A11 (system Xc- transporter) expression, promoting erastin-induced ferroptosis in gastric cancer MGC803 cells. GDF15 knockdown reduces intracellular GSH and increases lipid ROS levels, and blocks the erastin-induced upregulation of SLC7A11, indicating GDF15 supports ferroptosis resistance via SLC7A11. GDF15 siRNA knockdown, CCK-8 cell viability assay, qRT-PCR and western blotting for SLC7A11, glutamate/GSH measurement, lipid ROS detection Biochemical and biophysical research communications Low 32209255
2022 GDF15 overexpression in transgenic mice inhibits HFD/STZ-induced non-alcoholic steatohepatitis by suppressing oxidative stress-mediated mitochondrial damage and double-strand DNA release into the cytosol, thereby blocking AIM2 inflammasome activation and reducing IL-18 and IL-1β secretion. This effect is independent of reduced food intake. NAG-1/GDF15 transgenic mice on HFD, free fatty acid-treated hepatocyte steatosis models, GDF15 siRNA knockdown, oxidative stress markers, dsDNA cytosolic release assay, AIM2 inflammasome activation assay (IL-18/IL-1β ELISA) Redox biology Medium 35504134
2022 GDF15 NAG-1 inhibits HFD/STZ-induced diabetic nephropathy by inhibiting the AGE/RAGE axis and associated downstream TLR4/MyD88/NF-κB inflammatory signaling, as well as reducing adhesion molecules, in both transgenic mice and high-glucose-treated HK-2 renal tubular cells. NAG-1/GDF15 transgenic mice with HFD/STZ DN model, transcriptome analysis, recombinant GDF15 protein treatment of HK-2 cells, western blotting for AGE/RAGE, TLR4/MyD88/NF-κB pathway components Life sciences Medium 36367498
2022 GDF15 promotes skin pigmentation by stimulating melanogenesis through MITF/tyrosinase upregulation via β-catenin signaling in melanocytes. This effect is mediated by GDF15 secreted from UV-irradiated senescent fibroblasts. GDF15 lentiviral overexpression and shRNA knockdown in fibroblasts, co-culture of melanocytes with GDF15-expressing fibroblasts, β-catenin signaling analysis, ex vivo skin culture, reconstituted human skin model The Journal of investigative dermatology Medium 32416083
2022 GDF15 expression in IPF lung-derived extracellular matrix is markedly elevated, and recombinant GDF15 stimulates α-smooth muscle actin (αSMA) expression in normal human lung fibroblasts through the ALK5 (TGF-β type I receptor) pathway. GDF15 neutralization in a bleomycin lung fibrosis mouse model significantly reduces fibrosis. 3D spheroid fibroblast assay with IPF ECM, proteomics of IPF ECM, recombinant GDF15 stimulation with ALK5 inhibitor, αSMA expression, bleomycin lung fibrosis mouse model with GDF15 neutralizing antibody, collagen gel migration assay JCI insight Medium 35993367
2023 In addition to suppressing appetite via GFRAL, GDF15 counteracts adaptive thermogenesis (compensatory energy expenditure reduction) during caloric restriction. This effect requires a GFRAL-β-adrenergic receptor-dependent signaling axis that increases fatty acid oxidation and calcium futile cycling in skeletal muscle, resulting in maintained energy expenditure during weight loss. Recombinant GDF15 treatment in calorie-restricted mice, GFRAL-knockout mice, β-adrenergic blocker pharmacology, skeletal muscle fatty acid oxidation assays, calcium cycling measurements, NAFLD assessment Nature High 37380764
2023 GDF15 and leptin synergize in the hindbrain to enhance weight and adiposity loss; LepR-expressing neurons in the NTS are extensively connected with GFRAL-expressing neurons, and LepR knockdown in the NTS reduces GDF15-mediated activation of area postrema neurons, establishing that leptin receptor signaling in the hindbrain potentiates GDF15's metabolic actions. Combined GDF15 and leptin infusion in HFD mice, competitive leptin antagonist in normal mice, ob/ob mice (leptin-deficient), AAV-mediated LepR knockdown in NTS, hindbrain neuronal activation mapping Cell metabolism Medium 37433299
2023 GDF15 ameliorates liver fibrosis by reprogramming macrophage metabolic pathways toward oxidative phosphorylation, inducing an anti-inflammatory functional fate. Adoptive transfer of GDF15-preprogrammed macrophages to CCl4 fibrosis mouse models attenuates inflammation and liver fibrosis progression. Gdf15-knockout mice in CCl4 and DDC diet fibrosis models, AAV8-mediated GDF15 overexpression in hepatocytes, recombinant GDF15 treatment, CyTOF/flow cytometry for immune profiling, metabolic flux analysis of macrophages, adoptive transfer of GDF15-preprogrammed macrophages Cellular and molecular gastroenterology and hepatology Medium 37499753
2024 GDF15 activates hepatic AMPK and inhibits gluconeogenesis and fibrosis by attenuating the TGF-β1/SMAD3 pathway independently of its central receptor GFRAL. Gdf15-knockout mice show reduced hepatic AMPK phosphorylation, elevated pSMAD3, increased TGF-β1, and enhanced gluconeogenesis/fibrosis. Recombinant GDF15 in primary hepatocytes reduces pSMAD3 and gluconeogenic markers, and pharmacological SMAD3 inhibition in Gdf15-KO mice rescues AMPK activity and metabolic phenotype. Gdf15-knockout mice, recombinant GDF15 in primary hepatocytes and Huh-7 cells, SMAD3 pharmacological inhibition, AMPK phosphorylation western blotting, gluconeogenic gene expression, liver fibrosis histology Metabolism: clinical and experimental Medium 38176644
2024 Cardiac stress upregulates GDF15 expression in cardiomyocytes via ISR/eIF2α phosphatase (PPP1R15A) pathway, and elevated circulating GDF15 drives weight loss and worsens cardiac function (cardiac cachexia). GDF15 blockade prevents cachexia and slows heart failure progression in a dilated cardiomyopathy mouse model. PPP1R15A-knockout mouse model with irradiation-induced dilated cardiomyopathy, cardiac GDF15 expression analysis, GDF15 blocking antibody treatment, lean mass and cardiac function measurements Cardiovascular research Medium 39312445

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2020 A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature 3411 32353859
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
1997 MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-beta superfamily. Proceedings of the National Academy of Sciences of the United States of America 1030 9326641
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2008 An empirical framework for binary interactome mapping. Nature methods 652 19060904
2007 High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin. Nature medicine 646 17721544
2017 GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates. Nature medicine 615 28846097
2020 Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms. Science (New York, N.Y.) 564 33060197
2006 The transforming growth factor-beta superfamily member growth-differentiation factor-15 protects the heart from ischemia/reperfusion injury. Circulation research 546 16397141
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2017 GFRAL is the receptor for GDF15 and is required for the anti-obesity effects of the ligand. Nature medicine 538 28846099
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