Affinage

GLP2R

Glucagon-like peptide 2 receptor · UniProt O95838

Length
553 aa
Mass
63.0 kDa
Annotated
2026-06-10
12 papers in source corpus 9 papers cited in narrative 9 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GLP2R is a receptor for the gut hormone GLP-2 that orchestrates intestinal mucosal growth, epithelial barrier integrity, and host-bacterial defense (PMID:22253424, PMID:41345787). Genetic loss of GLP2R abolishes GLP-2-driven intestinal c-fos induction, bowel conductance changes, and mucosal growth, and disables Paneth cell antimicrobial output, leading to impaired bactericidal activity and increased bacterial translocation after small bowel injury (PMID:22253424); GLP2R signaling is likewise specifically required for adaptive jejunal villus lengthening under chronic cold stress, a function not substituted by GLP-1R or GIPR (PMID:41345787), and for maintaining barrier function and limiting bacteremia during immune-mediated (graft-versus-host) gut injury (PMID:41419097). In intestinal epithelial cells, GLP-2 acting through GLP2R upregulates tight junction proteins (ZO-1, claudin-1, occludin) via the PI3K/Akt/mTOR/p70S6K pathway (PMID:28158914). Beyond the gut epithelium, GLP2R is expressed on gastrointestinal smooth muscle cells (PMID:34660576) and on hepatic stellate cells, where its loss promotes stellate cell activation, fibrosis, and hepatic inflammation, defining a gut hormone–liver axis (PMID:32191643), and it operates within a central neural circuit upstream of MC4R to mobilize gut-stored lipids into lymph (PMID:40362725). In colorectal cancer cells, GLP2R activates Hippo signaling to suppress YAP1-mediated glycolysis, and its transcription is driven by MEOX1 binding to the GLP2R promoter, an input lost when the MEOX1 promoter is silenced by DNA hypermethylation (PMID:41612494).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2012 High

    Established GLP2R as essential not only for GLP-2-driven intestinal growth signaling but specifically for Paneth cell antimicrobial function and host-bacterial defense, linking the receptor to mucosal immunity.

    Evidence Glp2r-/- knockout mice with pharmacological GLP-2R challenge, c-fos and antimicrobial gene expression, bactericidal and bacterial translocation assays across injury models

    PMID:22253424

    Open questions at the time
    • Downstream signaling linking receptor activation to Paneth cell antimicrobial output not defined
    • Cell type directly transducing the c-fos signal not resolved
  2. 2017 Medium

    Placed GLP2R-driven barrier protection on a defined intracellular signaling pathway, connecting receptor activation to tight junction protein expression.

    Evidence GLP-2 treatment of GLP-2R-expressing IPEC-J2 cells with PI3K (LY-294002) and mTOR (rapamycin) inhibitors and Western blots for pathway components and junction proteins

    PMID:28158914

    Open questions at the time
    • Single porcine cell line, not validated in vivo
    • Direct receptor coupling to PI3K not demonstrated
  3. 2020 High

    Extended GLP2R function beyond the gut epithelium by localizing the receptor to hepatic stellate cells and showing its loss drives fibrosis, defining a gut–liver axis.

    Evidence Cell fractionation localization, Glp2r-/- mice on high-fat diet, and ex vivo GLP-2 treatment of isolated hepatic stellate cells with gene expression analysis

    PMID:32191643

    Open questions at the time
    • Signaling pathway in stellate cells not mapped
    • Whether effect is direct or relayed through other hepatic cells unresolved
  4. 2021 Low

    Localized GLP2R expression to gastrointestinal smooth muscle cells, refining the cellular site of receptor action.

    Evidence Cell-type-specific expression profiling and review of reporter/fate-mapping data

    PMID:34660576

    Open questions at the time
    • Review-based synthesis without new direct experiment
    • Functional consequence in smooth muscle not tested here
  5. 2025 Medium

    Demonstrated GLP-2R operates within a central neural circuit upstream of MC4R to control gut lipid mobilization, revealing a brain-mediated arm of GLP-2R physiology.

    Evidence Mesenteric lymph duct cannulation in rats with intracerebroventricular GLP-2R or MC4R antagonist and lymph triglyceride measurement

    PMID:40362725

    Open questions at the time
    • Neuroanatomical site of central GLP-2R not identified
    • Single study, pharmacological rather than genetic
  6. 2025 High

    Used genetic epistasis to attribute adaptive intestinal villus growth specifically to GLP-2R rather than related incretin receptors, isolating its non-redundant role.

    Evidence GLPDRKO and DIRKO knockout mouse lines under chronic cold stress with jejunal morphometry

    PMID:41345787

    Open questions at the time
    • Ligand and cellular trigger initiating cold-stress GLP-2R activation not defined
    • Downstream growth effectors unmapped
  7. 2026 Medium

    Showed endogenous GLP-2R signaling protects against immune-mediated gut injury, while documenting that agonist (teduglutide) failed to reduce GvHD severity, qualifying therapeutic translation.

    Evidence Allogeneic hematopoietic cell transplantation into Glp2r-/- recipients with bacteremia, survival, histology, and 16S microbiome analysis

    PMID:41419097

    Open questions at the time
    • Discrepancy with prior agonism study unexplained
    • Mechanism connecting receptor to barrier protection during immune injury not resolved
  8. 2026 Medium

    Identified a microbial dietary protein that protects the gut through GLP-2R independent of endogenous GLP-2, implying molecular mimicry of receptor activation.

    Evidence McB dietary intervention in mucositis/colitis mouse models with GLP-2R loss-of-function and histology

    PMID:41540065

    Open questions at the time
    • Identity of the mimetic ligand and its direct receptor engagement not established
    • Mechanism of GLP-2-independent activation inferred
  9. 2026 Medium

    Placed GLP2R in a tumor-suppressive transcriptional and signaling axis in colorectal cancer, linking its expression to MEOX1/methylation control and its output to Hippo-mediated glycolytic suppression.

    Evidence Lentiviral overexpression/knockout of GLP2R in CRC lines, ChIP-qPCR and dual-luciferase for MEOX1 binding, MeDIP/MSP for promoter methylation, Hippo inhibition, and orthotopic/metastasis/AOM-DSS mouse models

    PMID:41612494

    Open questions at the time
    • Mechanism coupling GLP2R to Hippo pathway activation not defined
    • Whether ligand-dependent in tumor context unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How GLP-2R couples to its diverse downstream effectors across distinct cell types — epithelial PI3K/Akt/mTOR, hepatic stellate cell activation, central MC4R circuitry, and tumor Hippo signaling — remains unresolved at the level of receptor-proximal signal transduction.
  • No unified receptor-proximal signaling mechanism established
  • Endogenous ligands beyond GLP-2 in non-canonical contexts not identified
  • Structural basis of GLP-2R signaling bias across tissues unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 2 GO:0048018 receptor ligand activity 1
Localization
GO:0005886 plasma membrane 2
Pathway
R-HSA-1266738 Developmental Biology 2 R-HSA-162582 Signal Transduction 2 R-HSA-168256 Immune System 2
Partners
GLP2MC4R

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 GLP-2R is required for intestinal epithelial c-fos induction in response to acute GLP-2 administration, and for changes in small bowel conductance and bowel growth following GLP-2R agonist treatment. Glp2r-/- mice showed reduced Paneth cell antimicrobial gene product expression, impaired mucosal bactericidal activity, and increased bacterial translocation after small bowel injury, establishing GLP-2R as essential for Paneth cell function and small bowel host-bacterial defense. Glp2r-/- knockout mouse model with pharmacological challenge, gene expression analysis, bacterial colonization assays, and mucosal injury models (indomethacin, irinotecan) Endocrinology High 22253424
2020 GLP-2R is expressed on hepatic stellate cells (HSCs), as determined by cell fractionation. Loss of Glp2r signaling in Glp2r-/- mice activates HSCs and increases markers of fibrosis and hepatic inflammation. GLP-2 directly modulates gene expression in isolated HSCs ex vivo, defining a gut hormone–HSC axis. Cell fractionation to localize Glp2r to HSCs; Glp2r-/- mouse model on high-fat diet; ex vivo GLP-2 treatment of isolated HSCs with gene expression analysis JCI insight High 32191643
2017 In GLP-2R-expressing IPEC-J2 intestinal cells, GLP-2 increases tight junction protein expression (ZO-1, claudin-1, occludin) through activation of the PI3K/Akt/mTOR/p70S6K signaling pathway; this effect is blocked by PI3K inhibitor LY-294002 or mTOR inhibitor rapamycin. Western blot for tight junction proteins and pathway components (p-PI3K, p-Akt, p-mTOR, p-p70S6K) in GLP-2-treated IPEC-J2 cells with pharmacological inhibitors Journal of animal physiology and animal nutrition Medium 28158914
2021 Glp2r mRNA/protein expression is localized to smooth muscle cells within the gastrointestinal tract, as established by cell-type-specific expression profiling in preclinical and clinical models. Cell-type-specific expression profiling and review of reporter/fate-mapping data from preclinical and clinical models Frontiers in cell and developmental biology Low 34660576
2025 Central (intracerebroventricular) administration of a GLP-2R antagonist (GLP-2(11-33)) attenuated the stimulatory effect of peripheral GLP-2 on lymph triglyceride output, demonstrating that GLP-2 acts partly through central GLP-2R to mobilize gut-stored lipids. Co-administration of an MC4R antagonist similarly attenuated this effect, placing GLP-2R upstream of MC4R in a neural pathway for gut lipid secretion. Mesenteric lymph duct cannulation in rats with intracerebroventricular infusion of GLP-2R antagonist or MC4R antagonist; measurement of lymph triglyceride output Nutrients Medium 40362725
2025 GLP-2R signaling is required for jejunal villus lengthening in response to chronic cold stress. Glp1r-/-Glp2r-/- double-knockout (GLPDRKO) mice failed to show cold stress-induced increases in jejunal circumference, villus length, and crypt depth, despite elevated plasma active GLP-1, whereas Glp1r-/-Gipr-/- (DIRKO) mice showed normal adaptation, establishing that GLP-2R (not GLP-1R or GIPR) is specifically required for this intestinal adaptive growth response. Genetic epistasis using GLPDRKO and DIRKO knockout mouse models under chronic cold stress; jejunal morphometry (circumference, villus length, crypt depth) Communications biology High 41345787
2026 GLP-2R is required for protection against gastrointestinal inflammation induced by a microbial lysate dietary protein (McB). McB's protective effects on villus architecture, mucosal integrity, and disease severity in mucositis/colitis models depended on functional GLP-2R signaling but were independent of endogenous GLP-2 secretion, suggesting fermentation-driven molecular mimicry of GLP-2R activation. McB dietary intervention in mouse models of mucositis and colitis with GLP-2R loss-of-function; histological assessment of villus architecture and mucosal integrity Nature communications Medium 41540065
2026 In colorectal cancer cells, GLP2R overexpression inhibits YAP1-mediated glycolysis by activating the Hippo signaling pathway; blocking Hippo signaling reversed the anti-tumor effects of GLP2R overexpression. MEOX1 transcription factor promotes GLP2R transcription by binding to its promoter, and DNA hypermethylation of the MEOX1 promoter silences MEOX1 and thereby reduces GLP2R expression. Lentiviral overexpression and knockout of GLP2R in CRC cell lines; ChIP-qPCR and dual-luciferase assays for MEOX1 binding to GLP2R promoter; MeDIP and MSP for MEOX1 promoter methylation; Hippo pathway inhibition experiments; orthotopic, liver metastasis, and AOM/DSS mouse models Cell & bioscience Medium 41612494
2025 Loss of GLP-2R signaling in Glp2r-/- bone marrow transplant recipient mice decreased survival and increased bacteremia in the context of immune-mediated (graft-versus-host disease) gut epithelial injury, implicating endogenous GLP-2R signaling in maintaining intestinal barrier function during immune-mediated injury. GLP-2R agonism with teduglutide did not reduce aGvHD severity, failing to replicate a prior study. Allogeneic hematopoietic cell transplantation into Glp2r-/- recipient mice; measurement of bacteremia, survival, circulating cytokines, gut histology, and gut microbiome (16S rRNA) Molecular metabolism Medium 41419097

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 25 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 14 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 3 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 DNA methylation-mediated silencing of MEOX1 promotes glycolysis and immune evasion in colorectal cancer cells through inhibition of GLP2R transcription. Cell & bioscience 1 41612494
2026 Microbial activation of the GLP-2R mitigates gastrointestinal inflammation. Nature communications 0 41540065
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

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