Affinage

GLP2R

Glucagon-like peptide 2 receptor · UniProt O95838

Length
553 aa
Mass
63.0 kDa
Annotated
2026-04-28
12 papers in source corpus 8 papers cited in narrative 8 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GLP2R is a G protein-coupled receptor that serves as the principal mediator of intestinal mucosal growth, barrier integrity, and host defense in response to the gut hormone GLP-2. GLP-2R signaling drives jejunal villus lengthening under adaptive stress, maintains Paneth cell antimicrobial function and mucosal bactericidal activity, and reinforces epithelial tight junctions (ZO-1, claudin-1, occludin) through the PI3K/Akt/mTOR/p70S6K pathway (PMID:22253424, PMID:41345787, PMID:28158914, PMID:41419097). Beyond the gut, GLP-2R expressed on hepatic stellate cells maintains stellate cell quiescence and restrains hepatic fibrosis, while central nervous system GLP-2R cooperates with MC4R to stimulate gut lipid secretion via a neural gut–brain–gut axis (PMID:32191643, PMID:40362725). In colorectal cancer, GLP2R transcription is driven by MEOX1 binding its promoter and GLP-2R activates Hippo signaling to suppress YAP1-mediated glycolysis, functioning as a tumor suppressor (PMID:41612494).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2012 High

    Establishing that endogenous GLP-2R signaling is not merely a pharmacological target but is required for baseline Paneth cell antimicrobial defense and intestinal mucosal homeostasis resolved a key question about whether GLP-2R has a constitutive physiological role.

    Evidence Glp2r−/− knockout mice with gene expression, bactericidal, and injury-model analyses

    PMID:22253424

    Open questions at the time
    • Identity of the downstream signaling cascade linking GLP-2R to Paneth cell defensin transcription not defined
    • Whether GLP-2R on Paneth cells is cell-autonomous or acts via intermediary cell types not resolved
    • Role in large intestinal defense not examined
  2. 2017 Medium

    Defining the PI3K/Akt/mTOR/p70S6K cascade as the intracellular pathway through which GLP-2R upregulates tight junction proteins established the first complete signaling axis for GLP-2R-mediated barrier reinforcement.

    Evidence Pharmacological inhibition (LY-294002, rapamycin) in GLP-2R-expressing IPEC-J2 cells with western blot for TJ proteins and phospho-kinases

    PMID:28158914

    Open questions at the time
    • Pathway defined in a single porcine cell line; confirmation in primary human intestinal epithelium lacking
    • Coupling mechanism from GPCR activation to PI3K not identified
    • In vivo relevance of this cascade for barrier protection not tested
  3. 2020 High

    Localizing GLP-2R to hepatic stellate cells and demonstrating that its loss activates HSCs and promotes fibrosis markers extended GLP-2R function beyond the intestine, revealing a gut hormone–liver axis.

    Evidence Liver cell fractionation, Glp2r−/− knockout mice, ex vivo HSC gene expression, immunohistochemistry in mouse and human liver

    PMID:32191643

    Open questions at the time
    • Signaling pathway downstream of GLP-2R in HSCs not characterized
    • Whether pharmacological GLP-2R agonism can reverse established fibrosis not tested
    • Relative contribution of hepatic vs. intestinal GLP-2R to liver phenotype not dissected
  4. 2025 Medium

    Demonstrating that peripheral GLP-2 stimulates lymph triglyceride output partly through central brain GLP-2R and downstream MC4R revealed a neural gut–brain–gut circuit for lipid absorption control, broadening the receptor's role beyond mucosal trophism.

    Evidence Intracerebroventricular GLP-2R and MC4R antagonist infusion in mesenteric lymph-cannulated rats

    PMID:40362725

    Open questions at the time
    • Brain cell types expressing functional GLP-2R in this circuit not identified
    • How central MC4R activation feeds back to jejunal lipid handling not mechanistically defined
    • Single-lab pharmacological study; genetic confirmation lacking
  5. 2025 High

    Genetic epistasis using double Glp1r/Glp2r knockout mice under cold stress proved that GLP-2R specifically mediates adaptive jejunal villus lengthening, disambiguating it from GLP-1R contributions.

    Evidence Double KO vs. single KO mice; chronic cold exposure; jejunal morphometry

    PMID:41345787

    Open questions at the time
    • Downstream proliferative or anti-apoptotic signals driving villus elongation not identified
    • Whether crypt stem cell dynamics or differentiated cell survival mediates villus growth unclear
    • Cold-induced GLP-2 secretion kinetics not measured
  6. 2025 Medium

    Showing that Glp2r−/− transplant recipients have increased bacteremia and reduced survival in graft-versus-host disease established GLP-2R as essential for intestinal barrier maintenance under immune-mediated injury, beyond infectious or chemical insults.

    Evidence Allogeneic HCT in Glp2r−/− mice; bacterial cultures, histology, microbiome sequencing

    PMID:41419097

    Open questions at the time
    • Whether barrier failure is epithelial-intrinsic or immune-mediated not separated
    • Therapeutic potential of GLP-2R agonism in GVHD not tested
    • Single-lab study
  7. 2026 Medium

    Identifying MEOX1 as a direct transcriptional activator of GLP2R and showing that GLP-2R suppresses YAP1-mediated glycolysis via Hippo signaling in CRC provided the first transcriptional regulatory mechanism for GLP2R and a tumor-suppressive signaling axis.

    Evidence ChIP-qPCR, dual-luciferase reporter, MeDIP/MSP for promoter methylation; lentiviral overexpression/KO in CRC cell lines; orthotopic and metastasis mouse models; Hippo pathway inhibition

    PMID:41612494

    Open questions at the time
    • Whether MEOX1-GLP2R axis operates in normal intestinal epithelium not shown
    • Direct binding partner linking GLP-2R to LATS1/2 kinase activation unknown
    • Single-lab finding; independent replication absent
  8. 2026 Medium

    Demonstrating that microbial fermentation products activate GLP-2R independently of endogenous GLP-2 secretion to protect against GI inflammation revealed non-canonical receptor activation and expanded the ligand repertoire concept for GLP-2R.

    Evidence Mucositis and colitis mouse models with pharmacological/genetic GLP-2R dependency testing; microbiota manipulation; GLP-2 secretion measurement

    PMID:41540065

    Open questions at the time
    • Molecular identity of the microbial-derived GLP-2R agonist not determined
    • Whether activation is direct ligand binding or indirect receptor transactivation not distinguished
    • Mechanism linking GLP-2R to regulatory T cell induction not elucidated

Open questions

Synthesis pass · forward-looking unresolved questions
  • The identity of microbial-derived molecules that activate GLP-2R, the coupling mechanism from the receptor to Hippo kinase activation, the cell-autonomous versus paracrine nature of GLP-2R signaling in Paneth cells, and the neuronal circuitry connecting central GLP-2R to peripheral lipid handling remain unresolved.
  • No structural model of GLP-2R in complex with non-peptide agonists exists
  • Cell-type-specific conditional knockout studies in intestinal epithelium not reported
  • Integration of PI3K/Akt, Hippo, and other downstream pathways into a unified signaling model lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-1643685 Disease 2
Partners
MC4RMEOX1YAP1

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 Glp2r knockout mice exhibit impaired Paneth cell antimicrobial gene expression and reduced mucosal bactericidal activity, establishing that endogenous GLP-2R signaling is required for Paneth cell function and intestinal host-bacterial defense. GLP-2R is also required for intestinal epithelial c-fos induction and changes in small bowel conductance and growth in response to GLP-2R agonists. Glp2r−/− knockout mouse model; gene expression analysis; mucosal bactericidal activity assays; bacterial colonization measurements; indomethacin/irinotecan enteritis models Endocrinology High 22253424
2020 GLP-2R is expressed on hepatic stellate cells (HSCs), localized there by cell fractionation, and loss of Glp2r signaling activates HSCs and increases hepatic fibrosis markers; GLP-2 directly modulates gene expression in isolated HSCs ex vivo, defining a gut hormone-HSC axis. Cell fractionation of liver; Glp2r−/− knockout mice; ex vivo HSC gene expression assay; immunohistochemistry; mouse and human liver receptor detection JCI insight High 32191643
2017 GLP-2 improves intestinal tight junction protein expression (ZO-1, claudin-1, occludin) in GLP-2R-expressing IPEC-J2 cells through the PI3K/Akt/mTOR/p70S6K signaling pathway, as demonstrated by PI3K inhibitor (LY-294002) and mTOR inhibitor (rapamycin) blockade. GLP-2R+ cell line (IPEC-J2); western blot for TJ proteins and phosphorylated pathway components; pharmacological inhibition with LY-294002 and rapamycin Journal of animal physiology and animal nutrition Medium 28158914
2025 Peripheral GLP-2 stimulates gut lipid secretion partly through central (brain) GLP-2R and downstream MC4R signaling; intracerebroventricular administration of a GLP-2R antagonist (GLP-2(11-33)) or MC4R antagonist (SHU9119) attenuated GLP-2-stimulated lymph triglyceride output, implicating a neural gut-brain-gut axis. Mesenteric lymph duct cannulation in rats; intracerebroventricular cannula infusion of GLP-2R antagonist or MC4R antagonist; triglyceride output measurement; jejunal gene expression analysis Nutrients Medium 40362725
2025 GLP-2R signaling is required for jejunal villus length expansion under cold-stress conditions; Glp1r−/−Glp2r−/− double knockout mice fail to expand jejunal villi during chronic cold exposure despite elevated GLP-1 levels, demonstrating that GLP-2R specifically mediates this intestinal adaptation. Glp1r−/−Glp2r−/− (GLPDRKO) double knockout mice; cold exposure model (6°C, 5 weeks); morphometric analysis of jejunal circumference, villi length, crypt depth; plasma active GLP-1 measurement Communications biology High 41345787
2025 Loss of GLP-2R signaling in transplant recipient mice increases bacteremia and reduces survival in experimental graft-versus-host disease, demonstrating an essential endogenous role for GLP-2R in maintaining intestinal barrier function under immune-mediated gut injury. Allogeneic hematopoietic cell transplantation in Glp2r−/− mice; flow cytometry; cytokine measurement; histological scoring; 16S rRNA microbiome sequencing; blood bacterial cultures Molecular metabolism Medium 41419097
2026 GLP-2R overexpression in colorectal cancer cells inhibits YAP1-mediated glycolysis by activating Hippo signaling; blocking Hippo signaling reverses the anti-tumor effects of GLP-2R overexpression. Additionally, the transcription factor MEOX1 directly binds the GLP2R promoter to promote its transcription, and MEOX1 promoter DNA hypermethylation reduces GLP2R expression in CRC. Lentiviral overexpression/knockout in CRC cell lines; orthotopic, liver metastasis, and AOM/DSS animal models; ChIP-qPCR; dual-luciferase reporter assay; MeDIP; MSP; Hippo pathway inhibition Cell & bioscience Medium 41612494
2026 Microbial fermentation products activate GLP-2R to protect against gastrointestinal inflammation; mechanistic effects of a microbial lysate (McB) on mucosal integrity and regulatory T cell induction depend on functional GLP-2R signaling but are independent of endogenous GLP-2 secretion, indicating fermentation-driven molecular mimicry of GLP-2R activation. Mucositis and colitis mouse models; GLP-2R signaling dependency assessed by pharmacological/genetic approaches; gut microbiota manipulation; GLP-2 secretion measurement; immune cell profiling Nature communications Medium 41540065

Source papers

Stage 0 corpus · 12 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Disruption of the murine Glp2r impairs Paneth cell function and increases susceptibility to small bowel enteritis. Endocrinology 63 22253424
2020 Loss of Glp2r signaling activates hepatic stellate cells and exacerbates diet-induced steatohepatitis in mice. JCI insight 24 32191643
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 12 34660576
2017 Effect of porcine glucagon-like peptides-2 on tight junction in GLP-2R + IPEC-J2 cell through the PI3 k/Akt/mTOR/p70S6K signalling pathway. Journal of animal physiology and animal nutrition 6 28158914
2017 Increased GLP2R expression in gastric chief cells of patients with severe obesity regardless of diabetes status. International journal of obesity (2005) 5 28337026
2025 Glucagon-like Peptide-2 Acts Partially Through Central GLP-2R and MC4R in Mobilizing Stored Lipids from the Intestine. Nutrients 2 40362725
2022 GLP2-GLP2R signal affects the viability and EGFR-TKIs sensitivity of PC9 and HCC827 cells. BMC pulmonary medicine 2 35027025
2020 Methylation Status of GLP2R, LEP and IRS2 in Small for Gestational Age Children with and without Catch-up Growth. Journal of clinical research in pediatric endocrinology 2 32936762
2026 Microbial activation of the GLP-2R mitigates gastrointestinal inflammation. Nature communications 0 41540065
2026 DNA methylation-mediated silencing of MEOX1 promotes glycolysis and immune evasion in colorectal cancer cells through inhibition of GLP2R transcription. Cell & bioscience 0 41612494
2025 Intestinal adaptation to cold-induced metabolic demand and feeding requires GLP-1R and GLP-2R signalling. Communications biology 0 41345787
2025 Loss of GLP-2R signaling in Glp2r-/- mice increases the long-term severity of graft versus host disease. Molecular metabolism 0 41419097