Affinage

FFAR3

Free fatty acid receptor 3 · UniProt O14843

Length
346 aa
Mass
38.6 kDa
Annotated
2026-04-28
100 papers in source corpus 34 papers cited in narrative 34 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FFAR3 (GPR41) is a Gi/o-coupled receptor for short-chain fatty acids—principally propionate, butyrate, and pentanoate—that transduces microbial metabolite signals into neuroendocrine, metabolic, and immune responses across enteroendocrine cells, sympathetic and vagal neurons, immune cells, airway smooth muscle, and other tissues. Ligand binding engages Gβγ-dependent PLC-β/Ca²⁺ and ERK1/2–p38 MAPK cascades to regulate PYY and GLP-1 secretion from enteroendocrine cells, leptin release from adipocytes, norepinephrine release from sympathetic neurons via synapsin 2b phosphorylation, and cytokine/chemokine production in intestinal epithelial and immune cells (PMID:12496283, PMID:18931303, PMID:23885020, PMID:21518883, PMID:22673524, PMID:23665276). FFAR3 also couples to N-type calcium (CaV2.2) channels in sympathetic neurons and forms heteromers with FFAR2 that shift signaling toward β-arrestin-2 recruitment and p38 activation (PMID:30478340, PMID:28883043). The ketone body β-hydroxybutyrate acts as an endogenous antagonist, suppressing FFAR3-mediated sympathetic outflow and hormone secretion, thereby linking ketogenic metabolic states to reduced SCFA signaling (PMID:21518883, PMID:38791266).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2002 High

    Deorphanization of GPR41 established that SCFAs (propionate, butyrate, pentanoate) are its cognate ligands signaling through Gi/o, resolving the receptor's pharmacology and enabling all subsequent functional studies.

    Evidence Ca²⁺ mobilization, [³⁵S]GTPγS binding, and GIRK channel assays in transfected mammalian cells and Xenopus oocytes

    PMID:12496283

    Open questions at the time
    • Endogenous tissue expression patterns unknown
    • Physiological functions uncharacterized
    • Receptor selectivity versus GPR43/FFAR2 not resolved
  2. 2004 High

    Linking FFAR3 to leptin regulation in adipocytes provided the first physiological function, connecting gut-derived SCFAs to an endocrine energy-balance signal.

    Evidence SCFA stimulation of leptin mRNA/protein in mouse adipocytes in vitro and oral propionate increasing circulating leptin in vivo

    PMID:14722361

    Open questions at the time
    • Receptor specificity versus FFAR2 not genetically dissected
    • Signaling cascade downstream of Gi/o in adipocytes unresolved
  3. 2008 High

    Gpr41 knockout mice revealed that the receptor is required for microbiota-dependent PYY expression, normal gut motility, and body weight regulation, establishing FFAR3 as a key sensor linking gut microbiota to host energy homeostasis.

    Evidence Gpr41⁻/⁻ mice with germ-free and gnotobiotic colonization showing reduced PYY, faster transit, and leaner phenotype

    PMID:18931303

    Open questions at the time
    • Enteroendocrine cell-type specificity not mapped
    • Downstream signaling pathway in enteroendocrine cells uncharacterized
  4. 2011 High

    Discovery that FFAR3 operates in sympathetic ganglia to promote sympathetic outflow via Gβγ-PLCβ-MAPK, and that β-hydroxybutyrate acts as an endogenous antagonist, revealed a neuroendocrine axis linking SCFAs and ketone bodies to autonomic regulation.

    Evidence siRNA knockdown and pharmacological inhibition in primary sympathetic neurons plus in vivo energy expenditure in mice

    PMID:21518883

    Open questions at the time
    • Molecular basis of β-hydroxybutyrate antagonism (binding site) unknown
    • Relative contribution of neuronal vs. non-neuronal FFAR3 to whole-body energy expenditure not dissected
  5. 2012 High

    Dissection of the sympathetic signaling cascade identified synapsin 2b as an ERK1/2-interacting effector phosphorylated upon FFAR3 activation, linking SCFA sensing to vesicular norepinephrine release; concurrently, metabolic phenotyping of KO mice confirmed sex-specific roles in energy expenditure.

    Evidence Co-immunoprecipitation of synapsin 2b with ERK1/2 in primary sympathetic neurons plus metabolic phenotyping of male Gpr41⁻/⁻ mice

    PMID:22673524 PMID:23110765

    Open questions at the time
    • Direct phosphorylation sites on synapsin 2b not mapped
    • Mechanism of sex-specific metabolic phenotype unexplained
  6. 2013 High

    Two studies expanded FFAR3's tissue map and functional roles: it was shown to activate ERK1/2/p38 in intestinal epithelium driving chemokine-mediated immune cell recruitment, and reporter-mouse mapping revealed FFAR3 expression across all major enteroendocrine cell types and enteric neurons, with functional GLP-1 release confirmed.

    Evidence Gpr41⁻/⁻ mice in inflammatory models plus transgenic mRFP reporter mice with GLP-1 secretion assays from colonic crypts

    PMID:23665276 PMID:23885020

    Open questions at the time
    • Enteric neuron-specific functions of FFAR3 not dissected
    • Whether FFAR3 drives GLP-1 release in vivo independently of FFAR2 not established
  7. 2015 High

    Comprehensive neuroanatomical mapping confirmed FFAR3 expression in postganglionic sympathetic, vagal, dorsal root, and trigeminal ganglia but not brain or spinal cord, defining the receptor as a peripheral neural sensor for SCFAs.

    Evidence Transgenic mRFP reporter mice validated by ISH, IHC, and qPCR across ganglia

    PMID:25637492

    Open questions at the time
    • Functional roles in DRG and trigeminal ganglia unknown
    • Whether FFAR3 absence from CNS is absolute under all conditions not tested
  8. 2017 High

    Discovery that FFAR2 and FFAR3 form heteromers with dramatically enhanced β-arrestin-2 recruitment and shifted signaling (gain of p38, loss of cAMP inhibition) revealed that receptor stoichiometry determines SCFA signaling output in monocytes/macrophages.

    Evidence PLA in primary human monocytes/macrophages, BiFC, FRET, and functional signaling assays in HEK293 cells

    PMID:28883043

    Open questions at the time
    • Physiological consequences of heteromerization in vivo unknown
    • Structural basis of heteromer-specific signaling not determined
  9. 2018 High

    Multiple studies in 2018 extended FFAR3 function to airway smooth muscle contraction (via Gβγ-PLC-IP3/Ca²⁺), GIP secretion suppression (FFAR3-specific, not FFAR2), and coupling to CaV2.2 channels in sympathetic neurons, broadening the receptor's effector repertoire.

    Evidence Ex vivo human airway contraction with pharmacological pathway dissection; Ffar3⁻/⁻ vs Ffar2⁻/⁻ mice for GIP; patch-clamp electrophysiology in reporter-identified neurons with two independent KO models

    PMID:30400014 PMID:30478340 PMID:32209026

    Open questions at the time
    • Whether airway FFAR3 contributes to asthma pathophysiology in vivo untested
    • Mechanism of CaV2.2 coupling (direct Gβγ or indirect) not resolved
  10. 2019 High

    FFAR3-specific (not FFAR2) mediation of dietary SCFA protection against high-fat diet-induced obesity and hepatic lipid synthesis was demonstrated, establishing a liver-relevant metabolic axis.

    Evidence FFAR3⁻/⁻ vs FFAR2⁻/⁻ mice on HFD with hepatic lipid analysis

    PMID:31719611

    Open questions at the time
    • Hepatocyte-autonomous vs. indirect (neural/endocrine) mechanism not distinguished
    • Signaling pathway in hepatocytes not characterized
  11. 2021 High

    Vagal neuron-specific FFAR3 knockout demonstrated that the receptor in vagal afferents controls meal size, food intake, and propionate-induced anorexia, with cross-talk to CCK and leptin receptor pathways, defining a gut–brain feeding circuit.

    Evidence Cre-driven vagal-specific Ffar3 KO mice with feeding behavior, fasting/refeeding assays, and ex vivo vagal cultures with transcriptomics

    PMID:34626852

    Open questions at the time
    • Precise vagal neuron subtype(s) mediating anorexia not identified
    • Signal integration mechanism between FFAR3, CCK-R, and LepR at molecular level unknown
  12. 2022 Medium

    Identification of RGS4 as a negative regulator of FFAR3 signaling in cardiomyocytes, activated by catecholamine/PKA, revealed a feedback mechanism whereby sympathetic tone attenuates SCFA-driven cardiac inflammation.

    Evidence siRNA-mediated RGS4 depletion in H9c2 cardiomyocytes with cAMP, p38, and cytokine readouts; sympathetic neuron–cardiomyocyte co-culture

    PMID:35628613

    Open questions at the time
    • In vivo cardiac relevance of RGS4-FFAR3 axis not validated
    • Whether RGS4 regulation is specific to FFAR3 among Gi-coupled receptors untested
  13. 2024 Medium

    FFAR3 was shown to reprogram pulmonary ILC2s toward an anti-inflammatory IL-10-producing phenotype via EGFR upregulation, and to modulate dendritic cell maturation through SOCS3/STAT3, expanding its immune-regulatory roles beyond epithelial chemokine induction.

    Evidence Collaborative Cross genetic mapping with FFAR3 loss-of-function in ILC2s; Gpr41⁻/⁻ BMDC adoptive transfer accelerating T1D

    PMID:38514862 PMID:41484153

    Open questions at the time
    • EGFR-dependent mechanism in ILC2s not fully delineated
    • Whether DC maturation phenotype is cell-autonomous or secondary to altered SCFA metabolism not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis of FFAR3 ligand selectivity, the molecular mechanism of β-hydroxybutyrate antagonism, the relative contributions of heteromeric vs. homomeric receptor pools in vivo, and cell-type-specific signaling bias in different tissues remain unresolved.
  • No crystal or cryo-EM structure available
  • Heteromer stoichiometry and regulation in native tissues unknown
  • Cell-type-specific biased agonism not systematically characterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 6
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-112316 Neuronal System 4 R-HSA-1430728 Metabolism 4 R-HSA-168256 Immune System 3
Partners
ARRB2FFAR2PLCB3RGS4SYN2
Complex memberships
FFAR2-FFAR3 heteromer

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 GPR41 (FFAR3) is activated by short-chain fatty acids (SCFAs) including propionate, butyrate, and pentanoate, with pentanoate being the most potent agonist; activation was confirmed using Ca2+ mobilization assays, [35S]GTPγS binding, and GIRK channel co-expression in Xenopus oocytes after transfection into mammalian cells. Ca2+ mobilization assay, [35S]GTPγS binding, GIRK channel co-expression in Xenopus oocytes, transient transfection in mammalian cells The Journal of biological chemistry High 12496283
2004 GPR41 activation by C2–C6 short-chain fatty acids stimulates leptin expression in mouse adipocytes and adipose tissue; acute oral propionate administration increases circulating leptin in mice. Mouse adipocyte cell line and primary culture experiments, in vivo oral propionate administration in mice, leptin mRNA/protein measurement Proceedings of the National Academy of Sciences of the United States of America High 14722361
2008 GPR41 (FFAR3) expressed on enteroendocrine cells mediates SCFA-dependent regulation of host energy balance by promoting PYY expression, inhibiting gut motility, and increasing energy harvest from the diet; Gpr41-/- mice are significantly leaner with faster intestinal transit and reduced PYY expression in a gut-microbiota-dependent manner. Gpr41 knockout mouse model, germ-free and gnotobiotic colonization experiments, functional genomics, biochemical and physiologic studies Proceedings of the National Academy of Sciences of the United States of America High 18931303
2011 GPR41 is a Gi/o-coupled receptor expressed in sympathetic ganglia that directly regulates sympathetic nervous system activity; SCFA propionate promotes sympathetic outflow via GPR41 through Gβγ-PLCβ-MAPK signaling, while the ketone body β-hydroxybutyrate antagonizes GPR41 to suppress SNS activity. Pharmacological inhibition, siRNA knockdown in primary sympathetic neurons, in vivo energy expenditure measurements in mice, signaling pathway analysis Proceedings of the National Academy of Sciences of the United States of America High 21518883
2012 GPR41-mediated activation of sympathetic neurons by SCFA propionate involves Gβγ-PLCβ3-ERK1/2-synapsin 2b signaling; synapsin 2b directly interacts with activated ERK1/2 and is phosphorylated on serine upon SCFA stimulation, regulating norepinephrine release. Pharmacological inhibition, siRNA knockdown, primary-cultured mouse sympathetic cervical ganglion neurons, co-immunoprecipitation of synapsin 2b with ERK1/2 FEBS letters High 22673524
2013 GPR41 (FFAR3) activates ERK1/2 and p38 MAPK signaling in intestinal epithelial cells upon SCFA stimulation, inducing production of chemokines and cytokines to recruit leukocytes and activate effector T cells; Gpr41-/- mice show reduced inflammatory responses. GPR41 knockout mice, in vitro primary colon epithelial cells, ELISA, immunohistochemistry, flow cytometry, ethanol/TNBS/Citrobacter rodentium inflammatory models Gastroenterology High 23665276
2013 FFAR3 (GPR41) is expressed as a cosensor for SCFAs in all major enteroendocrine cell types (CCK, GIP, secretin, GLP-1, PYY, neurotensin, somatostatin, substance P cells) in the small and large intestine, and is also expressed in enteric neurons of the submucosal and myenteric ganglia; FFAR3-specific synthetic ligands release GLP-1 from colonic crypt cultures. Transgenic mRFP reporter mice, immunohistochemistry, FACS purification, quantitative PCR, GLP-1 secretion assay from colonic crypt cultures Endocrinology High 23885020
2015 FFAR3 (GPR41) is expressed in postganglionic sympathetic neurons of the superior cervical, thoracic, and lumbar sympathetic ganglia, prevertebral ganglia, vagal ganglia, dorsal root ganglia, and trigeminal ganglia, but not in brain or spinal cord; expression confirmed at mRNA and protein levels. Transgenic mRFP reporter mice, immunohistochemistry, radioactive in situ hybridization, qRT-PCR, anti-FFAR3 antibody validation Neuroscience High 25637492
2012 Male GPR41 knockout mice fed a low-fat diet exhibit increased body fat mass, impaired glucose tolerance, reduced soleus muscle and heart weights, and reduced energy expenditure, indicating GPR41 promotes energy expenditure; female KO mice are unaffected. GPR41 knockout mouse model, metabolic phenotyping, body composition analysis, glucose tolerance tests, energy expenditure measurements The British journal of nutrition High 23110765
2017 FFAR2 and FFAR3 interact to form a receptor heteromer in primary human monocytes and macrophages, as well as in HEK293 cells; FFAR2-FFAR3 heteromerization enhances cytosolic Ca2+ signaling (1.5-fold), dramatically increases β-arrestin-2 recruitment (30-fold), gains the ability to induce p38 phosphorylation, and loses the ability to inhibit cAMP production compared to parent homomers. Proximity ligation assay in primary human monocytes/macrophages, bimolecular fluorescence complementation (BiFC), FRET, pharmacological inhibition in HEK293 cells FASEB journal High 28883043
2018 FFAR3 (GPR41) is functionally expressed in human airway smooth muscle (ASM); acute FFAR3 activation by SCFAs inhibits forskolin-stimulated cAMP accumulation, increases intracellular Ca2+ via Gβγ-PLC-IP3 pathway (sensitive to pertussis toxin, gallein, U73122, xestospongin C), potentiates acetylcholine-stimulated Ca2+ increases, stress fiber formation, and contraction of ex vivo human airway tissues. Western blot for protein expression in native human ASM, cAMP accumulation assay, Ca2+ imaging, pharmacological inhibitors, ex vivo human airway contraction assay, primary cultured HASM cells American journal of physiology. Lung cellular and molecular physiology High 32209026
2018 FFAR3 (GPR41) mediates gut carbohydrate-induced suppression of GIP secretion via a microbiota/SCFA/FFAR3 pathway; this GIP suppression by maltose/miglitol was absent in Ffar3-deficient mice but present in Ffar2-deficient mice, indicating FFAR3 specificity. Ffar3 and Ffar2 knockout mice, germ-free mice, antibiotic-treated mice, oral carbohydrate/inhibitor administration, portal vein SCFA measurement, GIP secretion assay The Journal of endocrinology High 30400014
2019 Dietary SCFAs protect against high-fat diet-induced obesity and suppress hepatic lipid synthesis via FFAR3; these metabolic effects were abolished in FFAR3-deficient mice but not FFAR2-deficient mice, demonstrating FFAR3-specific hepatic metabolic regulation. FFAR3 and FFAR2 knockout mice, high-fat diet model, cecal SCFA measurement, plasma SCFA measurement, hepatic lipid analysis Scientific reports High 31719611
2021 FFAR3 expressed in vagal sensory neurons is necessary for normal feeding behavior; vagal-specific FFAR3 knockout mice show increased meal size, increased food intake during fasting/refeeding, and loss of propionate-induced anorexia; FFAR3 signaling in vagal neurons cross-talks with CCK and leptin receptor pathways. Cre-recombinase-driven vagal-specific FFAR3 knockout mice, feeding behavior analysis, fasting/refeeding assays, western diet challenge, propionate supplementation, ex vivo organotypic vagal cultures, transcriptomic sequencing Molecular metabolism High 34626852
2018 GPR41 (FFAR3) activation by SCFAs mediates anti-inflammatory effects in endothelial cells; specifically, acetate's inhibitory effects on IL-6 and IL-8 production and propionate/butyrate's inhibitory effects on IL-6 production required GPR41/43, demonstrated by reversal with the GPR41 antagonist β-hydroxybutyrate. GPR41/43 expression confirmed by immunofluorescence in HUVEC; pharmacological antagonism with β-hydroxybutyrate (SHB) and GLPG0974; IL-6, IL-8, VCAM-1 measurement; HDAC activity assay Frontiers in pharmacology Medium 29875665
2020 Sodium butyrate activates the GPR41/Gβγ/PI3K/Akt pathway to attenuate neuronal apoptosis after middle cerebral artery occlusion; GPR41 siRNA knockdown in PC12 cells and pharmacological inhibition reversed the neuroprotective effects, confirming the mechanistic link. Rat MCAO model, intranasal sodium butyrate administration, PC12 cell oxygen-glucose deprivation model, siRNA knockdown, pharmacological inhibition, Western blot for GPR41/PI3K/pAkt Journal of cerebral blood flow and metabolism Medium 32151222
2017 SCFAs attenuate TNF-α-induced MCP-1 expression in human renal cortical epithelial cells via GPR41/43-dependent inhibition of p38 and JNK phosphorylation; this effect was blocked by Gi/o protein inactivation, Gβγ(i/o) blocker, and by siRNA silencing of GPR41 and GPR43. siRNA knockdown of GPR41/GPR43, pharmacological Gi/o inhibition, Gβγ blocker, Western blot for p38/JNK phosphorylation, MCP-1 ELISA in primary human renal cortical epithelial cells Biochemical and biophysical research communications Medium 28322790
2012 Butyrate-induced GPR41 activation in cells stably expressing hGPR41 counteracts butyrate-induced histone H3 hyperacetylation and modulates cell cycle: GPR41 expression induces G1 arrest, while butyrate activation of GPR41 allows more cells to pass the G1 checkpoint, and GPR41 has inhibitory effects on butyrate-induced anti-proliferation and apoptosis. Stable cell line expressing hGPR41, Western blot for histone acetylation, cell cycle analysis, proliferation/apoptosis assays, butyrate treatment Journal of genetics and genomics Medium 22884094
2018 SCFA-induced t-PA expression in primary normal human bronchial epithelial cells requires both GPR41 (FFAR3) and GPR43 (FFAR2); propionic acid was the strongest inducer, and gene silencing of GPR41 and GPR43 each reduced SCFA-induced t-PA induction. siRNA gene silencing of GPR41/GPR43 in primary NHBE cells, t-PA mRNA/protein measurement, immunohistochemistry for receptor expression Clinical and experimental allergy Medium 29431874
2018 FFAR3 (GPR41) in sympathetic neurons couples to N-type calcium (CaV2.2) channels; FFAR3-expressing neurons identified via reporter mouse show 2.5-fold less variability and 1.5-fold greater CaV2.2 inhibition than unlabeled neurons; complete loss-of-function confirmed in two Ffar3 knockout models; FFAR3-expressing neurons are predominantly vasoconstrictor-phenotype neurons. FFAR3 reporter mouse, whole-cell patch-clamp electrophysiology, Ffar3 knockout mice (two models), immunofluorescence Scientific reports High 30478340
2020 AR420626, a selective GPR41/FFA3 agonist, suppresses hepatocellular carcinoma cell growth by inducing apoptosis through mTOR-phosphorylation-dependent proteasome activation, HDAC protein reduction, and subsequent TNF-α upregulation; GPR41 siRNA silencing blocked these effects. HepG2 xenograft in nude mice, flow cytometry, Western blot, siRNA knockdown of GPR41 and HDAC3/5/7, TaqMan RT-PCR Therapeutic advances in medical oncology Medium 33014144
2022 RGS4 attenuates FFAR3 (GPR41) signaling in cardiomyocytes; RGS4 depletion by siRNA enhances propionate-dependent Gi/o activation, cAMP lowering, p38 MAPK activation, IL-1β, IL-6, and TGF-β production; catecholamine pretreatment blocks FFAR3 signaling via PKA-dependent RGS4 activation; RGS4 also opposes FFAR3-dependent norepinephrine release from sympathetic neurons co-cultured with cardiomyocytes. siRNA-mediated RGS4 depletion in H9c2 cardiomyocytes, Neuro-2a co-culture with H9c2 cells, cAMP assay, p38 MAPK phosphorylation, cytokine ELISA, pharmacological PKA activation International journal of molecular sciences Medium 35628613
2023 GPR41 activation by AR420626 increases intracellular Ca2+ influx and phosphorylates CaMKII, CREB, and p38 MAPK via Gαi signaling in C2C12 myotubes, enhancing glucose uptake; these effects were blocked by pertussis toxin, Ca2+ channel blocker, and GPR41 siRNA, and AR420626 improved glucose tolerance in diabetic mouse models. siRNA knockdown of GPR41 in C2C12 cells, pertussis toxin inhibition, Ca2+ imaging, glucose uptake assay, GLUT4 translocation measurement, in vivo diabetic mouse models (STZ and HFD) Obesity Medium 37309717
2024 FFAR3 signaling reprograms pulmonary ILC2s to an anti-inflammatory state by promoting survival, reducing Type 2 cytokines, and enhancing IL-10 expression; this anti-inflammatory reprogramming is mediated by EGFR upregulation and is IL-2-dependent; partially conserved in human ILC2s. Collaborative Cross mouse genetic mapping, QTL analysis, FFAR3 loss-of-function experiments, ILC2 functional assays, cytokine measurement, EGFR inhibition Nature communications Medium 41484153
2024 Ketone body β-hydroxybutyrate antagonizes FFAR3 (GPR41) to suppress catecholamine and adipokine (leptin, adiponectin) secretion from adrenal chromaffin PC12 cells; propionate-activated FFAR3 promotes CA secretion via Gi/o-derived free Gβγ-PLC-β/Ca2+ pathway, similar to its role in sympathetic neurons. PC12 cell pharmacological studies, GRK2 blockade, propionate/BHB treatment, catecholamine secretion assay, adipokine measurement International journal of molecular sciences Medium 38791266
2024 FFAR3 (GPR41) expressed in enteroendocrine GLUTag cells mediates ketone body inhibition of GLP-1 secretion via the Gαi/o signaling pathway; FFAR3 expression is upregulated by high-fat diet and downregulated after Roux-en-Y gastric bypass. Western blot and immunohistochemistry in human and mouse intestinal biopsies, GLUTag cell GLP-1 secretion assay, Gαi/o inhibition with pertussis toxin Biochemistry and biophysics reports Medium 38910871
2009 Bovine GPR41 and GPR43 proteins, when overexpressed in cells, inhibit luciferase reporter expression from a cAMP-responsive promoter upon treatment with acetate, propionate, or butyrate, demonstrating coupling to Gαi/11. Heterologous overexpression in cells, cAMP-responsive luciferase reporter assay, sequence characterization Journal of dairy science Medium 19448003
2009 GPR42 (closely related to GPR41) may be polymorphic rather than an inactive pseudogene; mutagenesis showed that amino acid R174 (found in GPR41) is important for functional SCFA signaling, while W174 (found in some GPR42 alleles) silences the response; 61% of GPR42 alleles carry the functional R174. Site-directed mutagenesis, genotyping of 202 GPR42 alleles DNA and cell biology Medium 19630535
2025 FFAR3 (GPR41) mediates the protective effects of butyrate against aortic dissection by maintaining vascular smooth muscle cell contractile phenotype and suppressing NADPH oxidase 4-dependent ROS production; these protective effects were abolished in GPR41 knockout mice but not GPR109A knockout mice. GPR41 and GPR109A knockout mice, BAPN aortic dissection mouse model, exogenous butyrate supplementation, SMC contractile marker expression, NADPH oxidase 4/ROS measurement Acta pharmacologica Sinica Medium 40550961
2025 GPR41 deficiency promotes dendritic cell maturation by inhibiting SOCS3 expression and enhancing STAT3 phosphorylation, leading to enhanced gut immune dysregulation and increased migration of IFN-γ+ T cells to the pancreas; adoptive transfer of BMDCs from Gpr41-/- mice accelerates type 1 diabetes. Gpr41-/- mice, STZ-induced T1D model, bone marrow-derived DC adoptive transfer, flow cytometry, Western blot for SOCS3/STAT3 phosphorylation Acta pharmacologica Sinica Medium 38514862
2020 Cat FFAR3, when transfected into CHO-K1 cells, inhibits intracellular cAMP concentrations upon SCFA treatment and shows propionate-induced β-arrestin-2 (Arrestin-3) recruitment; unlike FFAR2, FFAR3 activation does not activate NFAT-luciferase reporter, indicating distinct downstream signaling. cDNA cloning, CHO-K1 transfection, cAMP assay, NFAT-luciferase reporter, NanoBiT split-luciferase β-arrestin recruitment assay Veterinary medicine and science Medium 32929853
2025 GPR41 activation by propionate downregulates mitochondrial fission protein DRP1, contributing to maintenance of mitochondrial homeostasis in hippocampal neurons; this effect was demonstrated in AD model mice and cultured cells. In vivo propionate supplementation in AD model mice, in vitro hippocampal neuronal cell culture, GPR41 knockdown, DRP1 protein expression measurement, cognitive behavioral tests Microbiome Low 39833898
2025 Propionate activates FFAR3 in brain endothelial cells to reduce paracellular permeability and restore tight junction proteins (claudin-1, occludin) as demonstrated by FFAR3-mediated signaling in transcriptomic analyses, and is linked to improved blood-brain barrier integrity. Mouse and transcriptomic analyses, dietary supplementation model, mechanistic inference from pathway analyses in brain endothelial cells Journal of agricultural and food chemistry Low 40600293
2025 The maternal gut microbiota-derived propionate influences embryonic enteric nervous system development via the GPR41-GDNF/RET/SOX10 signaling pathway; preconception maternal antibiotic exposure disrupts this axis and leads to abnormal ENS development in offspring. Mouse model with preconception antibiotic exposure, Limosilactobacillus reuteri and propionate gestational supplementation, metagenomics, targeted metabolomics, transcriptomics iMeta Low 40236770

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
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
2008 Effects of the gut microbiota on host adiposity are modulated by the short-chain fatty-acid binding G protein-coupled receptor, Gpr41. Proceedings of the National Academy of Sciences of the United States of America 1144 18931303
2013 Short-chain fatty acids activate GPR41 and GPR43 on intestinal epithelial cells to promote inflammatory responses in mice. Gastroenterology 853 23665276
2011 Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41). Proceedings of the National Academy of Sciences of the United States of America 833 21518883
2004 Short-chain fatty acids stimulate leptin production in adipocytes through the G protein-coupled receptor GPR41. Proceedings of the National Academy of Sciences of the United States of America 545 14722361
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
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
2018 The Anti-inflammatory Effects of Short Chain Fatty Acids on Lipopolysaccharide- or Tumor Necrosis Factor α-Stimulated Endothelial Cells via Activation of GPR41/43 and Inhibition of HDACs. Frontiers in pharmacology 282 29875665
2010 Roles of GPR41 and GPR43 in leptin secretory responses of murine adipocytes to short chain fatty acids. FEBS letters 259 20399779
2016 GPR41 and GPR43 in Obesity and Inflammation - Protective or Causative? Frontiers in immunology 241 26870043
2009 Expression of short-chain fatty acid receptor GPR41 in the human colon. Biomedical research (Tokyo, Japan) 241 19574715
2013 Effects of short chain fatty acid producing bacteria on epigenetic regulation of FFAR3 in type 2 diabetes and obesity. Gene 209 24325907
2015 Expression of the short chain fatty acid receptor GPR41/FFAR3 in autonomic and somatic sensory ganglia. Neuroscience 204 25637492
2012 Short-chain free fatty acid receptors FFA2/GPR43 and FFA3/GPR41 as new potential therapeutic targets. Frontiers in endocrinology 204 23060857
2017 Short-chain fatty acids, GPR41 and GPR43 ligands, inhibit TNF-α-induced MCP-1 expression by modulating p38 and JNK signaling pathways in human renal cortical epithelial cells. Biochemical and biophysical research communications 169 28322790
2020 Sodium butyrate attenuated neuronal apoptosis via GPR41/Gβγ/PI3K/Akt pathway after MCAO in rats. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 154 32151222
2020 Anti-neuroinflammatory Effect of Short-Chain Fatty Acid Acetate against Alzheimer's Disease via Upregulating GPR41 and Inhibiting ERK/JNK/NF-κB. Journal of agricultural and food chemistry 150 32583667
2017 Soluble Fibre Meal Challenge Reduces Airway Inflammation and Expression of GPR43 and GPR41 in Asthma. Nutrients 145 28075383
2019 Dietary short-chain fatty acid intake improves the hepatic metabolic condition via FFAR3. Scientific reports 128 31719611
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 A unique polysaccharide from Hericium erinaceus mycelium ameliorates acetic acid-induced ulcerative colitis rats by modulating the composition of the gut microbiota, short chain fatty acids levels and GPR41/43 respectors. International immunopharmacology 108 31059977
2012 Male mice that lack the G-protein-coupled receptor GPR41 have low energy expenditure and increased body fat content. The British journal of nutrition 98 23110765
2009 Identification and characterization of the bovine G protein-coupled receptor GPR41 and GPR43 genes. Journal of dairy science 87 19448003
2012 Short-chain fatty acid receptor GPR41-mediated activation of sympathetic neurons involves synapsin 2b phosphorylation. FEBS letters 86 22673524
2017 FFAR2-FFAR3 receptor heteromerization modulates short-chain fatty acid sensing. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 83 28883043
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
2021 Vagal neuron expression of the microbiota-derived metabolite receptor, free fatty acid receptor (FFAR3), is necessary for normal feeding behavior. Molecular metabolism 74 34626852
2014 Regulation of Energy Homeostasis by GPR41. Frontiers in endocrinology 73 24904531
2024 GPR41 and GPR43: From development to metabolic regulation. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 69 38744220
2012 Butyrate-induced GPR41 activation inhibits histone acetylation and cell growth. Journal of genetics and genomics = Yi chuan xue bao 65 22884094
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 Polysaccharides from Tetrastigma Hemsleyanum Diels et Gilg ameliorated inflammatory bowel disease by rebuilding the intestinal mucosal barrier and inhibiting inflammation through the SCFA-GPR41/43 signaling pathway. International journal of biological macromolecules 56 37558022
2018 A short-chain fatty acid, propionate, enhances the cytotoxic effect of cisplatin by modulating GPR41 signaling pathways in HepG2 cells. Oncotarget 56 30140374
2001 Orphan G protein-coupled receptor, GPR41, induces apoptosis via a p53/Bax pathway during ischemic hypoxia and reoxygenation. The Journal of biological chemistry 53 11335718
2024 Abnormalities in microbiota/butyrate/FFAR3 signaling in aging gut impair brain function. JCI insight 51 38329121
2022 Propionate alleviates myocardial ischemia-reperfusion injury aggravated by Angiotensin II dependent on caveolin-1/ACE2 axis through GPR41. International journal of biological sciences 47 35002530
2014 Short-chain fatty acids and acidic pH upregulate UT-B, GPR41, and GPR4 in rumen epithelial cells of goats. American journal of physiology. Regulatory, integrative and comparative physiology 43 25519731
2014 Butyrate increases intracellular calcium levels and enhances growth hormone release from rat anterior pituitary cells via the G-protein-coupled receptors GPR41 and 43. PloS one 41 25310566
2018 Short-chain fatty acids induce tissue plasminogen activator in airway epithelial cells via GPR41&43. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 38 29431874
2020 Sodium butyrate promotes milk fat synthesis in bovine mammary epithelial cells via GPR41 and its downstream signalling pathways. Life sciences 37 32891612
2022 Regulator of G-Protein Signaling-4 Attenuates Cardiac Adverse Remodeling and Neuronal Norepinephrine Release-Promoting Free Fatty Acid Receptor FFAR3 Signaling. International journal of molecular sciences 35 35628613
2022 Butyrate Attenuates Hepatic Steatosis Induced by a High-Fat and Fiber-Deficient Diet via the Hepatic GPR41/43-CaMKII/HDAC1-CREB Pathway. Molecular nutrition & food research 34 36382553
2025 Time-restricted feeding mitigates Alzheimer's disease-associated cognitive impairments via a B. pseudolongum-propionic acid-FFAR3 axis. iMeta 32 40236783
2017 IL-1β and TNFα inhibit GPR120 (FFAR4) and stimulate GPR84 (EX33) and GPR41 (FFAR3) fatty acid receptor expression in human adipocytes: implications for the anti-inflammatory action of n-3 fatty acids. Archives of physiology and biochemistry 31 28835131
2025 Gut Microbiota Metabolites Sensed by Host GPR41/43 Protect Against Hypertension. Circulation research 30 39840468
2018 Microbial fermentation of flaxseed fibers modulates the transcriptome of GPR41-expressing enteroendocrine cells and protects mice against diet-induced obesity. American journal of physiology. Endocrinology and metabolism 29 30562060
2018 Gut carbohydrate inhibits GIP secretion via a microbiota/SCFA/FFAR3 pathway. The Journal of endocrinology 28 30400014
2021 Structural characterization of polysaccharide from yellow sweet potato and ameliorates DSS-induced mice colitis by active GPR41/MEK/ERK 1/2 signaling pathway. International journal of biological macromolecules 25 34597702
2019 Modulatory effect of Lactobacillus acidophilus KLDS 1.0738 on intestinal short-chain fatty acids metabolism and GPR41/43 expression in β-lactoglobulin-sensitized mice. Microbiology and immunology 25 31218724
2009 Sequence polymorphisms provide a common consensus sequence for GPR41 and GPR42. DNA and cell biology 25 19630535
2020 The short-chain free fatty acid receptor FFAR3 is expressed and potentiates contraction in human airway smooth muscle. American journal of physiology. Lung cellular and molecular physiology 24 32209026
2017 Ligands at the Free Fatty Acid Receptors 2/3 (GPR43/GPR41). Handbook of experimental pharmacology 24 27757758
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
2023 The propionate-GPR41 axis in infancy protects from subsequent bronchial asthma onset. Gut microbes 21 37131293
2019 Sodium Butyrate Modulates Mucosal Inflammation Injury Mediated by GPR41/43 in the Cecum of Goats Fed a High Concentration Diet. Frontiers in physiology 19 31543829
2022 Bone loss is ameliorated by fecal microbiota transplantation through SCFA/GPR41/ IGF1 pathway in sickle cell disease mice. Scientific reports 18 36450880
2020 AR420626, a selective agonist of GPR41/FFA3, suppresses growth of hepatocellular carcinoma cells by inducing apoptosis via HDAC inhibition. Therapeutic advances in medical oncology 18 33014144
2017 Cloning, molecular characterization, and spatial and developmental expression analysis of GPR41 and GPR43 genes in New Zealand rabbits. Animal : an international journal of animal bioscience 17 28241897
2018 Selective tracking of FFAR3-expressing neurons supports receptor coupling to N-type calcium channels in mouse sympathetic neurons. Scientific reports 14 30478340
2019 Microbial community shifts elicit inflammation in the caecal mucosa via the GPR41/43 signalling pathway during subacute ruminal acidosis. BMC veterinary research 13 31426783
2024 Lacticaseibacillus plantarum postbiotics prepared by the combined technique of pasteurization and ultrasound: effective measures to alleviate obesity based on the SCFAs-GPR41/GPR43 signaling pathway. Food & function 12 39420807
2023 Sodium acetate regulates milk fat synthesis through the activation of GPR41/GPR43 signaling pathway. Frontiers in nutrition 12 36969813
2023 3-(4-Hydroxy-3-methoxyphenyl) propionic acid contributes to improved hepatic lipid metabolism via GPR41. Scientific reports 11 38040866
2025 Preconception maternal gut dysbiosis affects enteric nervous system development and disease susceptibility in offspring via the GPR41-GDNF/RET/SOX10 signaling pathway. iMeta 10 40236770
2024 Differential Modulation of Catecholamine and Adipokine Secretion by the Short Chain Fatty Acid Receptor FFAR3 and α2-Adrenergic Receptors in PC12 Cells. International journal of molecular sciences 10 38791266
2024 The short-chain fatty acid receptors Gpr41/43 regulate bone mass by promoting adipogenic differentiation of mesenchymal stem cells. Frontiers in endocrinology 10 39363899
2023 Breast milk jaundice affects breastfeeding: From the perspective of intestinal flora and SCFAs-GPR41/43. Frontiers in nutrition 9 36895274
2020 Molecular characterization of free fatty acid receptors FFAR2 and FFAR3 in the domestic cat. Veterinary medicine and science 9 32929853
2023 GPR41 Regulates the Proliferation of BRECs via the PIK3-AKT-mTOR Pathway. International journal of molecular sciences 8 36835615
2014 Uptake of the butyrate receptors, GPR41 and GPR43, in lipidic bicontinuous cubic phases suitable for in meso crystallization. Journal of colloid and interface science 8 25490566
2022 The Cognitive Improvement and Alleviation of Brain Hypermetabolism Caused by FFAR3 Ablation in Tg2576 Mice Is Persistent under Diet-Induced Obesity. International journal of molecular sciences 7 36362376
2020 Morphological elucidation of short-chain fatty acid receptor GPR41-positive enteric sensory neurons in the colon of mice with dextran sulfate sodium-induced colitis. Heliyon 7 33319102
2024 GPR41 deficiency aggravates type 1 diabetes in streptozotocin-treated mice by promoting dendritic cell maturation. Acta pharmacologica Sinica 6 38514862
2024 GPR41 and GPR43 regulate CD8+ T cell priming during herpes simplex virus type 1 infection. Frontiers in immunology 6 38524121
2022 Seasonal expressions of GPR41 and GPR43 in the colon of the wild ground squirrels (<em>Spermophilus dauricus</em>). European journal of histochemistry : EJH 6 35057584
2022 Overexpression of GPR41 attenuated glucose production in propionate-induced bovine hepatocytes. Frontiers in veterinary science 6 36118357
2024 Carvacrol improves blood lipid and glucose in rats with type 2 diabetes mellitus by regulating short-chain fatty acids and the GPR41/43 pathway. The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology 5 38154959
2025 Acidipropionibacterium acidipropionici, a propionate-producing bacterium, contributes to GPR41 signaling and metabolic regulation in high-fat diet-induced obesity in mice. Frontiers in nutrition 4 40248033
2023 Gαi -coupled GPR41 activation increases Ca2+ influx in C2C12 cells and shows a therapeutic effect in diabetic animals. Obesity (Silver Spring, Md.) 4 37309717
2020 Expression of FFAR3 and FFAR4 Is Increased in Gastroesophageal Reflux Disease. Journal of clinical medicine 4 33419235
2025 Gut microbiota-derived butyrate prevents aortic dissection via GPR41. Acta pharmacologica Sinica 3 40550961
2025 Tryptophan-Rich Diet Improves High-Fat Diet-Induced Cognitive Dysfunction and Blood-Brain Barrier Disruption in C57BL/6 Mice through FFAR3 Activation. Journal of agricultural and food chemistry 3 40600293
2024 Modified Zuo Gui Wan Ameliorates Ovariectomy-Induced Osteoporosis in Rats by Regulating the SCFA-GPR41-p38MAPK Signaling Pathway. Drug design, development and therapy 3 39741920
2021 The Specificity and Broad Multitarget Properties of Ligands for the Free Fatty Acid Receptors FFA3/GPR41 and FFA2/GPR43 and the Related Hydroxycarboxylic Acid Receptor HCA2/GPR109A. Pharmaceuticals (Basel, Switzerland) 3 34681211
2025 The Pro-vs. Anti-Angiogenic Capacity of Short Chain Fatty Acids is Dependent on the Bioavailability of FFAR3 in Peripheral Artery Disease. bioRxiv : the preprint server for biology 2 40060555
2025 Gut Microbiota-Derived Lipopolysaccharides and Short-Chain Fatty Acids Regulate Immune Responses via FFAR2/FFAR3 in Lung Ischemia-Reperfusion Injury. Annals of the New York Academy of Sciences 2 41031863
2025 Corrigendum: The short-chain fatty acid receptors Gpr41/43 regulate bone mass by promoting adipogenic differentiation of mesenchymal stem cells. Frontiers in endocrinology 1 39839472
2025 Aberrant Reduction of Short-Chain Fatty Acid (SCFA) Receptor GPR41 and Transporter MCT4 in Prion-Infected Rodent and Cell Models. ACS chemical neuroscience 1 40340312
2025 Abdominal Massage Decreases Food Intake and Body Weight in High-Fat Diet-Induced Obese Rats Through Upregulating GPR41/GPR43-PYY/GLP-1 Axis. Diabetes, metabolic syndrome and obesity : targets and therapy 1 40416929
2025 High-Fat Diet-Induced Gut Microbiota Disruption Promotes Colorectal Cancer Lymphatic Metastasis via Propionate/GPR41 Signaling. Digestion 1 40435940
2024 Structure-activity relationship studies of tetrahydroquinolone derivatives as GPR41 modulators. Bioorganic & medicinal chemistry letters 1 38641152
2026 Metabolic benefits of 1,3-diacylglycerol in type 2 diabetes mellitus and its association with gut microbiota-derived SCFAs-GPR41-GLP-1 signaling. Food & function 0 41405391
2026 Genetic diversity of Collaborative Cross mice implicates FFAR3 as a target for ILC2 anti-inflammatory reprogramming. Nature communications 0 41484153
2026 Aucubin Restores Intestinal Mucosal Immunity and Barrier Integrity in Experimental Colitis via the Microbiota-SCFAs-GPR41/GPR43 Axis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 0 41677424
2025 Effective mechanism of polysaccharides from Erxian herbal pair in promoting bone repair in traumatic osteomyelitis by activating osteoblast GPR41 and inhibiting the MEK/ERK/MAPK signalling axis. International journal of biological macromolecules 0 40058443
2025 GPR41 and GPR43 modulate rodent pancreatic α-cell function and growth. Life sciences 0 40818660
2025 Gut Acetic Acid Alleviates Cognitive Impairment by Inhibiting Tau Hyperphosphorylation via Regulating FFAR3/Erk Pathway in Chronic Cerebral Ischemia Mice. Molecular neurobiology 0 41276732
2025 Sodium butyrate attenuates early brain injury and neuronal apoptosis after subarachnoid hemorrhage in rats via GPR41/PI3K/Akt pathway. Neuroreport 0 41342722
2025 GPR41 deficiency alters the gut microbiota-bile acid axis, reduces ileal expression of Npc1l1, and attenuates hypercholesterolemia in male mice. Gut microbes 0 41395766
2024 Role of FFAR3 in ketone body regulated glucagon-like peptide 1 secretion. Biochemistry and biophysics reports 0 38910871