Affinage

GLP1R

Glucagon-like peptide 1 receptor · UniProt P43220

Length
463 aa
Mass
53.0 kDa
Annotated
2026-06-10
100 papers in source corpus 37 papers cited in narrative 38 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GLP-1R is a class B G protein-coupled receptor that converts peptide and small-molecule agonist binding into Gs-coupled cAMP/PKA signaling, governing metabolic, neuronal, immune, and epithelial processes (PMID:35013280, PMID:36027914). Cryo-EM structures of the receptor bound to GLP-1, oxyntomodulin, exendin-4, dual GLP-1R/GCGR agonists, and diverse small molecules show that agonists engage an orthosteric pocket and that distinctions in peptide N-terminal interactions and dynamics with the transmembrane domain are reciprocally linked to allosteric coupling efficiency to Gs (PMID:35013280, PMID:37549266); non-peptide agonists such as PF 06882961 occupy a site overlapping GLP-1's, while others adopt distinct poses conferring biased signaling (PMID:33027691, PMID:35561211), and Gs protein alone can pre-open the intracellular cavity and rewire the orthosteric pocket toward an active state even without ligand (PMID:38346960). Ligand dissociation kinetics (Koff), not association, dictate the onset and duration of G protein coupling and cAMP output, and agonists activate distinct compartmentalized signaling neighborhoods that map onto clinical effect profiles (PMID:35300966, PMID:37813859). GLP-1R internalization is atypical: it is GRK-dependent but β-arrestin-independent, with GRK2 required for β-arrestin recruitment, and β-arrestin 2 tuning desensitization, recycling, ubiquitination, and the balance of plasma-membrane versus endosomal/trans-Golgi signaling (PMID:38461904, PMID:33658023, PMID:37134170). In pancreatic β-cells, GLP-1R–cAMP–PKA signaling amplifies glucose-stimulated insulin secretion through downstream effectors including PPP1R1A, and human loss-of-function variants that reduce surface expression impair glucose control and increase adiposity but can be rescued by allosteric ligands (PMID:33631146, PMID:37709961). In the nervous system, anatomically distinct GLP-1R neuronal populations partition function: NTS neurons drive satiety without aversion while area postrema neurons drive aversion, hypothalamic LepRb/Glp1r and lateral septal GABAergic neurons projecting to the lateral hypothalamus mediate anorexia, and GLP-1R activation suppresses VTA dopamine responses to oppose hedonic eating (PMID:38987598, PMID:37581939, PMID:38763494, PMID:40146831). In peripheral tissues, GLP-1R signaling restrains intraepithelial-lymphocyte T cell receptor signaling via PKA, sustains colonic epithelial maintenance and intestinal mucosal growth through an Fgf7-dependent pathway, and modulates carotid body chemoreflex and sympathetic output (PMID:36027914, PMID:38521185, PMID:25738454, PMID:35100822).

Mechanistic history

Synthesis pass · year-by-year structured walk · 24 steps
  1. 2018 Medium

    Established that GLP-1R agonism could be combined with GIPR antagonism to enhance metabolic efficacy, framing GLP-1R within the incretin pharmacology landscape.

    Evidence Crystallography of an anti-GIPR antibody plus in vivo studies in DIO mice and non-human primates

    PMID:30567927

    Open questions at the time
    • GLP-1R structure itself not resolved here
    • combination mechanism inferred from in vivo weight loss only
  2. 2020 High

    Resolved how non-peptide agonists engage GLP-1R, showing that pharmacological mimicry of GLP-1 depends on whether a small molecule occupies the overlapping orthosteric pocket and reconstitutes its water-mediated hydrogen-bond network.

    Evidence High-resolution cryo-EM of PF 06882961- and CHU-128-bound receptor with pharmacological assays

    PMID:33027691

    Open questions at the time
    • Does not map full conformational trajectory to G protein coupling
    • limited to two compounds
  3. 2021 High

    Defined the molecular basis of differential peptide engagement among clinical agonists, linking distinct receptor and peptide motions to differing signaling profiles.

    Evidence Cryo-EM with 3D variability analysis of semaglutide- and taspoglutide-bound GLP-1R–Gs complexes

    PMID:34260945

    Open questions at the time
    • Static structures only partially capture dynamics
    • signaling consequences inferred
  4. 2022 High

    Connected peptide N-terminal transmembrane interactions to allosteric Gs coupling kinetics, explaining how subtle ligand differences tune G protein activation.

    Evidence Cryo-EM, molecular dynamics, mutagenesis and pharmacology across four peptide agonists

    PMID:35013280

    Open questions at the time
    • Kinetic correlations not validated against in vivo signaling outcomes
  5. 2022 Medium

    Showed that ligand dissociation kinetics, rather than association, govern the timing and persistence of receptor–G protein coupling and cAMP output.

    Evidence Quantitative kinetic binding, BRET G protein engagement, and cAMP assays for a peptide agonist series

    PMID:35300966

    Open questions at the time
    • Single lab, in vitro only
    • physiological relevance of Koff to insulin secretion not tested
  6. 2022 Medium

    Identified a druggable cryptic allosteric pocket in the cytoplasmic half of TM3/TM5/TM6 that enlarges the orthosteric site to facilitate GLP-1 binding.

    Evidence Molecular dynamics, mutagenesis and signaling assays for small-molecule positive allosteric modulators

    PMID:34570476

    Open questions at the time
    • No experimental structure of PAM-bound receptor
    • probe-dependence limits generalization
  7. 2024 High

    Revealed that small-molecule agonists Boc5 and WB4-24 achieve peptidomimetic and biased signaling by inserting into both the orthosteric pocket and distinct transmembrane clefts.

    Evidence Cryo-EM of receptor–ligand–Gs complexes with pharmacological validation

    PMID:35561211

    Open questions at the time
    • Bias quantified in vitro, not linked to in vivo outcomes
  8. 2023 High

    Defined determinants of GLP-1R versus GCGR selectivity in dual agonists, showing ligand N-terminal side chains and ECL1 reshaping control dual agonism.

    Evidence Cryo-EM of receptor–Gs with three dual GLP-1R/GCGR agonists

    PMID:37549266

    Open questions at the time
    • Selectivity rules derived from limited ligand set
  9. 2024 High

    Demonstrated that Gs protein alone can pre-activate GLP-1R by opening the intracellular cavity and rewiring the orthosteric pocket, distinguishing it from GCGR and GIPR.

    Evidence Cryo-EM of ligand-free GLP-1R–Gs complexes compared across three receptors

    PMID:38346960

    Open questions at the time
    • Functional significance of ligand-independent pre-coupling in cells unknown
  10. 2021 High

    Established the atypical trafficking logic of GLP-1R, showing internalization is GRK-dependent but β-arrestin-independent and that GRK2 is required for β-arrestin recruitment and tunes insulin release kinetics.

    Evidence CRISPR GRK/β-arrestin knockouts, nanoBRET, GRK2 hemizygous mice and isolated islet assays

    PMID:33658023 PMID:38461904

    Open questions at the time
    • No single GRK isoform assigned exclusive role
    • GRK2 islet effects on early-phase secretion mechanism partly correlative
  11. 2021 Medium

    Contrasted GLP-1R and GIPR trafficking, showing GLP-1R favors internalization, degradation and endosomal cAMP whereas GIPR favors recycling and signal amplification.

    Evidence Parallel surface expression, trafficking, and spatiotemporal cAMP assays in β-cells

    PMID:36774542

    Open questions at the time
    • Single lab comparison
    • in vivo consequences not addressed
  12. 2021 Medium

    Identified PPP1R1A as a downstream effector linking GLP-1R–PKA signaling to amplification of glucose-stimulated insulin secretion and mitochondrial coupling.

    Evidence siRNA knockdown in INS1 cells with GSIS, PKA phosphorylation and mitochondrial assays plus human islet correlation

    PMID:33631146

    Open questions at the time
    • Single lab
    • mechanism of PPP1R1A action on secretion not fully defined
  13. 2023 High

    Showed β-arrestin 2 controls the temporal phases of GLP-1R signaling in β-cells, balancing desensitization, recycling, ubiquitination and compartmentalized cAMP.

    Evidence Adult β-cell-specific β-arrestin 2 conditional KO with cAMP, trafficking and glucose tolerance assays

    PMID:37134170

    Open questions at the time
    • Compensation by β-arrestin 1/PDE4 complicates clean attribution
  14. 2023 High

    Mapped the spatiotemporal signaling diversity of GLP-1R agonists across pathways and compartments, linking signaling neighborhoods to clinical adverse-event profiles.

    Evidence 15-biosensor panel across four compartments, structure analysis, microscopy and phosphoproteomics

    PMID:37813859

    Open questions at the time
    • Clinical correlations associative, not causal
  15. 2023 High

    Connected human GLP1R genetic variation to metabolic disease, showing loss-of-function variants reduce surface expression and impair glucose control, with rescue by allosteric ligands.

    Evidence Functional profiling of 60 variants across four pathways, INS-1 rescue, UK Biobank association

    PMID:37709961

    Open questions at the time
    • Not all variant phenotypes validated in vivo
  16. 2019 High

    Localized the critical neural substrate for physiological GLP-1R metabolic control to Phox2b+ autonomic/vagal neurons.

    Evidence Cell-type-specific conditional Glp1r knockouts (Phox2b-Cre, Wnt1-Cre2) with glucose tolerance and gastric emptying assays

    PMID:31189118

    Open questions at the time
    • Does not resolve downstream circuit
    • single lab
  17. 2023 High

    Established hypothalamic LepRb/Glp1r and lateral septal GLP-1R neurons as necessary and sufficient mediators of GLP-1R agonist anorexia.

    Evidence Conditional KO and re-expression, chemogenetics, region-specific knockdown and fiber photometry

    PMID:37581939 PMID:39225090

    Open questions at the time
    • Integration across hypothalamic and septal nodes not fully mapped
  18. 2024 High

    Dissociated satiety from aversion at the circuit level, showing NTS-GLP1R neurons drive satiety without aversion while AP-GLP1R neurons drive aversion, and traced dLS-GLP1R GABAergic projections to the lateral hypothalamus.

    Evidence Two-photon calcium imaging, chemogenetics, optogenetics and circuit tracing

    PMID:38763494 PMID:38987598

    Open questions at the time
    • Downstream effector neurons of each population incompletely defined
  19. 2024 High

    Identified the hedonic eating circuit opposing GLP-1R-driven appetite reduction, showing GLP-1R activation suppresses VTA dopamine responses to food.

    Evidence Photometry-calibrated optogenetics and feeding behavior with semaglutide

    PMID:40146831

    Open questions at the time
    • Receptor locus on VTA circuit not fully resolved
  20. 2024 Medium

    Placed BDNFmNTS neurons downstream of GFRAL/GLP1R neurons as a required node for GLP-1R agonist weight loss, and showed CNS GIPR plus GLP-1R cooperate for maximal weight loss.

    Evidence Genetic and chemogenetic gain/loss-of-function, c-FOS mapping, drug biodistribution

    PMID:39737892 PMID:40301582

    Open questions at the time
    • BDNFmNTS findings single lab
    • molecular coupling between receptors and BDNF neurons unresolved
  21. 2024 High

    Showed dual GLP-1R/LepR agonism acts through dorsomedial hypothalamic LepRGlp1r neurons, with re-expression on a null background sufficient for efficacy.

    Evidence Conditional KO and re-expression mouse models with dual agonist pharmacology

    PMID:39630884

    Open questions at the time
    • Downstream projection targets not defined
  22. 2022 High

    Defined peripheral immunomodulatory and chemosensory roles, showing GLP-1R restrains intraepithelial-lymphocyte TCR signaling via PKA and modulates carotid body chemoreflex and sympathetic output.

    Evidence IEL-specific conditional KO with PKA inhibitors and microbiota analysis; carotid body RNA-seq and in vivo functional assays

    PMID:31189118 PMID:35100822 PMID:36027914

    Open questions at the time
    • Carotid body receptor signaling pathway less detailed than IEL PKA axis
  23. 2015 High

    Established a non-incretin epithelial role, showing GLP-1R controls intestinal mucosal growth through Fgf7, independent of EGF/IGF1 receptors, and later colonic epithelial maintenance during energy deprivation.

    Evidence Glp1r-/- and Fgf7-/- mice with exendin-4 and Apc(Min/+) models; GF GLP-1R KO with organoid and dietary/microbiota rescue

    PMID:25738454 PMID:38521185

    Open questions at the time
    • Receptor-expressing cell type driving Fgf7 induction not fully resolved
  24. 2025 Medium

    Extended GLP-1R signaling to neuroprotection, showing agonists engage CaMKK2-AMPK to reduce BACE1-mediated APP cleavage and Aβ generation while promoting microglial Aβ phagocytosis.

    Evidence AD model mice with biochemical CaMKK2-AMPK-BACE1 pathway analysis and microglial assays

    PMID:40394225

    Open questions at the time
    • Single lab
    • direct receptor-to-CaMKK2 coupling mechanism not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How agonist-specific receptor conformations and compartmentalized signaling neighborhoods translate into the divergent therapeutic and adverse effects across distinct β-cell, neuronal, immune, and epithelial cell types remains unresolved.
  • No unified model linking biased signaling to cell-type-specific physiology
  • in vivo causal link between Koff/location bias and clinical outcomes untested
  • molecular effectors downstream of cAMP/PKA characterized only in selected tissues

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0048018 receptor ligand activity 2 GO:0098772 molecular function regulator activity 1
Localization
GO:0005886 plasma membrane 3 GO:0005768 endosome 2
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-162582 Signal Transduction 3 R-HSA-1430728 Metabolism 2 R-HSA-168256 Immune System 2 R-HSA-5653656 Vesicle-mediated transport 2
Partners
ARRB1ARRB2GNASGRK2
Complex memberships
GLP-1R–Gs protein complex

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2020 Cryo-EM structures revealed that the non-peptide GLP-1R agonist PF 06882961 has a binding site that substantially overlaps with GLP-1's binding site, whereas CHU-128 adopts a unique binding mode with a more open receptor conformation at the extracellular face. Extensive water-mediated hydrogen bond networks explain why PF 06882961 but not CHU-128 closely mimics GLP-1 pharmacological properties. High-resolution cryo-EM structural determination combined with pharmacological assays Molecular cell High 33027691
2022 Cryo-EM structures and molecular dynamics simulations of GLP-1R bound to four peptide agonists (GLP-1, oxyntomodulin, exendin-4, exendin-P5) demonstrated that distinctions in peptide N-terminal interactions and dynamics with the transmembrane domain are reciprocally associated with differences in allosteric coupling to G proteins; transient interactions with residues at the base of the binding cavity correlate with enhanced kinetics for G protein activation. Cryo-EM, molecular dynamics simulations, receptor mutagenesis, pharmacological assays Nature communications High 35013280
2021 Cryo-EM structures of semaglutide- and taspoglutide-bound GLP-1R–Gs protein complexes revealed similar peptide interactions to GLP-1 but different motions within the receptor and bound peptides, providing molecular determinants of differential peptide engagement and signaling profiles. Cryo-EM with 3D variability analysis Cell reports High 34260945
2022 Cryo-EM structures of small-molecule agonists Boc5 and WB4-24 bound to GLP-1R–Gs revealed that one arm of each compound inserts deeply into the orthosteric binding pocket overlapping with GLP-1 residues A8–D15, while other arms extend into TM1-TM7, TM1-TM2, and TM2-TM3 clefts, creating a unique conformation that confers peptidomimetic agonism and biased signaling. Cryo-EM structural determination of receptor–ligand–Gs complexes Proceedings of the National Academy of Sciences of the United States of America High 35561211
2023 Cryo-EM structures of GLP-1R in complex with Gs protein and three dual GLP-1R/GCGR agonists (peptide 15, MEDI0382, SAR425899) identified key residues for ligand recognition and dual agonism; side chain orientations within the first three residues of the ligand determine receptor selectivity, and ECL1 conformation of GLP-1R is reshaped by dual agonists relative to GCGR. Cryo-EM structural determination combined with published pharmacological data Proceedings of the National Academy of Sciences of the United States of America High 37549266
2024 Cryo-EM structures of ligand-free GLP-1R in complex with Gs protein (without cognate peptide) showed that Gs protein alone directly opens the intracellular binding cavity and rewires the extracellular orthosteric pocket; the extracellular portion of GLP-1R adopts a conformation close to the active state even without ligand, distinct from GCGR and GIPR. Cryo-EM structural determination of ligand-free receptor–Gs complexes Cell discovery High 38346960
2018 Crystallographic studies of an anti-human GIPR antibody showed it displaced GIP and bound GIPR using the same conserved hydrophobic residues as GIP, and combined GLP-1R agonists with GIPR antagonism produced enhanced weight loss in preclinical models. Crystallography plus in vivo pharmacological studies (DIO mice and NHP) Science translational medicine Medium 30567927
2021 GLP-1R undergoes an atypical β-arrestin-independent mode of internalization; GRK2/3/4/5/6 knockout experiments using CRISPR/Cas9 demonstrated that GLP-1R internalisation is GRK-dependent, β-arrestin 1 recruitment is more sensitive to GRK knockout than β-arrestin 2 recruitment, and no single GRK isoform exclusively drives these pathways. CRISPR/Cas9 endogenous GRK and β-arrestin knockouts, quantitative trafficking assays Biochemical pharmacology High 38461904
2021 GRK2 associates with GLP-1R upon agonist stimulation (demonstrated by nanoBRET in β-cell lines), and GRK2 protein and kinase activity are required for subsequent β-arrestin recruitment to GLP-1R. Reduced GRK2 levels in vivo enhanced early-phase insulin release stimulated by GLP-1R agonists without affecting late-phase secretion, correlating with an increased readily releasable pool of insulin granules. NanoBRET, GRK2 hemizygous mouse model, isolated pancreatic islet assays, β-cell line experiments BMC biology High 33658023
2023 Adult β-cell-specific β-arrestin 2 knockout mice showed impaired acute GLP-1R agonist (exendin-4, semaglutide, tirzepatide) responses but improved responses 6 hours post-injection. The acute cAMP impairment was attributed to enhanced β-arrestin 1 and phosphodiesterase 4 activity compensating for β-arrestin 2 loss; reduced desensitization co-occurred with impaired GLP-1R recycling/lysosomal targeting, increased trans-Golgi network signaling, and reduced GLP-1R ubiquitination. Adult β-cell-specific β-arrestin 2 conditional KO mice, cAMP assays, trafficking assays, in vivo glucose tolerance Science advances High 37134170
2022 GLP-1R peptide agonist dissociation kinetics (Koff), but not association kinetics (Kon), were positively correlated with onset of receptor–G protein coupling, onset of cAMP production, and duration of cAMP signaling, mechanistically linking ligand–receptor interaction kinetics to downstream signaling onset. Quantitative kinetic binding assays, BRET-based G protein engagement assays, cAMP measurement for a series of peptide agonists Biochemical pharmacology Medium 35300966
2023 Using 15 signaling biosensors across 4 cellular compartments, GLP-1R was shown to activate distinct signaling neighborhoods in a pathway- and compartment-selective manner; comparative structure analysis, time-lapse microscopy, and phosphoproteomics revealed unique signaling signatures for different GLP-1R agonists at the level of receptor conformation, functional selectivity, and location bias, linking specific signaling neighborhoods to clinical adverse event profiles. Biosensor panel (15 pathways, 4 compartments), structure analysis, time-lapse microscopy, phosphoproteomics Nature communications High 37813859
2021 Small-molecule positive allosteric modulators (PAMs) of GLP-1R were identified that bind a cryptic pocket formed by the cytoplasmic half of TM3, TM5, and TM6; molecular dynamics simulations and mutagenesis studies indicated the PAM enlarges the orthosteric pocket to facilitate GLP-1 binding, and signaling assays characterized probe-dependent signaling profiles. Molecular dynamics simulations, mutagenesis, signaling assays ACS chemical biology Medium 34570476
2019 Selective reduction of Glp1r expression within Phox2b-Cre neurons (autonomic/vagal neurons) impaired glucose homeostasis and gastric emptying and attenuated GLP-1R agonist-induced weight loss; widespread neural Glp1r loss in Wnt1-Cre2 mice preserved glucoregulatory actions of GLP-1R agonists, demonstrating that Phox2b+ neurons are the critical neural substrate for physiological GLP-1R-mediated metabolic control. Cell-type-specific conditional Glp1r knockout (Phox2b-Cre, Wnt1-Cre2), glucose tolerance tests, gastric emptying measurements Cell reports High 31189118
2024 In vivo two-photon imaging of hindbrain GLP1R neurons showed that area postrema (AP) GLP1R neurons are broadly responsive to both nutritive and aversive stimuli, while nucleus of the solitary tract (NTS) GLP1R neurons are biased towards nutritive stimuli. Selective chemogenetic/optogenetic manipulation demonstrated that NTS-GLP1R neuron activation triggers satiety without aversion, while AP-GLP1R activation triggers aversion with food intake reduction. Anatomical tracing showed NTS-GLP1R and AP-GLP1R project to different downstream brain regions. In vivo two-photon calcium imaging, chemogenetics, optogenetics, anatomical circuit tracing Nature High 38987598
2022 GLP1R is expressed in carotid body chemosensory cells in rat and human; targeted GLP1R agonist administration to the carotid body lowered basal discharge and attenuated chemoreflex-evoked blood pressure and sympathetic responses; hyperglycemia-induced peripheral chemoreflex sensitization and sympathetic overactivity were abolished by GLP1R activation in the carotid body. RNA-seq, molecular characterization, in situ/in vivo carotid body functional assays with targeted drug delivery Circulation research High 35100822
2022 GLP-1R signaling in gut intraepithelial lymphocytes (IELs) is required for the full effects of GLP-1R agonists on gut microbiota composition and selectively restrains local and systemic T cell-induced (but not LPS-induced) inflammation; the mechanism involves suppression of IEL effector functions via dampening of proximal T cell receptor signaling in a protein kinase A-dependent manner. IEL-specific GLP-1R conditional knockout mice, microbiota analysis, in vivo inflammatory models, PKA inhibitor experiments Cell metabolism High 36027914
2015 GLP-1R signaling controls mucosal expansion of the small bowel and colon via a mechanism requiring Fgf7 (fibroblast growth factor 7) but independent of EGF or IGF1 receptors; exendin-4 increased Fgf7 expression in colonic polyps, and exendin-4 failed to increase intestinal growth in Fgf7-null mice. Glp1r-/- mice, Fgf7-/- mice, exendin-4 treatment, Apc(Min/+) mouse model, gene expression analysis Cell metabolism High 25738454
2023 GLP-1R agonist liraglutide directly activates POMC neurons in vivo via GLP-1R expression in POMC neurons, requiring a downstream mixed cation channel comprising TRPC5 subunits; it also indirectly upregulates excitatory input to POMC neurons from glutamatergic cells (also requiring TRPC5), and inhibits NPY/AgRP neurons indirectly through activation of K-ATP and TRPC5 channels in GABAergic neurons. Neuron-specific transgenic mouse models, patch-clamp electrophysiology, in vivo fiber photometry Molecular metabolism High 34626854
2023 GLP-1R-positive (GLP-1R+) neurons in the lateral septum (LS) mediate anorectic and weight-loss effects of liraglutide; these neurons are activated by liraglutide, their activity rapidly decreases during naturalistic feeding, chemogenetic activation suppresses feeding, and targeted GLP-1R knockdown in the LS (but not hypothalamus) substantially attenuated liraglutide's ability to inhibit feeding and reduce body weight. Chemogenetics (DREADD), GLP-1R knockdown in specific brain regions, fiber photometry, behavioral analysis The Journal of clinical investigation High 39225090
2024 dLS GLP-1R neurons project GABAergic axons to the lateral hypothalamic area (LHA); chemogenetic inhibition of dLSGLP-1R neurons or the dLSGLP-1R→LHA pathway promotes food intake; optogenetic stimulation of dLSGLP-1R→LHA terminals in the LHA rapidly suppresses feeding; GLP-1R agonist exendin-4 enhances dLSGLP-1R→LHA GABA release. Channelrhodopsin-assisted circuit mapping, chemogenetics, optogenetics, electrophysiology in Glp1r-ires-Cre mice Molecular metabolism High 38763494
2023 GABAergic hypothalamic neurons co-expressing Glp1r and Lepr (LepRbGlp1r neurons) are required for leptin-mediated suppression of food intake; ablating Lepr from these neurons caused hyperphagic obesity; restoration of Glp1r expression specifically in LepRb neurons on an otherwise Glp1r-null background was sufficient to permit food intake suppression by the GLP1R agonist liraglutide. Cell-type-specific Cre-lox conditional KO and re-expression, single-nucleus RNA-seq, behavioral metabolic phenotyping The Journal of clinical investigation High 37581939
2020 Exendin-4 activates the GLP1R–PKA–PPARγ-dependent phosphatases PTEN and PTP1B, which inhibit key kinases within both EGFR and STAT6 signaling cascades to restore FOXA2 expression and normalize airway mucus production in COPD and cystic fibrosis airway cells. In vitro airway cell assays, COPD/CF disease cell lines, in vivo mouse lung model, pathway inhibitor experiments Mucosal immunology Medium 32034274
2022 GLP-1 regulates skeletal muscle remodeling and exercise endurance via GLP-1R signaling-mediated phosphorylation of AMPK; AMPK knockdown reversed the effects of GLP-1R activation on glucose uptake, type I fiber formation, and mitochondrial respiration in vitro. AAV-mediated GLP-1 overexpression in muscle, in vitro AMPK knockdown, ex vivo mitochondrial respiration assays Biochimica et biophysica acta. Molecular cell research Medium 35636559
2023 GLP-1R activation inhibits pulmonary fibrosis by disrupting the interaction between NLRP3 inflammasome and PFKFB3-driven glycolysis in lung fibroblasts, subsequently preventing lactate-mediated histone lactylation that drives pro-fibrotic gene expression; GLP-1R activation also inhibited p300-mediated histone lactylation in exogenous lactate-treated fibroblasts. In vitro lung fibroblast assays, RNA-seq, ChIP-qPCR for histone lactylation, cell metabolism assays, mouse silica fibrosis model Journal of translational medicine Medium 39434134
2023 GLP1R loss-of-function variants that reduce cell surface expression are associated with impaired glucose control and increased adiposity; 60 GLP1R variants were functionally profiled across four signaling pathways revealing a diversity of phenotypes including defective cell surface expression, pathway-specific gain and loss of function; defective insulin secretion of LoF variants can be rescued by allosteric GLP1R ligands or high concentrations of exendin-4/semaglutide in INS-1 cells. Functional profiling of 60 variants across 4 signaling pathways, rescue experiments with allosteric ligands in INS-1 cells, genetic association in UK Biobank Nature metabolism High 37709961
2023 GLP-1R agonist liraglutide in gut IELs suppresses feeding via protein kinase A-dependent dampening of proximal T cell receptor signaling, reducing effector functions of intraepithelial lymphocytes; this mechanism is specifically required for restraining T cell-induced but not LPS-induced inflammation. Conditional GLP-1R KO in IELs, PKA inhibitor experiments, T cell functional assays Cell metabolism High 36027914
2021 GLP-1R shows increased cell surface levels, internalization, degradation, and higher endosomal versus plasma membrane cAMP activity compared to GIPR in pancreatic beta cells; GIPR is instead associated with increased plasma membrane recycling, reduced desensitization, and enhanced downstream signal amplification. Direct comparison of surface expression, trafficking (internalization/recycling/degradation), and spatiotemporal cAMP signaling assays in pancreatic beta cells Endocrinology Medium 36774542
2021 The MafA target gene PPP1R1A is expressed in β-cells, and PPP1R1A silencing in INS1 cells impairs GLP-1R-mediated amplification of glucose-stimulated insulin secretion, PKA-target protein phosphorylation, and mitochondrial coupling efficiency, demonstrating PPP1R1A as a downstream effector of GLP-1R-PKA signaling in β-cells. siRNA knockdown in INS1 β-cells, GSIS assays, PKA phosphorylation assays, mitochondrial function assays, human islet RNA correlation Metabolism: clinical and experimental Medium 33631146
2024 GLP-1R activation by semaglutide suppresses VTA dopamine (VTADA) neuron responsiveness during food consumption, opposing hedonic eating; mice recovered palatable food appetite and VTADA activity during repeated semaglutide treatment, which was reversed by consumption-triggered VTADA neuron inhibition, demonstrating that the hedonic eating circuit opposes GLP-1R-mediated appetite reduction. Photometry-calibrated optogenetics, in vivo fiber photometry, behavioral feeding assays Science (New York, N.Y.) High 40146831
2024 BDNFmNTS neurons in the medial nucleus of the tractus solitarius are downstream of GFRAL/GLP1R neurons; these BDNF neurons are required for weight-reducing actions of both GDF15 and the GLP1RA exendin-4, and acute activation of BDNFmNTS neurons is sufficient to reduce food intake and drive fatty acid oxidation. Mouse genetic models, chemogenetics, in vivo metabolic measurements Nature communications Medium 39737892
2024 LepRGlp1r neurons in the dorsomedial hypothalamus mediate the food intake-suppressing and body weight-reducing effects of a GLP-1R/LepR dual agonist; ablating Lepr from Glp1r-expressing neurons abrogated dual agonist efficacy on food intake, while reactivating Glp1r in Lepr neurons on a Glp1r-null background was sufficient to permit the food intake and body weight suppression. Conditional KO and re-expression mouse models (LeprGlp1rKO, Glp1rLeprRe), in vivo pharmacology with dual agonist Science translational medicine High 39630884
2024 Both CNS GIPR and CNS GLP-1R are required for maximal weight loss by a GIPR-Ab/GLP-1 peptide-antibody conjugate; the conjugate is detected in circumventricular organs and activates c-FOS in downstream appetite-regulating brain regions; dulaglutide (GLP-1R agonist alone) achieves greater weight loss in CNS GIPR KO mice. CNS GIPR conditional KO mice, dulaglutide + GIPR-Ab combination experiments, c-FOS immunostaining, drug biodistribution Nature metabolism High 40301582
2014 GLP-1R knockdown in human RPE cells (ARPE-19) increased intracellular ROS generation and activated p53-mediated Bax promoter activity and ER stress signaling; ER stress-mediated p53 expression was regulated upstream by ROS, as antioxidant treatment and Prx1 overexpression attenuated GLP-1R knockdown-induced ER stress and p53 expression. siRNA knockdown, ROS measurement, ER stress signaling assays, Bax promoter reporter, antioxidant rescue experiments The international journal of biochemistry & cell biology Medium 25483438
2022 GLP-1R signaling modulates colonic goblet cell number, epithelial integrity, energy metabolism, and survival; GF GLP-1R KO mice developed enlarged ceca, reduced goblet cells, colonocyte energy deprivation, increased ER stress, mitochondrial fragmentation, elevated oxygen levels, and loss of stemness; restoring energy via Western-style diet or microbiota colonization normalized these phenotypes, demonstrating GLP-1R has a non-incretin role in colonic epithelial maintenance during energy deprivation. GF GLP-1R KO mouse model, histology, gene expression, intestinal organoid stemness assays, dietary and microbiota rescue experiments Molecular metabolism High 38521185
2023 GLP1R overexpression in endometrial carcinoma cells promotes apoptosis and activates the cAMP/PKA signaling pathway, while inhibiting cell proliferation, invasion, and migration; these effects were abrogated by PKA knockdown, placing GLP1R upstream of cAMP/PKA in this signaling axis. GLP1R overexpression vector, PKA siRNA, ELISA for cAMP, Western blot, in vitro cell behavior assays, mouse xenograft Journal of clinical laboratory analysis Medium 35989517
2020 Loureirin B binds to GLP-1R (demonstrated by surface plasmon resonance and spectroscopy) and promotes insulin secretion in Ins-1 cells through GLP-1R; siRNA-mediated GLP-1R knockdown reduced the insulin secretion-promoting effect of Loureirin B. Molecular docking, surface plasmon resonance, spectroscopy, GLP-1R siRNA knockdown, insulin secretion assay Journal of cellular and molecular medicine Medium 33300675
2025 GLP-1R agonists increase CaMKK2-AMPK signaling in neurons, which reduces BACE1-mediated cleavage of APP and Aβ generation; GLP-1R agonists also increase AMPK activity in microglia, inhibiting neuroinflammation and promoting Aβ phagocytosis. AD model mouse in vivo experiments, biochemical pathway analysis (CaMKK2-AMPK-BACE1 axis), microglial functional assays Nature aging Medium 40394225

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 Anti-obesity effects of GIPR antagonists alone and in combination with GLP-1R agonists in preclinical models. Science translational medicine 195 30567927
2020 Differential GLP-1R Binding and Activation by Peptide and Non-peptide Agonists. Molecular cell 164 33027691
2015 GLP-1R agonists promote normal and neoplastic intestinal growth through mechanisms requiring Fgf7. Cell metabolism 119 25738454
2024 Dissociable hindbrain GLP1R circuits for satiety and aversion. Nature 118 38987598
2022 Divergent roles for the gut intraepithelial lymphocyte GLP-1R in control of metabolism, microbiota, and T cell-induced inflammation. Cell metabolism 115 36027914
2022 BI 456906: Discovery and preclinical pharmacology of a novel GCGR/GLP-1R dual agonist with robust anti-obesity efficacy. Molecular metabolism 107 36356832
2023 GIPR/GLP-1R dual agonist therapies for diabetes and weight loss-chemistry, physiology, and clinical applications. Cell metabolism 106 37591245
2019 Distinct Neural Sites of GLP-1R Expression Mediate Physiological versus Pharmacological Control of Incretin Action. Cell reports 93 31189118
2023 Semaglutide ameliorates cognition and glucose metabolism dysfunction in the 3xTg mouse model of Alzheimer's disease via the GLP-1R/SIRT1/GLUT4 pathway. Neuropharmacology 87 37730113
2022 GLP-1 regulates exercise endurance and skeletal muscle remodeling via GLP-1R/AMPK pathway. Biochimica et biophysica acta. Molecular cell research 86 35636559
2022 GLP1R Attenuates Sympathetic Response to High Glucose via Carotid Body Inhibition. Circulation research 85 35100822
2013 DNA methylation of the glucagon-like peptide 1 receptor (GLP1R) in human pancreatic islets. BMC medical genetics 84 23879380
2022 Targeting the GLP-1/GLP-1R axis to treat osteoarthritis: A new opportunity? Journal of orthopaedic translation 76 35280931
2014 Molecular mechanisms underlying physiological and receptor pleiotropic effects mediated by GLP-1R activation. British journal of pharmacology 75 23889512
2021 Time and metabolic state-dependent effects of GLP-1R agonists on NPY/AgRP and POMC neuronal activity in vivo. Molecular metabolism 73 34626854
2017 GLP-1/GLP-1R Signaling in Regulation of Adipocyte Differentiation and Lipogenesis. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 72 28668964
2017 GLP-1R as a Target for the Treatment of Diabetic Retinopathy: Friend or Foe? Diabetes 66 28533296
2022 Dynamics of GLP-1R peptide agonist engagement are correlated with kinetics of G protein activation. Nature communications 64 35013280
2013 Recent advances in understanding GLP-1R (glucagon-like peptide-1 receptor) function. Biochemical Society transactions 61 23356279
2012 GLP-1R and amylin agonism in metabolic disease: complementary mechanisms and future opportunities. British journal of pharmacology 54 21671898
2023 Suppression of food intake by Glp1r/Lepr-coexpressing neurons prevents obesity in mouse models. The Journal of clinical investigation 50 37581939
2021 Structure and dynamics of semaglutide- and taspoglutide-bound GLP-1R-Gs complexes. Cell reports 48 34260945
2014 Hyperglycemia-induced GLP-1R downregulation causes RPE cell apoptosis. The international journal of biochemistry & cell biology 45 25483438
2013 GLP-1R agonist therapy for diabetes: benefits and potential risks. Current opinion in endocrinology, diabetes, and obesity 45 23403741
2024 GLP-1R-positive neurons in the lateral septum mediate the anorectic and weight-lowering effects of liraglutide in mice. The Journal of clinical investigation 44 39225090
2024 Comparative efficacy of THR-β agonists, FGF-21 analogues, GLP-1R agonists, GLP-1-based polyagonists, and Pan-PPAR agonists for MASLD: A systematic review and network meta-analysis. Metabolism: clinical and experimental 43 39357599
2024 The effect of GLP-1R agonists on the medical triad of obesity, diabetes, and cancer. Cancer metastasis reviews 42 38801466
2024 GLP-1R activation attenuates the progression of pulmonary fibrosis via disrupting NLRP3 inflammasome/PFKFB3-driven glycolysis interaction and histone lactylation. Journal of translational medicine 42 39434134
2023 Human GLP1R variants affecting GLP1R cell surface expression are associated with impaired glucose control and increased adiposity. Nature metabolism 41 37709961
2025 Hedonic eating is controlled by dopamine neurons that oppose GLP-1R satiety. Science (New York, N.Y.) 39 40146831
2021 Effect of GLP-1/GLP-1R on the Polarization of Macrophages in the Occurrence and Development of Atherosclerosis. Mediators of inflammation 38 33854404
2021 Reagents and models for detecting endogenous GLP1R and GIPR. EBioMedicine 37 34911028
2018 Glucagon-like peptide-1 receptor (GLP-1R) signaling ameliorates dysfunctional immunity in COPD patients. International journal of chronic obstructive pulmonary disease 37 30349227
2025 The role of glucagon-like peptide-1 receptor (GLP-1R) agonists in enhancing endothelial function: a potential avenue for improving heart failure with preserved ejection fraction (HFpEF). Cardiovascular diabetology 36 39920668
2023 The pleiotropic of GLP-1/GLP-1R axis in central nervous system diseases. The International journal of neuroscience 35 33941038
2023 Enhanced Endosomal Signaling and Desensitization of GLP-1R vs GIPR in Pancreatic Beta Cells. Endocrinology 35 36774542
2023 GLP-1R signaling neighborhoods associate with the susceptibility to adverse drug reactions of incretin mimetics. Nature communications 35 37813859
2013 Minireview: Signal bias, allosterism, and polymorphic variation at the GLP-1R: implications for drug discovery. Molecular endocrinology (Baltimore, Md.) 33 23864649
2021 Design of a highly potent GLP-1R and GCGR dual-agonist for recovering hepatic fibrosis. Acta pharmaceutica Sinica. B 32 35646543
2023 Structural analysis of the dual agonism at GLP-1R and GCGR. Proceedings of the National Academy of Sciences of the United States of America 31 37549266
2022 Anti-Inflammatory Effects of GLP-1R Activation in the Retina. International journal of molecular sciences 31 36293281
2025 Activation of AMPK by GLP-1R agonists mitigates Alzheimer-related phenotypes in transgenic mice. Nature aging 30 40394225
2021 The MafA-target gene PPP1R1A regulates GLP1R-mediated amplification of glucose-stimulated insulin secretion in β-cells. Metabolism: clinical and experimental 30 33631146
2023 GLP-1R Signaling and Functional Molecules in Incretin Therapy. Molecules (Basel, Switzerland) 29 36677809
2023 Divergent acute versus prolonged pharmacological GLP-1R responses in adult β cell-specific β-arrestin 2 knockout mice. Science advances 29 37134170
2023 Topical and systemic GLP-1R agonist administration both rescue retinal ganglion cells in hypertensive glaucoma. Frontiers in cellular neuroscience 29 37362000
2022 Structural basis of peptidomimetic agonism revealed by small- molecule GLP-1R agonists Boc5 and WB4-24. Proceedings of the National Academy of Sciences of the United States of America 29 35561211
2024 The role of G protein-coupled receptor kinases in GLP-1R β-arrestin recruitment and internalisation. Biochemical pharmacology 28 38461904
2023 Combination of an ACLY inhibitor with a GLP-1R agonist exerts additive benefits on nonalcoholic steatohepatitis and hepatic fibrosis in mice. Cell reports. Medicine 28 37729871
2020 Exendin-4 restores airway mucus homeostasis through the GLP1R-PKA-PPARγ-FOXA2-phosphatase signaling. Mucosal immunology 28 32034274
2023 Liraglutide Attenuates Myocardial Ischemia/Reperfusion Injury Through the Inhibition of Necroptosis by Activating GLP-1R/PI3K/Akt Pathway. Cardiovascular toxicology 27 36934206
2022 Differential association between the GLP1R gene variants and brain functional connectivity according to the severity of alcohol use. Scientific reports 27 35906358
2024 Immunomodulation and inflammation: Role of GLP-1R and GIPR expressing cells within the gut. Peptides 26 38555054
2023 GLP-1R agonists demonstrate potential to treat Wolfram syndrome in human preclinical models. Diabetologia 25 36995380
2023 Geniposide stimulates autophagy by activating the GLP-1R/AMPK/mTOR signaling in osteoarthritis chondrocytes. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 24 37769389
2024 Dorsolateral septum GLP-1R neurons regulate feeding via lateral hypothalamic projections. Molecular metabolism 23 38763494
2024 Specific loss of GIPR signaling in GABAergic neurons enhances GLP-1R agonist-induced body weight loss. Molecular metabolism 23 39612941
2021 Friend or foe? ACE2 inhibitors and GLP-1R agonists in COVID-19 treatment. Obesity medicine 23 33426364
2020 GLP-1R agonists for the treatment of obesity: a patent review (2015-present). Expert opinion on therapeutic patents 23 32799587
2024 GLP1R and GIPR expression and signaling in pancreatic alpha cells, beta cells and delta cells. Peptides 22 38360354
2024 Molecular features of the ligand-free GLP-1R, GCGR and GIPR in complex with Gs proteins. Cell discovery 21 38346960
2024 Glp1r-Lepr coexpressing neurons modulate the suppression of food intake and body weight by a GLP-1/leptin dual agonist. Science translational medicine 21 39630884
2025 Structural pharmacology and mechanisms of GLP-1R signaling. Trends in pharmacological sciences 20 40221226
2025 GIPR-Ab/GLP-1 peptide-antibody conjugate requires brain GIPR and GLP-1R for additive weight loss in obese mice. Nature metabolism 20 40301582
2023 Loganin alleviates myocardial ischemia-reperfusion injury through GLP-1R/NLRP3-mediated pyroptosis pathway. Environmental toxicology 20 37497884
2021 Long-term functional alterations following prenatal GLP-1R activation. Neurotoxicology and teratology 20 33864929
2022 Expanded LUXendin Color Palette for GLP1R Detection and Visualization In Vitro and In Vivo. JACS Au 19 35557759
2024 The GLP-1R as a model for understanding and exploiting biased agonism in next-generation medicines. The Journal of endocrinology 18 38451873
2024 Dual activation of GCGR/GLP1R signaling ameliorates intestinal fibrosis via metabolic regulation of histone H3K9 lactylation in epithelial cells. Acta pharmaceutica Sinica. B 18 40041889
2019 A free-energy landscape for the glucagon-like peptide 1 receptor GLP1R. Proteins 18 31294890
2024 Novel Angiogenesis Role of GLP-1(32-36) to Rescue Diabetic Ischemic Lower Limbs via GLP-1R-Dependent Glycolysis in Mice. Arteriosclerosis, thrombosis, and vascular biology 17 38511325
2024 Potential Role of Phytochemicals as Glucagon-like Peptide 1 Receptor (GLP-1R) Agonists in the Treatment of Diabetes Mellitus. Pharmaceuticals (Basel, Switzerland) 17 38931402
2024 Baicalein: A potential GLP-1R agonist improves cognitive disorder of diabetes through mitophagy enhancement. Journal of pharmaceutical analysis 17 39258173
2022 Implications of ligand-receptor binding kinetics on GLP-1R signalling. Biochemical pharmacology 17 35300966
2024 GLP-1R agonist promotes proliferation of neuroendocrine neoplasm cells expressing GLP-1 receptors. Surgery 16 39665969
2023 Schisandrin B, a potential GLP-1R agonist, exerts anti-diabetic effects by stimulating insulin secretion. Molecular and cellular endocrinology 16 37495090
2014 Expression of GLP-1R protein and its clinical role in intrahepatic cholangiocarcinoma tissues. Molecular biology reports 16 24577752
2025 Biased agonism of GLP-1R and GIPR enhances glucose lowering and weight loss, with dual GLP-1R/GIPR biased agonism yielding greater efficacy. Cell reports. Medicine 15 40460831
2024 GLP-1R signaling modulates colonic energy metabolism, goblet cell number and survival in the absence of gut microbiota. Molecular metabolism 15 38521185
2024 Binding sites and design strategies for small molecule GLP-1R agonists. European journal of medicinal chemistry 15 38959726
2024 Baicalein Ameliorates Insulin Resistance of HFD/STZ Mice Through Activating PI3K/AKT Signal Pathway of Liver and Skeletal Muscle in a GLP-1R-Dependent Manner. Antioxidants (Basel, Switzerland) 15 39456499
2022 Association of GLP1R variants rs2268641 and rs6923761 with obesity and other metabolic parameters in a Polish cohort. Frontiers in endocrinology 15 36339410
2015 Insulin dose adjustments with add-on glucagon-like peptide-1 receptor (GLP-1R) agonists in clinical practice. Expert opinion on pharmacotherapy 15 26077113
2025 Semaglutide Reprograms Macrophages via the GLP-1R/PPARG/ACSL1 Pathway to Suppress Papillary Thyroid Carcinoma Growth. The Journal of clinical endocrinology and metabolism 14 39908200
2021 Distinct Identity of GLP-1R, GLP-2R, and GIPR Expressing Cells and Signaling Circuits Within the Gastrointestinal Tract. Frontiers in cell and developmental biology 14 34660576
2020 Loureirin B activates GLP-1R and promotes insulin secretion in Ins-1 cells. Journal of cellular and molecular medicine 14 33300675
2024 GLP1R boosts survival, migration and invasion of endometrial cancer cells and protects against ferroptotic cell death. Journal of obstetrics and gynaecology : the journal of the Institute of Obstetrics and Gynaecology 13 38269495
2022 GLP1R inhibits the progression of endometrial carcinoma through activation of cAMP/PKA pathway. Journal of clinical laboratory analysis 13 35989517
2022 Loureirin B promotes insulin secretion through GLP-1R and AKT/PDX1 pathways. European journal of pharmacology 13 36347320
2021 GRK2 regulates GLP-1R-mediated early phase insulin secretion in vivo. BMC biology 13 33658023
2019 Mutagenesis facilitated crystallization of GLP-1R. IUCrJ 13 31709055
2018 Do glucagon-like peptide-1 receptor (GLP-1R) agonists have potential as adjuncts in the treatment of type 1 diabetes? Expert opinion on pharmacotherapy 13 30234389
2025 Mazdutide, a dual agonist targeting GLP-1R and GCGR, mitigates diabetes-associated cognitive dysfunction: mechanistic insights from multi-omics analysis. EBioMedicine 11 40479843
2021 Allosteric Modulators Enhancing GLP-1 Binding to GLP-1R via a Transmembrane Site. ACS chemical biology 11 34570476
2018 Age-related change of GLP-1R expression in rats can be detected by [18F]AlF-NOTA-MAL-Cys39-exendin-4. Brain research 11 30144405
2018 Exendin-4 improves behaviorial deficits via GLP-1/GLP-1R signaling following partial hepatectomy. Brain research 11 30408479
2014 Genetic variation in the GCG and in the GLP1R genes and antipsychotic-induced weight gain. Pharmacogenomics 11 24624910
2025 A GLP1R gene variant and sex influence the response to semaglutide treatment in patients with severe obesity. Obesity (Silver Spring, Md.) 10 40384505
2025 GLP-1R/GCGR dual agonism dissipates hepatic steatosis to restore insulin sensitivity and rescue pancreatic β-cell function in obese male mice. Nature communications 10 40399267
2024 Brainstem BDNF neurons are downstream of GFRAL/GLP1R signalling. Nature communications 10 39737892

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