Affinage

FFAR2

Free fatty acid receptor 2 · UniProt O15552

Length
330 aa
Mass
37.1 kDa
Annotated
2026-04-28
100 papers in source corpus 34 papers cited in narrative 35 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FFAR2 (GPR43) is a G-protein-coupled receptor for short-chain fatty acids and the ketone body acetoacetate that transduces microbiota-derived metabolic signals into immune, metabolic, and epithelial barrier responses across diverse tissues (PMID:12496283, PMID:31685604). It couples to Gαq/11 to mobilize intracellular Ca²⁺ and activate PLC/IP3, ERK/p38 MAPK, mTOR/STAT3, and NLRP3 inflammasome pathways, and to Gαi/o to inhibit cAMP and drive chemotaxis through PI3Kγ/Rac2, while also engaging β-arrestin-2 to suppress NF-κB signaling (PMID:26075576, PMID:21698257, PMID:25828455, PMID:34026223). These divergent signaling cascades underpin FFAR2's roles in neutrophil chemotaxis and priming, ILC3 proliferation and IL-22 production, GLP-1 and PYY secretion from enteroendocrine cells, glucose-stimulated insulin secretion in β-cells, suppression of adipocyte insulin signaling, antimicrobial peptide induction via mTOR/STAT3, dendritic cell–driven IgA responses, and antiviral IFN-β production in pulmonary epithelium (PMID:31628054, PMID:22190648, PMID:26023106, PMID:23652017, PMID:29411774, PMID:27966553, PMID:31332169). FFAR2 also forms functional heteromers with FFAR3 that alter signaling output in monocytes and macrophages (PMID:28883043).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2002 High

    Resolving the orphan status of GPR43, SCFA ligand screening established that acetate, propionate, and butyrate activate this GPCR, with Ca²⁺ mobilization and GTPγS binding confirming functional coupling — founding the field of SCFA receptor biology.

    Evidence Ligand bank screening in yeast, Ca²⁺ mobilization and [³⁵S]GTPγS binding in mammalian cells, GIRK channel coexpression in Xenopus oocytes

    PMID:12496283

    Open questions at the time
    • Downstream G-protein identity not resolved
    • No in vivo functional data
    • Endogenous cellular context unknown
  2. 2003 High

    Independent replication in primary human granulocytes confirmed FFAR2 as a functional SCFA receptor on immune cells, establishing that leukocytes are a primary site of FFAR2 action.

    Evidence Ca²⁺ mobilization in recombinant cells and primary human granulocytes, RT-PCR expression profiling

    PMID:12684041

    Open questions at the time
    • Specific immune cell functions mediated by FFAR2 not yet defined
    • G-protein coupling pathway not delineated
  3. 2006 Medium

    Cellular localization studies placed FFAR2 protein in intestinal PYY-positive enteroendocrine cells and mucosal mast cells, while signaling studies in MCF-7 cells identified selective p38 MAPK and HSP27 phosphorylation downstream of FFAR2, beginning to define tissue-specific signaling.

    Evidence Immunohistochemistry with co-localization markers in rat intestine; siRNA knockdown with p38/HSP27 phosphorylation in MCF-7 cells

    PMID:16453106 PMID:16887331

    Open questions at the time
    • Functional consequence of enteroendocrine localization not tested
    • p38 pathway relevance in immune cells not established
  4. 2009 High

    The first loss-of-function in vivo study demonstrated that FFAR2 is required for resolution of inflammatory responses, as KO mice showed exacerbated colitis, arthritis, and asthma — establishing FFAR2 as a bona fide mediator of microbiota-immune communication.

    Evidence GPR43 knockout mice in colitis, arthritis, and asthma models; germ-free mice phenocopying KO

    PMID:19865172

    Open questions at the time
    • Cell-type-specific contributions not dissected
    • Downstream signaling pathways in vivo not identified
  5. 2011 High

    Mechanistic dissection resolved that FFAR2 functions as a Gi-coupled chemotactic receptor in neutrophils through PI3Kγ/Rac2/p38/ERK, while simultaneously showing that it drives GLP-1 secretion from L cells via Gq/Ca²⁺ — demonstrating cell-type-dependent G-protein coupling.

    Evidence KO neutrophil chemotaxis with pathway inhibitors; KO mouse GLP-1 secretion with Ca²⁺ imaging in primary L cells

    PMID:21698257 PMID:22190648

    Open questions at the time
    • How cell-type context determines Gi vs Gq preference unknown
    • β-arrestin signaling arm not yet explored
  6. 2013 High

    Complementary gain- and loss-of-function mouse models established that FFAR2 suppresses adipocyte insulin signaling to regulate fat accumulation and promotes intestinal epithelial ERK/p38 cytokine responses for pathogen clearance, extending FFAR2's role beyond immune cells to metabolic and barrier tissues.

    Evidence Adipose-specific transgenic and global KO mice with metabolic phenotyping; KO mice in colitis/infection models with ERK/p38 signaling assays

    PMID:23652017 PMID:23665276

    Open questions at the time
    • Direct adipocyte signaling intermediates downstream of insulin inhibition not fully mapped
    • Whether epithelial and immune FFAR2 functions are synergistic or independent unclear
  7. 2015 High

    Three studies resolved key signaling branches: FFAR2 activates NLRP3 inflammasome via K⁺ efflux in colonic epithelium for barrier protection, potentiates GSIS through Gαq/PLC/IP3/Ca²⁺ in β-cells, and displays species-specific divergent Gαq vs Gαi/o coupling — revealing that the same receptor can drive opposing metabolic outputs depending on G-protein engagement.

    Evidence KO mice with electrophysiology for K⁺ efflux/NLRP3; isolated islets with IP3/Ca²⁺ measurements and hyperglycemic clamps; selective agonist pharmacology on mouse vs human islets

    PMID:25828455 PMID:26023106 PMID:26075576

    Open questions at the time
    • Structural basis for differential G-protein coupling not known
    • Species differences between mouse and human FFAR2 complicate translation
  8. 2015 High

    Identification of XBP1 as a transcriptional regulator binding the FFAR2 promoter in monocytes, induced by TNFα, established how FFAR2 expression is upregulated during inflammation.

    Evidence ChIP, luciferase reporters with mutagenesis, siRNA knockdown and overexpression of XBP1 in human monocytes

    PMID:25633224

    Open questions at the time
    • Other transcription factors regulating FFAR2 not identified
    • Whether XBP1 regulation applies in non-monocyte cell types unknown
  9. 2016 High

    FFAR2 was shown to promote enteroendocrine cell expansion for PYY production and to induce dendritic cell Aldh1a2 expression for retinoic acid–driven IgA class switching, revealing receptor functions in gut hormone homeostasis and adaptive mucosal immunity.

    Evidence KO mice with inulin diet and enteroendocrine cell quantification; KO mice with DC co-culture IgA switching assays and Aldh1a2 expression

    PMID:27966553 PMID:28123937

    Open questions at the time
    • Signaling pathway linking FFAR2 to Aldh1a2 induction not defined
    • Whether FFAR2 directly drives enteroendocrine progenitor differentiation or only proliferation unclear
  10. 2017 High

    Discovery that FFAR2 and FFAR3 form functional heteromers with altered signaling properties (enhanced Ca²⁺, gain of β-arrestin-2 recruitment, loss of cAMP inhibition) introduced receptor heteromerization as a mechanism for SCFA signaling diversification in monocytes/macrophages; simultaneously, a β-arrestin-2–mediated anti-inflammatory pathway (suppressing NF-κB via IκBα stabilization) was delineated.

    Evidence PLA in primary monocytes, BiFC/FRET in HEK293, Ca²⁺/cAMP/p38 assays for heteromer; Co-IP of GPR43–β-arrestin-2 and β-arrestin-2–IκBα with KO validation for NF-κB suppression

    PMID:28883043 PMID:34026223

    Open questions at the time
    • Physiological relevance of heteromer vs homomer ratio in vivo not determined
    • β-arrestin-2/NF-κB finding from single lab awaits independent replication
  11. 2018 High

    FFAR2 was linked to antimicrobial peptide (RegIIIγ, β-defensin) induction in intestinal epithelium through mTOR/STAT3, and to GVHD protection through ERK/NLRP3 in non-hematopoietic tissues, broadening the receptor's epithelial defense repertoire.

    Evidence KO enteroids with mTOR/STAT3 knockdown for AMP expression; KO mice in multiple GVHD models with ERK/NLRP3 assays

    PMID:29411774 PMID:30201970

    Open questions at the time
    • How mTOR/STAT3 and NLRP3 pathways are differentially engaged in different epithelial contexts not resolved
  12. 2019 High

    A burst of discoveries expanded FFAR2 biology in four directions: identification of acetoacetate as an endogenous ketogenic agonist; definition of the Ca²⁺/CaMKKβ/AMPK pathway suppressing hepatic gluconeogenesis; demonstration that FFAR2 on ILC3s drives IL-22 via AKT/STAT3 for gut barrier defense; and the antiviral IFN-β response in lung epithelium against RSV.

    Evidence Heterologous ligand screening plus KO mice under ketogenic conditions; HepG2 siRNA with Ca²⁺/AMPK cascade; ILC3 conditional analysis with AKT/STAT3/IL-22; KO mice in RSV model with IFN-β measurement

    PMID:31332169 PMID:31356781 PMID:31628054 PMID:31685604

    Open questions at the time
    • Relative contribution of acetoacetate vs SCFAs under mixed metabolic states unknown
    • Whether ILC3 and neutrophil FFAR2 pathways are coordinated in vivo not fully resolved
  13. 2019 High

    FFAR2 was found to facilitate influenza virus internalization via β-arrestin-1/AP2B1/clathrin-mediated endocytosis, with GRK2/5/6 involvement — an unexpected pro-viral function distinct from its antiviral IFN-β activity in epithelial cells.

    Evidence siRNA knockdown of FFAR2 in A549/RAW264.7 cells, Co-IP of FFAR2–β-arrestin-1 and β-arrestin-1–AP2B1, virus internalization quantification

    PMID:31694949

    Open questions at the time
    • How pro-viral endocytosis and antiviral IFN-β functions coexist in the same cell type not reconciled
    • In vivo relevance of FFAR2 in IAV pathogenesis not tested with KO mice
  14. 2020 High

    FFAR2 was shown to coordinate innate immunity against C. difficile by accelerating neutrophil inflammasome/IL-1β release and upregulating ILC3 IL-1R/IL-22 — establishing a two-cell-type cooperative circuit mediated by a single receptor.

    Evidence FFAR2 KO mice in acute CDI model with neutrophil and ILC3 functional assays

    PMID:31876919

    Open questions at the time
    • Whether this cooperative circuit operates in other enteric infections not tested
  15. 2021 Medium

    FFAR2 on MDSCs was shown to suppress anti-tumor T cell responses through Gαq/Ca²⁺/PPARγ/Arg1 axis, and FFAR2 inhibition enhanced checkpoint blockade — defining a tumor-promoting immunosuppressive function of FFAR2 distinct from its anti-inflammatory roles.

    Evidence Myeloid-specific Ffar2 KO mice in lung carcinogenesis, RNA-seq, L-Arg replenishment, PPARγ inhibition

    PMID:38402237

    Open questions at the time
    • Generalizability across tumor types not established
    • Whether FFAR2 MDSC function is ligand-specific not resolved
    • Single lab study
  16. 2023 Medium

    FFAR2 was linked to ferroptosis induction via dual suppression of SLC7A11 (through AKT/NRF2) and GPX4 (through mTORC1) in a cAMP-PKA-dependent manner, expanding the receptor's role to regulated cell death.

    Evidence FFAR2 knockdown/overexpression with ferroptosis assays, AKT/NRF2 and mTORC1 pathway analysis, xenograft models

    PMID:37185889

    Open questions at the time
    • Physiological relevance of FFAR2-driven ferroptosis in normal tissue not established
    • cAMP-PKA dependence seems at odds with Gi-mediated cAMP inhibition — reconciliation needed
    • Single lab study

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major unresolved questions include the structural basis for FFAR2's differential G-protein coupling across cell types, the physiological balance between pro-viral and antiviral FFAR2 functions, the in vivo stoichiometry and significance of FFAR2-FFAR3 heteromers, and whether FFAR2's tumor-promoting immunosuppressive activity can be therapeutically targeted without compromising its protective immune and metabolic roles.
  • No cryo-EM or crystal structure of FFAR2 in active state with different G proteins
  • Lack of conditional tissue-specific KO studies distinguishing cell-autonomous vs non-cell-autonomous effects in most contexts
  • Species differences between mouse and human FFAR2 pharmacology limit translational confidence

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 4 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 8 R-HSA-168256 Immune System 6 R-HSA-1430728 Metabolism 3 R-HSA-5357801 Programmed Cell Death 1
Partners
AP2B1ARRB1ARRB2FFAR3GRK2XBP1
Complex memberships
FFAR2-FFAR3 heteromer

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 GPR43 (FFAR2) was deorphanized as a G-protein-coupled receptor activated by short-chain fatty acids (SCFAs), with acetate as the primary agonist and propionate, butyrate, formate, and pentanoate also active; receptor activation was confirmed by Ca2+ mobilization, [35S]GTPγS binding assays, and GIRK channel coexpression in Xenopus oocytes; highest expression was found in immune cells. Ligand bank screening in yeast, transient transfection in mammalian cells (Ca2+ mobilization, [35S]GTPγS binding), Xenopus oocyte GIRK coexpression assay The Journal of biological chemistry High 12496283
2003 FFAR2 (GPR43) was independently confirmed as a SCFA receptor expressed on peripheral blood leukocytes; acetate and propionate were the most potent agonists; receptor activation mobilized intracellular calcium in recombinant systems and in human granulocytes. Receptor cloning, calcium mobilization assay in recombinant cells and primary human granulocytes, RT-PCR expression analysis Biochemical and biophysical research communications High 12684041
2009 SCFA-GPR43 signaling is necessary for normal resolution of inflammatory responses; GPR43-deficient mice showed exacerbated or unresolved inflammation in colitis, arthritis, and asthma models, with increased inflammatory mediator production by immune cells and increased immune cell recruitment; germ-free mice lacking SCFAs phenocopied GPR43 deficiency. GPR43 knockout mouse models (colitis, arthritis, asthma), cytokine measurement, immune cell recruitment assays, germ-free mouse experiments Nature High 19865172
2011 FFAR2 mediates SCFA-triggered GLP-1 secretion from intestinal L cells; SCFAs raised cytosolic Ca2+ in L cells consistent with Gq signaling; mice lacking ffar2 showed reduced SCFA-triggered GLP-1 secretion in vitro and in vivo and impaired glucose tolerance. Primary colonic culture GLP-1 secretion assay, Ca2+ imaging in primary L cells, Ffar2 knockout mice (in vitro and in vivo GLP-1 measurement, glucose tolerance test), quantitative PCR for receptor expression in FACS-sorted L cells Diabetes High 22190648
2011 GPR43-mediated SCFA signaling in neutrophils drives chemotaxis; GPR43 acts as a bona fide chemotactic receptor through Gi proteins, activating PKB, p38, and ERK; PI3Kγ, Rac2, p38, and ERK (but not mTOR) are required for GPR43-dependent chemotaxis; chemotaxis was abolished in GPR43-knockout neutrophils. Bone marrow-derived neutrophil chemotaxis assays (polycarbonate filter, EZ-Taxiscan), GPR43 knockout mice, synthetic agonist phenylacetamide-1, pertussis toxin treatment, pharmacological and genetic inhibition of signaling intermediates, Rac1/2 activation assay PloS one High 21698257
2013 GPR43 suppresses insulin signaling in adipocytes to inhibit fat accumulation; GPR43-deficient mice are obese on normal diet while adipose-specific GPR43 overexpression keeps mice lean even on high-fat diet; SCFAs activate GPR43 to promote metabolism of lipids and glucose in other tissues; effects were absent under germ-free conditions. GPR43 knockout mice, adipose-specific GPR43 transgenic mice, germ-free and antibiotic-treated mice, insulin signaling assays in adipocytes, body composition analysis, metabolic phenotyping Nature communications High 23652017
2013 GPR43 on intestinal epithelial cells activates ERK1/2 and p38 MAPK signaling pathways in response to SCFAs, leading to production of chemokines and cytokines that recruit leukocytes and activate effector T cells; GPR43-deficient mice had reduced inflammatory responses and slower pathogen clearance. GPR43 knockout mice (ethanol, TNBS, C. rodentium models), primary colon epithelial cell isolation, immunohistochemistry, ELISA, flow cytometry, ERK/p38 signaling assays Gastroenterology High 23665276
2015 SCFAs binding to GPR43 on colonic epithelial cells stimulates K+ efflux and membrane hyperpolarization, leading to NLRP3 inflammasome activation, which promotes gut epithelial integrity and protects against colitis. GPR43 knockout mice, dietary fiber/acetate intervention, electrophysiology (K+ efflux, hyperpolarization measurements), NLRP3 inflammasome activation assays, colitis models Nature communications High 25828455
2015 GPR43 in pancreatic β-cells potentiates glucose-stimulated insulin secretion (GSIS) via Gαq- and phospholipase C-dependent increases in IP3 and Ca2+; also promotes β-cell proliferation and differentiation gene expression; HFD-fed GPR43 KO mice develop glucose intolerance due to defective insulin secretion. GPR43 KO mice (HFD model), isolated murine and human islets ex vivo, Min6 cells, selective GPR43 agonist PA treatment, IP3 and Ca2+ measurements, β-cell mass quantification, gene expression analysis Diabetes High 26023106
2015 FFAR2 signals through divergent G protein pathways: Gαq/11 pathway potentiates GSIS while Gαi/o pathway inhibits GSIS in mouse islets; acetate potentiates GSIS in an FFAR2-dependent manner; mouse and human FFAR2 display different signaling properties in response to selective agonists. Ffar2 knockout mice, isolated mouse and human islets ex vivo, FFAR2-specific agonists, hyperglycemic clamp studies, Gαq/11 and Gαi/o pathway pharmacology Molecular endocrinology (Baltimore, Md.) High 26075576
2015 GPR43 transcription in human monocytes is regulated by XBP1, which binds directly to the GPR43 promoter as a core cis element; TNFα induces GPR43 expression via XBP1 activation. 5'-RACE mapping of TSS, luciferase reporter assays with stepwise deletions, site-directed mutagenesis, ChIP assay confirming XBP1 binding to endogenous GPR43 promoter, siRNA knockdown of XBP1, XBP1 overexpression Scientific reports High 25633224
2016 FFAR2 (Ffar2) promotes expansion of PYY-producing colonic enteroendocrine cells in response to fermentable carbohydrate (inulin), reducing food intake and preventing diet-induced obesity; this effect requires FFAR2 and involves increased PYY cell density and GLP-1 release. Ffar2 knockout mice, inulin-supplemented diet, enteroendocrine cell density measurements, intestinal organoids and colonic cultures, gut hormone measurements Molecular metabolism High 28123937
2016 GPR43 activation by SCFA acetate promotes intestinal IgA responses; mechanistically, acetate-GPR43 signaling induces dendritic cell expression of Aldh1a2, which converts Vitamin A to retinoic acid (RA), and RA then drives B-cell IgA class switching and IgA production. GPR43 knockout mice, B cell IgA class switching assays in vitro with WT vs GPR43-/- dendritic cells, Aldh1a2 expression analysis, RA signaling blockade experiments Mucosal immunology High 27966553
2017 FFAR2 and FFAR3 interact to form a receptor heteromer in primary human monocytes and macrophages; the FFAR2-FFAR3 heteromer displays enhanced Ca2+ signaling (~1.5-fold vs homomeric FFAR2) and β-arrestin-2 recruitment (~30-fold vs homomeric FFAR3), lacks cAMP inhibition but gains p38 phosphorylation activity via Gαq and Gαi pathways. Proximity ligation assay in primary human monocytes/macrophages, bimolecular fluorescence complementation and FRET in HEK293 cells, Ca2+ signaling, β-arrestin-2 recruitment, cAMP, p38 phosphorylation assays, selective antagonists (CATPB, YM254890, pertussis toxin) FASEB journal High 28883043
2018 GPR43 mediates SCFA-induced RegIIIγ and β-defensin expression in intestinal epithelial cells via activation of mTOR and STAT3 signaling pathways. GPR43 knockout mice, intestinal epithelial enteroids from WT and GPR43-/- mice, SCFA treatment, mTOR and STAT3 knockdown, AMP expression quantification Mucosal immunology High 29411774
2018 GPR43 activation results in induction of pro-inflammatory TNF-α in anti-inflammatory M2-type adipose tissue macrophages but not M1-type macrophages, suggesting distinct macrophage-type-dependent GPR43 functions in adipose tissue homeostasis. Gpr43-deficient mice, adipose-specific GPR43 transgenic mice, adipose tissue macrophage isolation, cytokine expression assays, M1/M2 macrophage differentiation PloS one Medium 28692672
2018 GPR43-dependent ERK phosphorylation and NLRP3 inflammasome activation in non-hematopoietic host tissues mediates SCFA protection against GVHD; specifically propionate and butyrate signal through GPR43 for these protective effects. Multiple murine GVHD models, GPR43 knockout mice, co-housing/antibiotic treatment/exogenous SCFA administration, ERK phosphorylation assays, NLRP3 inflammasome assays Nature communications High 30201970
2019 FFAR2 promotes IAV internalization into host cells via a signaling cascade involving β-arrestin1 interaction with the β2-subunit of the AP-2 adaptor complex (AP2B1), facilitating clathrin-mediated endocytosis; FFAR2 also interacts with GRK2, GRK5, and GRK6 which are required for efficient IAV replication. siRNA knockdown of FFAR2 in A549 and RAW264.7 cells, co-immunoprecipitation (FFAR2–β-arrestin1, β-arrestin1–AP2B1), nuclear NP accumulation assay, virus internalization quantification, Barbadin inhibitor treatment, siRNA knockdown of AP2B1 and GRKs Journal of virology High 31694949
2019 Ffar2 on colonic ILC3s promotes their in situ proliferation and IL-22 production via AKT and STAT3 signaling; Ffar2 agonism differentially activates AKT or ERK; Ffar2 deficiency in ILC3s decreases IL-22+ CCR6+ ILC3s and impairs gut barrier function. ILC3-specific Ffar2 conditional analysis, Ffar2 agonism in colonic cultures, AKT/ERK/STAT3 pathway analysis, ILC3 proliferation measurement, IL-22 production assays, colonic injury and bacterial infection models Immunity High 31628054
2019 Acetoacetate is identified as an endogenous agonist for GPR43 under ketogenic conditions; under fasting or ketogenic diet, plasma acetoacetate increases while SCFAs decrease; Gpr43-deficient mice show reduced weight loss and suppressed lipoprotein lipase activity during fasting. Ligand screening in heterologous expression system, Gpr43-deficient mice under fasting/ketogenic diet, plasma acetoacetate and SCFA measurement, lipoprotein lipase activity assay, gut microbiota composition analysis Proceedings of the National Academy of Sciences of the United States of America High 31685604
2019 Propionate suppresses hepatic gluconeogenesis via GPR43 activation: GPR43 binding triggers intracellular Ca2+ increase → CaMKKβ activation → AMPK phosphorylation → downregulation of G6Pase and PEPCK; siRNA knockdown of GPR43 abolishes propionate-induced AMPK activation and anti-gluconeogenic effects. HepG2 hepatocytes, siRNA knockdown of GPR43, intracellular Ca2+ measurement, CaMKKβ inhibitor, AMPK phosphorylation assay, G6Pase/PEPCK expression analysis, glucose production assay Archives of biochemistry and biophysics High 31356781
2019 GPR43 activation by acetate in pulmonary epithelial cells mediates antiviral interferon-β (IFN-β) response against RSV; IFNAR signaling is essential for acetate antiviral activity; effects were abolished in Gpr43-/- mice. Gpr43 knockout mice (RSV infection model), pulmonary epithelial cell lines with GPR43 activation/knockdown, IFN-β measurement, IFNAR blocking, viral load quantification, ISG expression analysis Nature communications High 31332169
2020 Acetate-FFAR2 signaling coordinates neutrophil and ILC3 responses against C. difficile: in neutrophils, acetate-FFAR2 accelerates recruitment, facilitates inflammasome activation, and promotes IL-1β release; in ILC3s, acetate-FFAR2 augments IL-1R expression, boosting IL-22 secretion in response to IL-1β. FFAR2 knockout mice (acute CDI model), acetate administration, neutrophil recruitment/inflammasome/IL-1β assays, ILC3 IL-1R expression and IL-22 secretion measurement The Journal of experimental medicine High 31876919
2020 Acetic acid activates GPR43 in L6 skeletal muscle myotubes, inducing intracellular Ca2+ influx that activates calcineurin, leading to nuclear localization of MEF2A, PGC-1α, and NFATc1, thereby promoting slow-twitch fiber proliferation-related gene expression; GPR43 siRNA abolishes these effects. L6 myotube cells, GPR43 siRNA knockdown, Ca2+ imaging, calcineurin activity assay, nuclear localization assays for MEF2A/PGC-1α/NFATc1, RT-PCR PloS one Medium 32997697
2006 GPR43 is expressed in enteroendocrine cells (PYY-positive, not 5-HT-positive) and mucosal mast cells in rat intestine, with protein localized to these specific cell types; no GPR43 was detected in smooth muscle or submucosa. RT-PCR, Western blotting, immunohistochemistry with antibody raised against rat GPR43 peptide fragment, co-localization with PYY and 5-HT markers Cell and tissue research Medium 16453106
2006 SCFAs activate GPR43 in MCF-7 breast cancer cells to selectively phosphorylate p38 MAPK and its downstream substrate HSP27 (at Ser-78 and Ser-82 but not Ser-15); propionate-induced Ca2+ elevation and p38 phosphorylation were inhibited by GPR43-specific siRNA. RT-PCR expression, intracellular Ca2+ measurement, cAMP assay, phospho-p38 and phospho-HSP27 Western blot, GPR43-specific siRNA knockdown Cellular signalling Medium 16887331
2016 FFAR2 in adipocytes signals via the Gi/o–Gβγ–phospholipase C–PKC–MAPK kinase pathway to stimulate adipogenesis and mitochondrial biogenesis in brown adipocytes; acetate activates ERK and CREB via this pathway, with effects mimicked by a synthetic GPR43 agonist and impaired by GPR43 knockdown. Brown adipocyte cell culture, Gi/o inhibitor (PTX), Gβγ inhibitor, PLC inhibitor, MEK inhibitor, GPR43 knockdown, ERK/CREB phosphorylation assays, mitochondrial biogenesis markers, adipogenic gene expression Endocrinology Medium 26990063
2017 Sodium butyrate protects against LPS-induced liver injury via a GPR43/β-arrestin-2/NF-κB pathway; butyrate treatment increases interaction between GPR43 and β-arrestin-2, and between β-arrestin-2 and IκBα, thereby suppressing NF-κB activation; protective effects were weakened in GPR43-KO mice and GPR43 siRNA-treated cells. GPR43 KO mice (LPS model), GPR43 siRNA in RAW264.7 cells, co-immunoprecipitation (GPR43–β-arrestin-2, β-arrestin-2–IκBα), NF-κB/TLR4 pathway Western blot, cytokine measurement Gastroenterology report Medium 34026223
2021 FFAR2 signaling in MDSC suppresses T cell function through Gαq/calcium/PPAR-γ/Arg1 axis; FFAR2 deficiency in MDSCs reduces Arg1 expression, relieving L-Arginine consumption and restoring T cell activity in the tumor microenvironment; FFAR2 inhibition enhances response to immune checkpoint blockade. Whole/myeloid Ffar2 knockout mice (lung carcinogenesis models), flow cytometry, RNA sequencing, Western blotting, L-Arginine replenishment, PPAR-γ inhibition, Gαq/calcium pathway analysis Journal of hematology & oncology Medium 38402237
2023 Butyrate promotes ferroptosis via FFAR2: FFAR2 activation by butyrate suppresses SLC7A11 via the FFAR2-AKT-NRF2 axis and suppresses GPX4 via the FFAR2-mTORC1 axis, both in a cAMP-PKA-dependent manner, leading to lipid ROS accumulation. Ferroptosis assays (RSL3/erastin), FFAR2 knockdown/overexpression, AKT/NRF2 pathway analysis, mTORC1 inhibition, SLC7A11 and GPX4 expression, cAMP-PKA pathway analysis, xenograft and colorectal carcinogenesis models Cell death & disease Medium 37185889
2022 GPR43 activation by SCFAs inhibits NLRP3 inflammasome-mediated atrial remodeling to protect against atrial fibrillation; GPR43 knockdown in HL-1 atrial cells abolished the protective effects of SCFAs on NLRP3 deactivation. Low/high fiber diet mouse model, burst pacing AF model, HL-1 cells with GPR43 knockdown, NLRP3 inflammasome activity assay, CaMKII phosphorylation and RyR2 phosphorylation measurement, collagen/fibrosis analysis International journal of biological sciences Medium 35844801
2022 GPR43 activation by SCFA acetate in podocytes activates the ERK/EGR1 pathway, increasing LDLR expression and inhibiting cholesterol autophagy, leading to cholesterol accumulation and lipotoxic podocyte injury in diabetic nephropathy; GPR43 gene deletion or pharmacological inhibition prevents these effects. Diabetic GPR43-knockout mice, podocyte cell culture, BODIPY staining, cholesterol assays, ERK1/2 and EGR1 expression, LC3/p62/beclin1 autophagy markers, LDLR expression, GPR43 siRNA and pharmacological inhibition International journal of biological sciences Medium 34975320
2020 FFAR2 mediates SCFA-induced SCFA-dependent innate defense against IAV through type 1 interferon (IFN-β) response in pulmonary epithelial cells; Gpr43-knockout mice lose the protective antiviral effects of dietary fiber/acetate. Gpr43 knockout mice (RSV model also covers IAV in context of antiviral signaling), pulmonary epithelial cell line FFAR2 activation, IFN-β measurement, IFNAR pathway analysis Nature communications High 31332169
2021 GPR43 activation by acetate primes neutrophils for enhanced chemotaxis, oxidative burst, cytokine release, and upregulation of phagocytic receptors; acetate administration rescues wild-type but not GPR43-deficient mice from severe S. aureus sepsis. Human neutrophil priming assays, GPR43-deficient mice (S. aureus sepsis model), acetate administration, ROS/oxidative burst assay, cytokine measurement, phagocytic receptor expression, bacterial load quantification Communications biology Medium 34330996
2025 Propionic acid activates GPR43 to enhance PINK1/PARKIN-mediated mitophagy in neuronal cells, while activating GPR41 to downregulate DRP1-mediated mitochondrial fission, thereby maintaining mitochondrial homeostasis in an Alzheimer's disease model. AD mouse model with oral propionate supplementation, cultured hippocampal neurons, GPR43 and GPR41 pathway analysis, DRP1/mitochondrial fission protein expression, PINK1/PARKIN mitophagy markers, cognitive behavioral tests Microbiome Medium 39833898

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature 2439 19865172
2002 The Orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids. The Journal of biological chemistry 1835 12496283
2011 Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the G-protein-coupled receptor FFAR2. Diabetes 1734 22190648
2013 The gut microbiota suppresses insulin-mediated fat accumulation via the short-chain fatty acid receptor GPR43. Nature communications 1116 23652017
2015 Metabolite-sensing receptors GPR43 and GPR109A facilitate dietary fibre-induced gut homeostasis through regulation of the inflammasome. Nature communications 1053 25828455
2013 Short-chain fatty acids activate GPR41 and GPR43 on intestinal epithelial cells to promote inflammatory responses in mice. Gastroenterology 853 23665276
2003 Identification of a free fatty acid receptor, FFA2R, expressed on leukocytes and activated by short-chain fatty acids. Biochemical and biophysical research communications 442 12684041
2013 GPR41/FFAR3 and GPR43/FFAR2 as cosensors for short-chain fatty acids in enteroendocrine cells vs FFAR3 in enteric neurons and FFAR2 in enteric leukocytes. Endocrinology 438 23885020
2016 Microbiota metabolite short-chain fatty acid acetate promotes intestinal IgA response to microbiota which is mediated by GPR43. Mucosal immunology 390 27966553
2018 GPR43 mediates microbiota metabolite SCFA regulation of antimicrobial peptide expression in intestinal epithelial cells via activation of mTOR and STAT3. Mucosal immunology 383 29411774
2006 Short-chain fatty acid receptor, GPR43, is expressed by enteroendocrine cells and mucosal mast cells in rat intestine. Cell and tissue research 359 16453106
2019 Microbiota-derived acetate protects against respiratory syncytial virus infection through a GPR43-type 1 interferon response. Nature communications 307 31332169
2008 Roles of short-chain fatty acids receptors, GPR41 and GPR43 on colonic functions. Journal of physiology and pharmacology : an official journal of the Polish Physiological Society 302 18812643
2020 Dietary Fiber Protects against Diabetic Nephropathy through Short-Chain Fatty Acid-Mediated Activation of G Protein-Coupled Receptors GPR43 and GPR109A. Journal of the American Society of Nephrology : JASN 285 32358041
2019 Metabolite-Sensing Receptor Ffar2 Regulates Colonic Group 3 Innate Lymphoid Cells and Gut Immunity. Immunity 268 31628054
2010 Roles of GPR41 and GPR43 in leptin secretory responses of murine adipocytes to short chain fatty acids. FEBS letters 259 20399779
2007 Expression of the short-chain fatty acid receptor, GPR43, in the human colon. Journal of molecular histology 244 17899402
2016 GPR41 and GPR43 in Obesity and Inflammation - Protective or Causative? Frontiers in immunology 241 26870043
2011 SCFAs induce mouse neutrophil chemotaxis through the GPR43 receptor. PloS one 215 21698257
2014 The SCFA Receptor GPR43 and Energy Metabolism. Frontiers in endocrinology 205 24926285
2012 Short-chain free fatty acid receptors FFA2/GPR43 and FFA3/GPR41 as new potential therapeutic targets. Frontiers in endocrinology 204 23060857
2015 A Role for Gut Microbiota and the Metabolite-Sensing Receptor GPR43 in a Murine Model of Gout. Arthritis & rheumatology (Hoboken, N.J.) 197 25914377
2010 Inulin-type fructans with prebiotic properties counteract GPR43 overexpression and PPARγ-related adipogenesis in the white adipose tissue of high-fat diet-fed mice. The Journal of nutritional biochemistry 189 21115338
2016 Fermentable carbohydrate stimulates FFAR2-dependent colonic PYY cell expansion to increase satiety. Molecular metabolism 188 28123937
2020 Acetate coordinates neutrophil and ILC3 responses against C. difficile through FFAR2. The Journal of experimental medicine 183 31876919
2015 GPR43 Potentiates β-Cell Function in Obesity. Diabetes 179 26023106
2013 GPR43/FFA2: physiopathological relevance and therapeutic prospects. Trends in pharmacological sciences 163 23489932
2015 An Acetate-Specific GPCR, FFAR2, Regulates Insulin Secretion. Molecular endocrinology (Baltimore, Md.) 152 26075576
2022 Faecalibacterium prausnitzii Attenuates CKD via Butyrate-Renal GPR43 Axis. Circulation research 148 36164984
2017 Soluble Fibre Meal Challenge Reduces Airway Inflammation and Expression of GPR43 and GPR41 in Asthma. Nutrients 145 28075383
2018 Microbial metabolite sensor GPR43 controls severity of experimental GVHD. Nature communications 126 30201970
2007 The relationship between the effects of short-chain fatty acids on intestinal motility in vitro and GPR43 receptor activation. Neurogastroenterology and motility 126 17187590
2021 Lung immune tone via gut-lung axis: gut-derived LPS and short-chain fatty acids' immunometabolic regulation of lung IL-1β, FFAR2, and FFAR3 expression. American journal of physiology. Lung cellular and molecular physiology 124 33851870
2019 Propionate suppresses hepatic gluconeogenesis via GPR43/AMPK signaling pathway. Archives of biochemistry and biophysics 121 31356781
2021 Commensal microbe-derived acetate suppresses NAFLD/NASH development via hepatic FFAR2 signalling in mice. Microbiome 120 34530928
2006 The G-protein-coupled receptor 40 family (GPR40-GPR43) and its role in nutrient sensing. Biochemical Society transactions 111 17052194
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2016 An essential role of Ffar2 (Gpr43) in dietary fibre-mediated promotion of healthy composition of gut microbiota and suppression of intestinal carcinogenesis. Oncogenesis 108 27348268
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2006 Short-chain fatty acids induce acute phosphorylation of the p38 mitogen-activated protein kinase/heat shock protein 27 pathway via GPR43 in the MCF-7 human breast cancer cell line. Cellular signalling 95 16887331
2018 The Metabolic Sensor GPR43 Receptor Plays a Role in the Control of Klebsiella pneumoniae Infection in the Lung. Frontiers in immunology 86 29515566
2018 Butyrate Modulates Inflammation in Chondrocytes via GPR43 Receptor. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 85 30448827
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2016 Human and mouse monocytes display distinct signalling and cytokine profiles upon stimulation with FFAR2/FFAR3 short-chain fatty acid receptor agonists. Scientific reports 81 27667443
2020 Bifidobacterium animalis subsp. lactis GCL2505 modulates host energy metabolism via the short-chain fatty acid receptor GPR43. Scientific reports 80 32139755
2021 Butyrate directly decreases human gut lamina propria CD4 T cell function through histone deacetylase (HDAC) inhibition and GPR43 signaling. Immunobiology 79 34365090
2020 The G Protein-Coupled Receptor FFAR2 Promotes Internalization during Influenza A Virus Entry. Journal of virology 75 31694949
2021 GPR43 deficiency protects against podocyte insulin resistance in diabetic nephropathy through the restoration of AMPKα activity. Theranostics 74 33754024
2018 Loss of FFAR2 promotes colon cancer by epigenetic dysregulation of inflammation suppressors. International journal of cancer 73 29524208
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2024 GPR41 and GPR43: From development to metabolic regulation. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 69 38744220
2011 Diet-induced obesity up-regulates the abundance of GPR43 and GPR120 in a tissue specific manner. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 69 22178946
2021 Short-Chain Fatty Acid and FFAR2 Activation - A New Option for Treating Infections? Frontiers in cellular and infection microbiology 67 34926327
2022 Commensal microbe-derived SCFA alleviates atrial fibrillation via GPR43/NLRP3 signaling. International journal of biological sciences 65 35844801
2021 The Butyrate-Producing Bacterium Clostridium butyricum Suppresses Clostridioides difficile Infection via Neutrophil- and Antimicrobial Cytokine-Dependent but GPR43/109a-Independent Mechanisms. Journal of immunology (Baltimore, Md. : 1950) 65 33597149
2025 Akkermansia muciniphila and its metabolite propionic acid maintains neuronal mitochondrial division and autophagy homeostasis during Alzheimer's disease pathologic process via GPR41 and GPR43. Microbiome 60 39833898
2023 Butyrate dictates ferroptosis sensitivity through FFAR2-mTOR signaling. Cell death & disease 59 37185889
2023 Butyrate suppresses atherosclerotic inflammation by regulating macrophages and polarization via GPR43/HDAC-miRNAs axis in ApoE-/- mice. PloS one 56 36888629
2021 Lithium carbonate alleviates colon inflammation through modulating gut microbiota and Treg cells in a GPR43-dependent manner. Pharmacological research 54 34801681
2021 Short chain fatty acids released by Fusobacterium nucleatum are neutrophil chemoattractants acting via free fatty acid receptor 2 (FFAR2). Cellular microbiology 51 33913592
2019 Microbiota Metabolite Short-Chain Fatty Acids Facilitate Mucosal Adjuvant Activity of Cholera Toxin through GPR43. Journal of immunology (Baltimore, Md. : 1950) 50 31076530
2018 Decreased expression of G-protein-coupled receptors GPR43 and GPR109a in psoriatic skin can be restored by topical application of sodium butyrate. Archives of dermatological research 47 30209581
2020 Acetic acid stimulates G-protein-coupled receptor GPR43 and induces intracellular calcium influx in L6 myotube cells. PloS one 46 32997697
2018 Butyrate ameliorated-NLRC3 protects the intestinal barrier in a GPR43-dependent manner. Experimental cell research 46 29689277
2020 Leuconostoc mesenteroides fermentation produces butyric acid and mediates Ffar2 to regulate blood glucose and insulin in type 1 diabetic mice. Scientific reports 43 32404878
2018 Similarities and differences between the responses induced in human phagocytes through activation of the medium chain fatty acid receptor GPR84 and the short chain fatty acid receptor FFA2R. Biochimica et biophysica acta. Molecular cell research 42 29477577
2013 Evaluation of the relationship between GPR43 and adiposity in human. Nutrition & metabolism 42 23327542
2015 The short-chain fatty acid receptor GPR43 is transcriptionally regulated by XBP1 in human monocytes. Scientific reports 41 25633224
2015 Selective novel inverse agonists for human GPR43 augment GLP-1 secretion. European journal of pharmacology 41 26683635
2021 GPR43 regulation of mitochondrial damage to alleviate inflammatory reaction in sepsis. Aging 38 34584017
2016 The Neutrophil Response Induced by an Agonist for Free Fatty Acid Receptor 2 (GPR43) Is Primed by Tumor Necrosis Factor Alpha and by Receptor Uncoupling from the Cytoskeleton but Attenuated by Tissue Recruitment. Molecular and cellular biology 36 27503855
2023 Eucommia bark/leaf extract improves HFD-induced lipid metabolism disorders via targeting gut microbiota to activate the Fiaf-LPL gut-liver axis and SCFAs-GPR43 gut-fat axis. Phytomedicine : international journal of phytotherapy and phytopharmacology 35 36638713
2022 GPR43 activation-mediated lipotoxicity contributes to podocyte injury in diabetic nephropathy by modulating the ERK/EGR1 pathway. International journal of biological sciences 34 34975320
2021 Short Chain Fatty Acids Prevent Glyoxylate-Induced Calcium Oxalate Stones by GPR43-Dependent Immunomodulatory Mechanism. Frontiers in immunology 34 34675921
2020 Microbiota-derived short chain fatty acid promotion of Amphiregulin expression by dendritic cells is regulated by GPR43 and Blimp-1. Biochemical and biophysical research communications 34 32958255
2020 GPR43 regulates sodium butyrate-induced angiogenesis and matrix remodeling. American journal of physiology. Heart and circulatory physiology 33 33356962
2024 FFAR2 expressing myeloid-derived suppressor cells drive cancer immunoevasion. Journal of hematology & oncology 31 38402237
2022 The Bufei Jianpi Formula Improves Mucosal Immune Function by Remodeling Gut Microbiota Through the SCFAs/GPR43/NLRP3 Pathway in Chronic Obstructive Pulmonary Disease Rats. International journal of chronic obstructive pulmonary disease 31 35673595
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2023 Pulsatilla chinensis saponins improve SCFAs regulating GPR43-NLRP3 signaling pathway in the treatment of ulcerative colitis. Journal of ethnopharmacology 28 36806339
2023 Sodium butyrate (SB) ameliorated inflammation of COPD induced by cigarette smoke through activating the GPR43 to inhibit NF-κB/MAPKs signaling pathways. Molecular immunology 28 37864932
2018 Neutrophil priming that turns natural FFA2R agonists into potent activators of the superoxide generating NADPH-oxidase. Journal of leukocyte biology 28 30134499
2015 GPR43 - A Prototypic Metabolite Sensor Linking Metabolic and Inflammatory Diseases. Trends in endocrinology and metabolism: TEM 28 26412151
2023 FFAR2 antagonizes TLR2- and TLR3-induced lung cancer progression via the inhibition of AMPK-TAK1 signaling axis for the activation of NF-κB. Cell & bioscience 27 37287005
2020 Sodium butyrate protects against lipopolysaccharide-induced liver injury partially via the GPR43/ β-arrestin-2/NF-κB network. Gastroenterology report 27 34026223
2015 Expanding Duplication of Free Fatty Acid Receptor-2 (GPR43) Genes in the Chicken Genome. Genome biology and evolution 27 25912043
2020 Low Expression of FFAR2 in Peripheral White Blood Cells May Be a Genetic Marker for Early Diagnosis of Acute Myocardial Infarction. Cardiology research and practice 26 32411444
2015 Role of Free Fatty Acid Receptor 2 (FFAR2) in the Regulation of Metabolic Homeostasis. Current drug targets 26 25850624
2024 EGCG drives gut microbial remodeling-induced epithelial GPR43 activation to lessen Th1 polarization in colitis. Redox biology 24 39116526
2017 Ligands at the Free Fatty Acid Receptors 2/3 (GPR43/GPR41). Handbook of experimental pharmacology 24 27757758
2024 Maternal Phlorizin Intake Protects Offspring from Maternal Obesity-Induced Metabolic Disorders in Mice via Targeting Gut Microbiota to Activate the SCFA-GPR43 Pathway. Journal of agricultural and food chemistry 23 38349207
2021 Probiotic Activity of Staphylococcus epidermidis Induces Collagen Type I Production through FFaR2/p-ERK Signaling. International journal of molecular sciences 23 33572500
2019 Alteration of GLP-1/GPR43 expression and gastrointestinal motility in dysbiotic mice treated with vancomycin. Scientific reports 23 30867532
2014 Effect of short chain fatty acids on the expression of free fatty acid receptor 2 (Ffar2), Ffar3 and early-stage adipogenesis. Nutrition & diabetes 23 25089883
2022 Novel GPR43 Agonists Exert an Anti-Inflammatory Effect in a Colitis Model. Biomolecules & therapeutics 22 34168098
2023 Neuroprotective effect of short-chain fatty acids against oxidative stress-induced SH-SY5Y injury via GPR43-dependent pathway. Journal of neurochemistry 21 37070532
2024 Gut Microbiota-Derived 3-Hydroxybutyrate Blocks GPR43-Mediated IL6 Signaling to Ameliorate Radiation Proctopathy. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20 38742466
2021 Acetate sensing by GPR43 alarms neutrophils and protects from severe sepsis. Communications biology 20 34330996