Affinage

FFAR4

Free fatty acid receptor 4 · UniProt Q5NUL3

Length
361 aa
Mass
40.5 kDa
Annotated
2026-04-28
100 papers in source corpus 37 papers cited in narrative 38 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FFAR4 (GPR120) is a G-protein-coupled receptor for long-chain unsaturated fatty acids—particularly omega-3 species such as DHA and EPA—that integrates lipid sensing with metabolic homeostasis, adipocyte differentiation, incretin hormone secretion, and anti-inflammatory signaling across diverse cell types. Ligand binding activates dual G-protein branches: a Gq/11 pathway coupling through PLC/Ca²⁺/CaMKK/AMPK to drive cholesterol efflux, hepatic SREBP-1c suppression, and cellular senescence regulation, and a Gi/Go pathway that suppresses cAMP to inhibit lipolysis in white adipocytes as an autocrine negative-feedback mechanism (PMID:33091626, PMID:32243091, PMID:29126901, PMID:36450712). A parallel β-arrestin-2 branch mediates anti-inflammatory effects by sequestering TAB1 from the TAK1–IKKβ–NF-κB cascade in macrophages, intestinal epithelial cells, podocytes, and microglia, and also suppresses NLRP3 inflammasome assembly (PMID:20813258, PMID:26791484, PMID:33436541). TULP3-dependent localization of FFAR4 to primary cilia in preadipocytes generates a compartmentalized cAMP/EPAC signal that remodels chromatin at the PPARγ and C/EBPα loci to initiate adipogenesis, while a reciprocal transcriptional loop links PPARγ activity to FFAR4 expression and FGF21-dependent thermogenic programs in brown and beige fat (PMID:31761534, PMID:32413335, PMID:27853148). A human loss-of-function variant (p.R270H) that selectively impairs G-protein but not β-arrestin signaling is associated with increased obesity risk (PMID:22343897, PMID:27068006).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2007 Medium

    Establishing that FFAR4 is expressed in adipose tissue and functionally required for adipocyte differentiation addressed the initial question of whether this orphan GPCR participates in adipogenesis.

    Evidence siRNA knockdown in 3T3-L1 cells blocked adipocyte differentiation; qRT-PCR showed upregulation during differentiation

    PMID:17250804

    Open questions at the time
    • No ligand specificity determined
    • Signaling pathway downstream of GPR120 in adipogenesis unknown
    • Single cell line, no in vivo validation
  2. 2010 High

    Identification of GPR120 as the functional receptor mediating omega-3 fatty acid anti-inflammatory and insulin-sensitizing effects answered the long-standing question of how DHA/EPA exert their metabolic benefits, and established the β-arrestin-2/TAB1 sequestration mechanism.

    Evidence siRNA in macrophages and GPR120-KO mice; high-fat diet with omega-3 supplementation; inflammatory and insulin signaling readouts

    PMID:20813258

    Open questions at the time
    • Tissue-specific contributions of GPR120 not resolved
    • Relative importance of G-protein vs β-arrestin branches unclear
  3. 2010 High

    Demonstrating GPR120 expression in taste bud cells and its requirement for fatty acid taste preference revealed a sensory role beyond metabolic tissues.

    Evidence GPR120-KO mice showed diminished fatty acid preference and reduced taste nerve responses; immunohistochemistry in type II taste cells

    PMID:20573884

    Open questions at the time
    • Downstream signaling in taste cells not characterized
    • Relative contribution of GPR40 vs GPR120 in fat taste not fully delineated
  4. 2012 High

    The finding that GPR120-KO mice develop diet-induced obesity and metabolic syndrome, combined with identification of a human loss-of-function variant (p.R270H) associated with obesity, established GPR120 as a metabolically protective receptor in both species.

    Evidence GPR120-KO mouse metabolic phenotyping on HFD; human exon sequencing with functional signaling assays for R270H

    PMID:22343897

    Open questions at the time
    • Mechanism by which R270H impairs signaling not resolved at structural level
    • Penetrance and effect size of R270H in diverse populations unknown
  5. 2014 High

    Multiple studies resolved cell-type-specific hormonal roles: GPR120 in pancreatic δ-cells inhibits somatostatin secretion, in intestinal K-cells drives GIP release, and modulates glucagon secretion from α-cells, placing it as a central fatty acid sensor in islet and gut endocrine function.

    Evidence GPR120-KO mice with islet hormone secretion assays; GIP-GFP K-cell purification; pharmacological inhibition; arginine stimulation and glucagon challenge tests

    PMID:24663807 PMID:24742677 PMID:25535828

    Open questions at the time
    • Intracellular signaling cascades in δ-cells and K-cells not fully delineated
    • Whether GPR120 signals through Gq or Gi in each endocrine cell type not resolved
  6. 2014 Medium

    Mechanistic dissection of the anti-inflammatory branch showed that agonist-induced GPR120 internalization recruits β-arrestin-2 which sequesters TAB1, blocking TAK1–IKKβ–NF-κB signaling; a parallel cPLA2/COX-2/PGE2/EP4 pathway was identified as an additional anti-inflammatory route in macrophages.

    Evidence β-arrestin-2 siRNA in Caco-2 and STC-1 cells; cPLA2 and COX-2 inhibitors with EP4 knockdown in RAW264.7 and primary macrophages

    PMID:24673159 PMID:24674717 PMID:26791484

    Open questions at the time
    • Relative contribution of β-arrestin-2/TAB1 vs PGE2/EP4 branches not quantified
    • Structural basis of β-arrestin-2–TAB1 interaction not defined
  7. 2014 Medium

    Discovery that oleic acid activates FFAR4 in hepatocytes to stimulate lipid droplet formation via a pertussis-toxin-sensitive (Gi) pathway through PI3K/AKT/PLD established a hepatic lipid storage role distinct from the anti-inflammatory mechanism.

    Evidence Pertussis toxin and PI3K/AKT/PLD inhibitors; FFAR4 knockdown; lipid droplet quantification in Huh-7 cells

    PMID:24876224

    Open questions at the time
    • In vivo hepatic lipid droplet phenotype in FFAR4-KO not assessed
    • Relationship to hepatic steatosis protection or promotion unclear
  8. 2016 High

    GPR120 was shown to promote brown adipose tissue activation and white fat browning through FGF21 as a downstream effector, and to mediate omega-3 fatty acid bone-protective effects in both osteoblasts and osteoclasts, broadening its role to thermogenesis and skeletal biology.

    Evidence GPR120-null × FGF21-null epistasis mice; fat-1 × FFA4-KO genetic crosses; bone histomorphometry; RNA-seq; thermogenesis assays

    PMID:27145004 PMID:27853148

    Open questions at the time
    • Whether FGF21 is direct transcriptional target of GPR120 signaling not confirmed by ChIP
    • Bone cell–specific signaling pathway downstream of FFAR4 not fully mapped
  9. 2016 Medium

    Functional characterization of the human R270H variant revealed selective impairment of Gq and Gi signaling with preserved β-arrestin recruitment, providing a molecular explanation for the obesity association and demonstrating pathway-biased signaling.

    Evidence Surface expression, Gq/Gi signaling, and β-arrestin recruitment assays in transfected cells

    PMID:27068006

    Open questions at the time
    • No structural model explaining R270H selectivity
    • Metabolic consequences of biased signaling not tested in vivo
  10. 2017 High

    Tissue-specific KO studies and bidirectional regulation with PPARγ established that GPR120 both upregulates PPARγ (via 15d-PGJ2 production and ERK inhibition) and is itself a PPARγ transcriptional target, creating a positive-feedback adipogenic/anti-inflammatory loop; Gi-mediated cAMP suppression was identified as the mechanism for lipolysis inhibition.

    Evidence Macrophage- and adipocyte-specific GPR120-KO mice; PPARγ ChIP; 15d-PGJ2 measurements; mini-G protein assays; cAMP accumulation; NEFA and glycerol measurements in FFAR4-KO mice

    PMID:28583918 PMID:32413335 PMID:33091626

    Open questions at the time
    • Whether the PPARγ–GPR120 loop operates in all adipose depots not determined
    • Kinetics and regulation of the autocrine lipolysis feedback loop not characterized
  11. 2019 High

    The discovery that FFAR4 localizes to primary cilia via TULP3, where it generates compartmentalized cAMP/EPAC signaling to remodel chromatin at PPARγ/C/EBPα loci, answered how a GPCR could initiate the transcriptional program of adipogenesis from a specific subcellular compartment.

    Evidence Cilia-specific ablation in mice; TULP3 manipulation; live-cell ciliary cAMP imaging; EPAC/CTCF chromatin remodeling assays; adipogenesis rescue experiments

    PMID:31761534

    Open questions at the time
    • Whether ciliary signaling is conserved in human preadipocytes not shown
    • How TULP3 specifically recognizes FFAR4 for ciliary trafficking not resolved
    • Whether other FFAR4 functions (anti-inflammatory, incretin) also require ciliary localization unknown
  12. 2020 Medium

    GPR120 was found to facilitate macrophage cholesterol efflux through PLC/Ca²⁺/CaMKK/AMPK-mediated upregulation of ABCA1/ABCG1, and to physically bind NLRP3 to inhibit inflammasome assembly, extending anti-inflammatory mechanisms beyond TAB1 sequestration.

    Evidence siRNA knockdown with PLC/CaMKK/AMPK inhibitors; cholesterol efflux assays; Co-IP of GPR120 with NLRP3; pyroptosis markers in Kupffer cells

    PMID:32243091 PMID:33436541

    Open questions at the time
    • GPR120–NLRP3 interaction shown by single Co-IP without reciprocal validation
    • Whether AMPK-dependent cholesterol efflux is relevant in vivo for atherosclerosis not tested
  13. 2021 High

    GPR120 activation in CD4⁺ T cells was shown to upregulate IL-10 via mTOR-driven glycolysis and Blimp1, establishing an adaptive immune anti-inflammatory role beyond innate immune cells.

    Evidence GPR120-deficient CD4⁺ T cell adoptive transfer colitis model; RNA-seq; Seahorse metabolic flux; IL-10-KO and Blimp1-KO epistasis

    PMID:34536451

    Open questions at the time
    • Whether this T cell mechanism operates in tissues other than the colon not tested
    • Direct vs indirect mTOR activation by GPR120 not resolved
  14. 2022 High

    FFAR4 signaling through Gq/CaMKKβ/AMPK was shown to maintain SirT3 expression and protect against cellular senescence in renal tubular epithelial cells, and oleic/linoleic acid were identified as endogenous islet GPR120 agonists with β-arrestin-2-dependent biased signaling controlling somatostatin release.

    Evidence Conditional TEC-specific FFAR4-KO mice with cisplatin AKI model; GPR120-KO islets with specific fatty acid stimulation and β-arrestin2 functional assays

    PMID:35472681 PMID:36450712

    Open questions at the time
    • Whether SirT3 maintenance is relevant outside of kidney injury not known
    • Structural basis for biased agonism by different fatty acid species at GPR120 unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major open questions include the structural basis for ligand-selective biased agonism at FFAR4, how ciliary versus plasma-membrane pools of the receptor are differentially regulated, and whether the diverse tissue-specific functions can be therapeutically targeted with pathway-biased agonists.
  • No high-resolution structure of FFAR4 with agonist or G-protein/β-arrestin complexes
  • Pharmacological separation of Gq, Gi, and β-arrestin arms not achieved in vivo
  • Ciliary signaling mechanism not tested in human tissues

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 8 GO:0008289 lipid binding 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 3 GO:0005929 cilium 1
Pathway
R-HSA-162582 Signal Transduction 9 R-HSA-168256 Immune System 7 R-HSA-1430728 Metabolism 6 R-HSA-8963743 Digestion and absorption 4 R-HSA-1266738 Developmental Biology 3
Partners
ARRB2GNAI1GNAQNLRP3PRKAA1TAB1TULP3

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 GPR120/FFAR4 functions as an omega-3 fatty acid (DHA, EPA) receptor/sensor in macrophages and adipocytes; stimulation produces broad anti-inflammatory effects and insulin sensitization that are abrogated by GPR120 knockdown or knockout, establishing GPR120 as the functional mediator of omega-3 FA anti-inflammatory signaling. siRNA knockdown in RAW264.7 cells and primary macrophages; GPR120 knockout mouse model; high-fat diet with omega-3 FA supplementation; inflammatory and insulin signaling readouts Cell High 20813258
2010 GPR120 and GPR40 are expressed in taste bud cells (mainly type II cells for GPR120) and mediate fatty acid taste preference; GPR120 knockout mice show diminished preference for linoleic and oleic acid and reduced taste nerve responses to fatty acids. GPR120 KO mouse behavioral preference tests; taste nerve recordings; immunohistochemistry of taste bud cell types The Journal of neuroscience High 20573884
2012 GPR120-deficient mice fed a high-fat diet develop obesity, glucose intolerance, fatty liver, decreased adipocyte differentiation, and enhanced hepatic lipogenesis; insulin resistance is associated with reduced insulin signaling and enhanced adipose tissue inflammation. A human loss-of-function mutation (p.R270H) inhibits GPR120 signaling activity and associates with increased obesity risk. GPR120 knockout mouse model; high-fat diet; metabolic phenotyping; human exon sequencing and functional signaling assays Nature High 22343897
2007 GPR120 mRNA is highly expressed in adipose tissue and its expression increases during adipocyte differentiation; siRNA-mediated knockdown of GPR120 in 3T3-L1 cells inhibits adipocyte differentiation, establishing a functional role for GPR120 in adipogenesis. siRNA knockdown; 3T3-L1 adipocyte differentiation assay; qRT-PCR in mouse and human adipose tissue Biochemical and biophysical research communications Medium 17250804
2014 GPR120/FFAR4 is preferentially expressed in pancreatic delta cells and selective GPR120 agonists inhibit glucose-induced somatostatin secretion; this response is absent in GPR120-knockout mice, establishing GPR120 as a regulator of somatostatin secretion from islet delta cells. GPR120 KO/LacZ knock-in mouse; β-galactosidase activity and immunofluorescence co-localization; islet hormone secretion assays with selective GPR120 agonists Diabetologia High 24663807
2014 GPR120 is highly expressed in enteroendocrine K cells of the upper small intestine and is critical for lipid-induced GIP secretion; GPR120-deficient mice show 75% reduction in GIP secretion after lard oil ingestion, and pharmacological inhibition of GPR120 in wild-type mice also attenuates GIP secretion. GIP-GFP knock-in mice to purify K cells; GPR120 KO mice; oral fat challenge; pharmacological inhibition with grifolic acid methyl ether Endocrinology High 25535828
2014 GPR120 activation by omega-3 FA leads to receptor interaction with β-arrestin-2, which then associates with TAB1, sequestering TAB1 from the TAK1-IKKβ-NF-κB inflammatory signaling cascade to produce anti-inflammatory effects in intestinal epithelial Caco-2 cells; this effect requires β-arrestin-2 and is absent when β-arrestin-2 is silenced. siRNA knockdown of β-arrestin-2; receptor internalization assays; NF-κB activation assays in Caco-2 and STC-1 cells American journal of physiology. Cell physiology Medium 26791484
2014 DHA activates cPLA2 via GPR120 receptor, G protein Gαq, and scaffold protein β-arrestin-2, leading to COX-2 activation and PGE2 release in macrophages; the resulting PGE2 acts through EP4 receptors to inhibit NF-κB signaling and reduce LPS-induced IL-6, contributing to anti-inflammatory effects. cPLA2 inhibitor and COX-2 inhibitor studies; siRNA knockdown of EP4; pharmacological dissection with specific inhibitors; RAW264.7 cells and primary human macrophages Immunology Medium 24673159
2014 GPR120 activation in hypothalamic neurons mediates anti-inflammatory actions of DHA; DHA activates both AKT and ERK signaling via GPR120, but the anti-inflammatory mechanism is AKT- and ERK-independent and likely involves the GPR120-TAB1 interaction. GPR120 knockdown by siRNA in immortalized rat hypothalamic rHypoE-7 neurons; phospho-specific antibody western blots; qRT-PCR for inflammatory cytokines Journal of neuroinflammation Medium 24674717
2014 GPR120 activation mediates anti-apoptotic effects in PC12 cells and anti-inflammatory effects in microglia via β-arrestin2 interaction; GPR120 knockdown abolishes DHA anti-inflammatory and anti-apoptotic effects in OGD models. GPR120 siRNA knockdown in BV2 microglia and PC12 cells; OGD model; β-arrestin2 interaction assays; MCAO mouse model for in vivo validation Journal of immunology Medium 30598514
2014 GPR120 knockout mice show altered glucagon secretion: palmitate- and DHA-potentiated glucagon secretion is greatly reduced in isolated GPR120 KO islets; GPR120 KO mice also display a hyperactive counter-regulatory response, increased glucagon sensitivity in the liver, and impaired glucose homeostasis linked to altered glucagon axis rather than solely insulin resistance. GPR120 KO mice; isolated islet hormone secretion assays; arginine stimulation test; glucagon challenge; insulin tolerance tests; hyperinsulinemic-euglycemic clamp The Journal of biological chemistry High 24742677
2014 Oleic acid stimulates lipid droplet formation in Huh-7 cells by activating FFAR4/GPR120, which signals through a pertussis-toxin-sensitive G-protein pathway involving PI3-kinase, AKT, and phospholipase D; this initial lipid droplet formation is not dependent on exogenous lipid uptake. Pertussis toxin treatment; PI3-kinase, AKT, and PLD inhibitors; FFAR4 knockdown; lipid droplet quantification in Huh-7 cells Journal of cell science Medium 24876224
2014 CD36 and GPR120 have nonoverlapping roles in Ca2+ signaling in human fungiform taste bud cells; high concentrations of linoleic acid activate Ca2+ signaling via both CD36 and GPR120, while low concentrations signal only via CD36. siRNA knockdown of each receptor selectively abolishes the corresponding Ca2+ response. GPR120 activation also mediates GLP-1 release. siRNA knockdown of CD36 and GPR120; Ca2+ imaging; CD36-KO mice; GLP-1 release assays; STC-1 cell model Gastroenterology Medium 24412488
2016 GPR120 promotes brown adipose tissue activation and induces FGF21 release from brown and beige adipocytes; GPR120 activation induces BAT activity and browning of white fat, effects impaired in FGF21-null mice, establishing FGF21 as a downstream mediator of GPR120-induced thermogenesis. GPR120-null mice; FGF21-null mice; RNA-seq; adipocyte differentiation and thermogenesis assays; plasma FGF21 measurements Nature communications High 27853148
2016 EPA activates FFAR4/GPR120 in brown preadipocytes to upregulate miR-30b and miR-378 and elevate cAMP, promoting brown adipogenesis and thermogenesis (UCP1 expression); these effects are abrogated in FFAR4-silenced cells, and locked nucleic acid inhibitors of miR-30b/378 attenuate FFAR4-mediated brown adipogenic programs. FFAR4 siRNA knockdown; miRNA mimic and locked nucleic acid inhibitors; oxygen consumption rate measurements; brown preadipocyte differentiation; cAMP measurements The Journal of biological chemistry Medium 27489163
2019 TULP3-dependent ciliary localization of FFAR4/GPR120 in preadipocytes promotes adipogenesis; omega-3 fatty acids and FFAR4 agonists, but not saturated fatty acids, trigger cAMP production inside cilia, activating EPAC signaling, CTCF-dependent chromatin remodeling, and transcriptional activation of PPARγ and CEBPα to initiate adipogenesis. Abolishing preadipocyte cilia severely impairs white adipose tissue expansion. Cilia-specific ablation in mice; TULP3 manipulation; live cell imaging of ciliary cAMP; EPAC signaling assays; chromatin remodeling assays; adipogenesis assays; FFAR4 localization studies Cell High 31761534
2017 GPR120 is a PPARγ target gene in adipocytes (PPARγ agonism upregulates GPR120), while GPR120 conversely augments PPARγ activity by inducing the endogenous ligand 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) and by blocking ERK-mediated phosphorylation/inhibition of PPARγ; macrophage- and adipocyte-specific GPR120 KO mice show distinct anti-inflammatory and insulin-sensitizing roles. Macrophage-specific and adipocyte-specific GPR120 KO mice; PPARγ ChIP; 15d-PGJ2 measurement; ERK phosphorylation assays; glucose tolerance and insulin sensitivity tests Cell metabolism High 32413335
2017 GPR120 activation suppresses lipolysis in primary white adipocytes by decreasing intracellular cAMP through Gi-mediated signaling; in vivo, FFAR4-deficient mice show elevated plasma NEFAs and glycerol consistent with increased lipolysis, and GPR120 functions as an autocrine, NEFA-activated negative feedback regulator of lipolysis. Mini G protein binding assays (Gi, Go, Gq) in transfected cells; cAMP accumulation assays; in vivo NEFA measurements in FFAR4-KO mice; selective FFAR4 antagonist AH7614; primary murine adipocyte cultures Journal of lipid research High 28583918 33091626
2017 GPR120-mediated GIP secretion from K cells is partially indirectly mediated by CCK: GPR120 KO mice show reduced CCK levels and impaired gallbladder contraction, and CCK analog treatment restores oil-induced GIP secretion in GPR120 KO mice but not GPR40 KO mice. GPR120 KO and GPR40 KO mice; CCK analog administration; oil gavage; plasma GIP and CCK measurements; gallbladder contraction measurements Endocrinology Medium 28324023
2016 DHA inhibits VEGF-induced migration of HUVECs through GPR120 by increasing PP2A enzyme activity and thereby decreasing ERK1/2 and eNOS phosphorylation; PP2A inhibitor okadaic acid reverses DHA's effects, placing GPR120-PP2A-ERK1/2-eNOS in the pathway for DHA inhibition of cell migration. PP2A activity assay; phospho-ERK1/2 and phospho-eNOS western blots; wound-healing migration assay; pharmacological inhibitors; GW9508 as GPR120 agonist Journal of agricultural and food chemistry Medium 24734983
2021 GPR120 endocytoses and physically binds to NLRP3 under LPS stimulation; DHA and arachidonic acid promote GPR120-NLRP3 interaction (shown by co-immunoprecipitation), thereby inhibiting NLRP3 inflammasome self-assembly and Kupffer cell pyroptosis. Co-immunoprecipitation of GPR120 with NLRP3; GPR120 siRNA knockdown; NLRP3 inflammasome assembly assays; pyroptosis markers (GSDMD, IL-1β, IL-18); in vivo hepatic injury model Cell death & disease Medium 33436541
2021 GPR120 regulates CD4+ T cell production of IL-10 by upregulating Blimp1 and enhancing glycolysis through mTOR signaling; GPR120 agonist-treated T cells fail to reduce colitis in IL-10-deficient and Blimp1-deficient backgrounds, establishing this pathway mechanistically. GPR120-deficient CD4+ T cell adoptive transfer colitis model; RNA sequencing; flow cytometry; Seahorse metabolic assays; IL-10-KO and Blimp1-KO mice as epistasis tools Gastroenterology High 34536451
2022 FFAR4 regulates cellular senescence in tubular epithelial cells via Gq subunit-mediated CaMKKβ/AMPK signaling to maintain SirT3 expression; pharmacological activation or overexpression of FFAR4 reverses cisplatin-induced decreases in SirT3 and senescence markers; conditional TEC-specific FFAR4 KO aggravates AKI. Systemic and conditional (TEC-specific) FFAR4 KO mice; FFAR4 overexpression; pharmacological activation with TUG-891; CaMKKβ/AMPK signaling assays; senescence markers (SA-β-gal, p53, p21, Lamin B1) Signal transduction and targeted therapy High 36450712
2022 Endogenous GPR120 in pancreatic δ-cells is activated by oleic acid and linoleic acid (identified as endogenous islet agonists); these LCFAs promote insulin secretion by inhibiting somatostatin secretion, with linoleic acid showing higher potency dependent on β-arrestin2 function; GPR120 signaling is impaired in db/db diabetic islets. GPR120 KO mouse islets; β-arrestin2 functional assays; insulin and somatostatin secretion measurements; glucose metabolism in db/db mice; OA and LA administration Diabetes Medium 35472681
2020 GPR120 activation facilitates ABCA1- and ABCG1-mediated cholesterol efflux in macrophages through a PLC/Ca2+/CaMKK/AMPK signaling cascade; AMPK activation induces neutral and acid cholesteryl ester hydrolysis and upregulates ABCA1/ABCG1 expression; GPR120 knockdown abolishes these effects. GPR120 siRNA knockdown; PLC inhibitor, calcium chelator, and CaMKK inhibitor; AMPK inhibitor; cholesterol efflux assays; ABCA1/ABCG1 expression; foam cell model in THP-1 and RAW264.7 cells The FEBS journal Medium 32243091
2015 GPR120 activation in BMMSCs determines bi-potential osteogenic/adipogenic differentiation in a ligand dose-dependent manner: high concentrations of TUG-891 promote osteogenesis via Ras-ERK1/2 signaling and upregulate integrin subunits α1, α2, β1, while low concentrations activate p38 and increase adipogenesis with upregulation of α5, β3 integrins. BMMSC osteogenic and adipogenic differentiation assays; ERK1/2 and p38 phosphorylation; integrin subunit expression; TUG-891 dose-response; in vivo estrogen-deficient bone loss model Scientific reports Medium 26365922
2017 DHA protects human hepatoma cells from LXR-mediated hepatic steatosis through FFA4/GPR120; the signaling cascade sequentially involves FFA4, Gq/11 proteins, CaMKK, and AMPK, leading to suppression of SREBP-1c; FFA4 siRNA knockdown and FFA4-antagonist (AH7614) abolish DHA-induced inhibition of lipid accumulation, and primary hepatocytes from FFA4-deficient mice fail to respond to DHA. FFA4 siRNA knockdown; AH7614 antagonist; FFA4 KO primary hepatocytes; lipid accumulation assays; CaMKK and AMPK pathway assays; SREBP-1c mRNA and protein Biochimica et biophysica acta. Molecular and cell biology of lipids Medium 29126901
2016 FFA4/GPR120 in bone mediates n-3 fatty acid effects on bone metabolism: FFA4 KO mice with high endogenous n-3 FA levels (via fat-1 transgene) lose the bone-protective effects (both stimulation of osteoblast bone formation and inhibition of osteoclast resorption) seen in wild-type fat-1 mice; in vitro studies confirm FFA4 activation by DHA in osteoclasts and osteoblasts. FFA4 KO × fat-1 transgenic mouse crosses; ovariectomy and high-fat diet bone loss models; bone histomorphometry; in vitro osteoclast and osteoblast assays Endocrinology High 27145004
2020 FFAR4 activation in podocytes suppresses diabetic nephropathy-associated inflammation and fibrosis by downregulating TAK1-binding protein-1 (TAB1) expression and inhibiting phosphorylation of TAK1, IKKβ, NF-κB p65, JNK, and p38 MAPK; GPR120 knockdown in podocytes produces opposite effects. TUG-891 agonist in db/db mice; GPR120 knockdown in MPC5 podocytes; phosphoprotein western blots; renal function and pathology measurements Acta pharmacologica Sinica Medium 32948825
2022 GPR120 overexpression reduces epileptic activity and neuronal death and downregulates NLRP3/Caspase-1/IL-1β inflammasome pathway; GPR120 knockdown exacerbates epileptic activity, and the effects of GPR120 knockdown are reversed by VX765 (Caspase-1 inhibitor), placing GPR120 upstream of the NLRP3/Caspase-1 axis. AAV-mediated GPR120 overexpression and knockdown; kainic acid epilepsy mouse model; VX765 Caspase-1 inhibitor; LFP recording; western blot; immunofluorescence Journal of neuroinflammation Medium 35624482
2016 p.R270H variant of FFAR4 reduces surface expression of FFAR4, eliminates ligand-independent activity, and strongly impairs Gq and Gi coupled signaling, but does not affect β-arrestin recruitment; this establishes a signaling-pathway-specific impact of the human obesity-associated mutation. In vitro surface expression assays; Gq and Gi signaling assays; β-arrestin recruitment assays in transfected cells Journal of medical genetics Medium 27068006
2020 FFAR4/GPR120 in white adipocytes preferentially signals through Gi and Go (over Gq) to inhibit cAMP accumulation and suppress lipolysis in an autocrine manner, triggered by NEFAs released during lipolysis; conditioned media from isoproterenol-stimulated adipocytes activates FFAR4 signaling in reporter cells. Mini G protein binding assays (Gi, Go-mini G proteins) in transfected 3T3-L1 cells; cAMP accumulation assays; LC-MS analysis of conditioned media; selective FFAR4 agonist (CpdA) and antagonist (AH7614); FFAR4 KO mice Molecular metabolism High 33091626
2020 10-hydroxy-2-decenoic acid (10H2DA), a component of royal jelly, directly binds to FFAR4 on osteoclasts, inhibiting RANKL-induced NF-κB signaling and thereby attenuating NFATc1 induction and osteoclastogenesis; identified by mass spectrometric fractionation and confirmed in vivo. RJ fractionation; mass spectrometry; FFAR4 binding assay; NF-κB signaling assays; NFATc1 expression; osteoclastogenesis assays; in vivo ovariectomized mouse model The Journal of biological chemistry Medium 32647011
2023 GPR120 mRNA is enriched in murine and human microglia; GPR120 agonism strongly attenuates LPS-induced TNF-α and IL-1β expression in primary microglia and inhibits NF-κB nuclear translocation; central administration of GPR120 agonist reduces neuroinflammation and sickness/anxiety-like behaviors in mice. In situ hybridization for GPR120 in microglia; primary microglial cultures with GPR120 agonist; NF-κB translocation assays; intracerebroventricular agonist administration; behavioral testing (locomotion, anxiety); TNF-α and IL-1β mRNA in nucleus accumbens Journal of neuroinflammation Medium 38111048
2021 In human colonic enteroendocrine cells, FFAR4 activates pCaMKII (distinct from GPR84 which activates pERK); co-activation of GPR84 and FFAR4 produces superadditive GLP-1 and PYY release via parallel intracellular pathways, and colonic delivery of combined agonists reduces energy intake and increases postprandial PYY in obese adults. Human colonic explants; immunostaining for phosphoproteins; co-activation experiments; randomized double-blind crossover clinical study with hormone measurements Gut Medium 34083384
2021 GPR120 activation by DHA and arachidonic acid protects hepatocytes from oxidative injury by promoting GPR120/ERK-mediated PINK/Parkin mitophagy; ERK1/2 signaling was reactivated by DHA and required for mitophagy induction. ERK1/2 inhibitor; PINK/Parkin mitophagy assays; ROS measurements; autophagic flux assays; in vitro H2O2 and in vivo CCl4 liver injury models International journal of molecular sciences Medium 34073582
2018 GPR120 promotes decidualization of human endometrial stromal cells by upregulating GLUT1-mediated glucose uptake and G6PD-mediated pentose phosphate pathway activity; FOXO1 is upregulated by GPR120 via ERK1/2 and AMPK signaling and increases GLUT1 expression. GPR120 KO mouse abortion models; HESCs and primary DSCs; GLUT1 and G6PD expression; glucose uptake assays; ERK1/2 and AMPK phosphorylation; FOXO1 expression; GPR120 agonist in vivo rescue EBioMedicine Medium 30578080
2020 GPR120 activation with GW9508 elevated ABCA1/ABCG1 expression and promoted cholesterol efflux from macrophage foam cells; activation was also accompanied by stimulation of AMPK pathway; knockdown of GPR120 or inhibition of PLC, calcium, or CaMKK abrogated these effects. GPR120 siRNA knockdown; PLC/Ca2+/CaMKK inhibitors; cholesterol efflux assays; ABCA1/ABCG1 expression; CE hydrolysis assays The FEBS journal Medium 32243091

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell 1938 20813258
2012 Dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human. Nature 538 22343897
2014 A Gpr120-selective agonist improves insulin resistance and chronic inflammation in obese mice. Nature medicine 320 24997608
2010 Taste preference for fatty acids is mediated by GPR40 and GPR120. The Journal of neuroscience : the official journal of the Society for Neuroscience 289 20573884
2019 Omega-3 Fatty Acids Activate Ciliary FFAR4 to Control Adipogenesis. Cell 208 31761534
2007 The regulation of adipogenesis through GPR120. Biochemical and biophysical research communications 205 17250804
2011 Targeting GPR120 and other fatty acid-sensing GPCRs ameliorates insulin resistance and inflammatory diseases. Trends in pharmacological sciences 204 21663979
2016 The lipid sensor GPR120 promotes brown fat activation and FGF21 release from adipocytes. Nature communications 196 27853148
2014 CD36- and GPR120-mediated Ca²⁺ signaling in human taste bud cells mediates differential responses to fatty acids and is altered in obese mice. Gastroenterology 150 24412488
2012 Discovery of a potent and selective GPR120 agonist. Journal of medicinal chemistry 145 22519963
2011 Free fatty acid receptors FFAR1 and GPR120 as novel therapeutic targets for metabolic disorders. Journal of pharmaceutical sciences 138 21618241
2009 Novel selective ligands for free fatty acid receptors GPR120 and GPR40. Naunyn-Schmiedeberg's archives of pharmacology 121 19471906
2014 GPR120 (FFAR4) is preferentially expressed in pancreatic delta cells and regulates somatostatin secretion from murine islets of Langerhans. Diabetologia 116 24663807
2014 Free fatty acid receptor GPR120 is highly expressed in enteroendocrine K cells of the upper small intestine and has a critical role in GIP secretion after fat ingestion. Endocrinology 105 25535828
2015 Dietary Fatty Acids and Their Potential for Controlling Metabolic Diseases Through Activation of FFA4/GPR120. Annual review of nutrition 96 26185978
2022 FFAR4 improves the senescence of tubular epithelial cells by AMPK/SirT3 signaling in acute kidney injury. Signal transduction and targeted therapy 91 36450712
2014 The fish oil ingredient, docosahexaenoic acid, activates cytosolic phospholipase A₂ via GPR120 receptor to produce prostaglandin E₂ and plays an anti-inflammatory role in macrophages. Immunology 90 24673159
2014 Activation of the omega-3 fatty acid receptor GPR120 mediates anti-inflammatory actions in immortalized hypothalamic neurons. Journal of neuroinflammation 90 24674717
2016 Eicosapentaenoic Acid Potentiates Brown Thermogenesis through FFAR4-dependent Up-regulation of miR-30b and miR-378. The Journal of biological chemistry 89 27489163
2017 FFA4/GPR120: Pharmacology and Therapeutic Opportunities. Trends in pharmacological sciences 84 28734639
2008 Colocalization of GPR120 with phospholipase-Cbeta2 and alpha-gustducin in the taste bud cells in mice. Neuroscience letters 82 19071193
2010 Structure-activity relationships of GPR120 agonists based on a docking simulation. Molecular pharmacology 81 20685848
2014 Alteration of the glucagon axis in GPR120 (FFAR4) knockout mice: a role for GPR120 in glucagon secretion. The Journal of biological chemistry 80 24742677
2012 Omega 3 fatty acids and GPR120. Cell metabolism 80 22560206
2015 Functions of omega-3 fatty acids and FFA4 (GPR120) in macrophages. European journal of pharmacology 78 25987421
2014 Lipid droplet formation in response to oleic acid in Huh-7 cells is mediated by the fatty acid receptor FFAR4. Journal of cell science 74 24876224
2021 GPR120 Inhibits Colitis Through Regulation of CD4+ T Cell Interleukin 10 Production. Gastroenterology 65 34536451
2022 GPR120 modulates epileptic seizure and neuroinflammation mediated by NLRP3 inflammasome. Journal of neuroinflammation 63 35624482
2015 Characterizing pharmacological ligands to study the long-chain fatty acid receptors GPR40/FFA1 and GPR120/FFA4. British journal of pharmacology 63 25131623
2015 Eicosapentaenoic acid upregulates VEGF-A through both GPR120 and PPARγ mediated pathways in 3T3-L1 adipocytes. Molecular and cellular endocrinology 60 25697344
2016 A novel anti-inflammatory role of GPR120 in intestinal epithelial cells. American journal of physiology. Cell physiology 58 26791484
2014 Potential roles of GPR120 and its agonists in the management of diabetes. Drug design, development and therapy 57 25114508
2020 Positive Reinforcing Mechanisms between GPR120 and PPARγ Modulate Insulin Sensitivity. Cell metabolism 56 32413335
2017 GPR120: a critical role in adipogenesis, inflammation, and energy metabolism in adipose tissue. Cellular and molecular life sciences : CMLS 55 28285320
2017 Long-Chain Free Fatty Acid Receptor GPR120 Mediates Oil-Induced GIP Secretion Through CCK in Male Mice. Endocrinology 55 28324023
2018 Activation of the Omega-3 Fatty Acid Receptor GPR120 Protects against Focal Cerebral Ischemic Injury by Preventing Inflammation and Apoptosis in Mice. Journal of immunology (Baltimore, Md. : 1950) 54 30598514
2016 Central Agonism of GPR120 Acutely Inhibits Food Intake and Food Reward and Chronically Suppresses Anxiety-Like Behavior in Mice. The international journal of neuropsychopharmacology 48 26888796
2018 Protective role of GPR120 in the maintenance of pregnancy by promoting decidualization via regulation of glucose metabolism. EBioMedicine 47 30578080
2017 Omega-3 polyunsaturated fatty acids protect human hepatoma cells from developing steatosis through FFA4 (GPR120). Biochimica et biophysica acta. Molecular and cell biology of lipids 45 29126901
2016 FFAR4 (GPR120) Signaling Is Not Required for Anti-Inflammatory and Insulin-Sensitizing Effects of Omega-3 Fatty Acids. Mediators of inflammation 45 27999451
2013 Ca2+ signaling in taste bud cells and spontaneous preference for fat: unresolved roles of CD36 and GPR120. Biochimie 45 23774298
2018 Omega-3 from Flaxseed Oil Protects Obese Mice Against Diabetic Retinopathy Through GPR120 Receptor. Scientific reports 44 30254287
2016 Free Fatty Acid Receptor 4 (GPR120) Stimulates Bone Formation and Suppresses Bone Resorption in the Presence of Elevated n-3 Fatty Acid Levels. Endocrinology 44 27145004
2014 Effects of obesity/fatty acids on the expression of GPR120. Molecular nutrition & food research 44 24913719
2014 Omega-3 Fatty Acids and FFAR4. Frontiers in endocrinology 44 25076939
2021 DHA/AA alleviates LPS-induced Kupffer cells pyroptosis via GPR120 interaction with NLRP3 to inhibit inflammasome complexes assembly. Cell death & disease 42 33436541
2020 Activation of GPR120 in podocytes ameliorates kidney fibrosis and inflammation in diabetic nephropathy. Acta pharmacologica Sinica 41 32948825
2017 FFA4 (GPR120) as a fatty acid sensor involved in appetite control, insulin sensitivity and inflammation regulation. Molecular aspects of medicine 41 28887275
2014 Regulation of Energy Homeostasis via GPR120. Frontiers in endocrinology 38 25071726
2017 GPR120 suppresses adipose tissue lipolysis and synergizes with GPR40 in antidiabetic efficacy. Journal of lipid research 37 28583918
2015 Different roles of GPR120 and GPR40 in the acquisition of malignant properties in pancreatic cancer cells. Biochemical and biophysical research communications 37 26282200
2023 Huangqin Decoction ameliorates ulcerative colitis by regulating fatty acid metabolism to mediate macrophage polarization via activating FFAR4-AMPK-PPARα pathway. Journal of ethnopharmacology 36 36997133
2021 DHA Protects Hepatocytes from Oxidative Injury through GPR120/ERK-Mediated Mitophagy. International journal of molecular sciences 36 34073582
2016 Topical Docosahexaenoic Acid (DHA) Accelerates Skin Wound Healing in Rats and Activates GPR120. Biological research for nursing 36 26747719
2015 FFA4 receptor (GPR120): A hot target for the development of anti-diabetic therapies. European journal of pharmacology 36 26123847
2015 GPR120: A bi-potential mediator to modulate the osteogenic and adipogenic differentiation of BMMSCs. Scientific reports 36 26365922
2018 Immunomodulatory Activity of Docosahexenoic Acid on RAW264.7 Cells Activation through GPR120-Mediated Signaling Pathway. Journal of agricultural and food chemistry 35 29307174
2012 G protein-coupled receptor120 (GPR120) transcription in intestinal epithelial cells is significantly affected by bacteria belonging to the Bacteroides, Proteobacteria, and Firmicutes phyla. Journal of animal science 35 23365268
2017 DHA supplementation prevent the progression of NASH via GPR120 signaling. European journal of pharmacology 34 29221950
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2013 The therapeutic potential of GPR120: a patent review. Expert opinion on therapeutic patents 34 24094095
2014 Docosahexaenoic acid inhibits vascular endothelial growth factor (VEGF)-induced cell migration via the GPR120/PP2A/ERK1/2/eNOS signaling pathway in human umbilical vein endothelial cells. Journal of agricultural and food chemistry 32 24734983
2022 Endogenous Lipid-GPR120 Signaling Modulates Pancreatic Islet Homeostasis to Different Extents. Diabetes 30 35472681
2015 Contribution of the low-frequency, loss-of-function p.R270H mutation in FFAR4 (GPR120) to increased fasting plasma glucose levels. Journal of medical genetics 30 26025001
2014 The oral lipid sensor GPR120 is not indispensable for the orosensory detection of dietary lipids in mice. Journal of lipid research 30 25489006
2024 EPA and DHA differentially improve insulin resistance by reducing adipose tissue inflammation-targeting GPR120/PPARγ pathway. The Journal of nutritional biochemistry 27 38631512
2020 Autocrine negative feedback regulation of lipolysis through sensing of NEFAs by FFAR4/GPR120 in WAT. Molecular metabolism 27 33091626
2019 Role of Host GPR120 in Mediating Dietary Omega-3 Fatty Acid Inhibition of Prostate Cancer. Journal of the National Cancer Institute 27 30202902
2021 Decoy bypass for appetite suppression in obese adults: role of synergistic nutrient sensing receptors GPR84 and FFAR4 on colonic endocrine cells. Gut 26 34083384
2018 Phytosphingosine is a novel activator of GPR120. Journal of biochemistry 26 29373685
2021 Pinocembrin and its linolenoyl ester derivative induce wound healing activity in HaCaT cell line potentially involving a GPR120/FFA4 mediated pathway. Bioorganic chemistry 25 33556697
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2015 Functional analysis of free fatty acid receptor GPR120 in human eosinophils: implications in metabolic homeostasis. PloS one 25 25790291
2020 GPR120 facilitates cholesterol efflux in macrophages through activation of AMPK signaling pathway. The FEBS journal 24 32243091
2024 α-linolenic acid mitigates microglia-mediated neuroinflammation of schizophrenia in mice by suppressing the NF-κB/NLRP3 pathway via binding GPR120-β-arrestin 2. International immunopharmacology 23 39236458
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2020 Agonism of GPR120 prevented IL-1β-induced reduction of extracellular matrix through SOX-9. Aging 23 32580167
2020 The key royal jelly component 10-hydroxy-2-decenoic acid protects against bone loss by inhibiting NF-κB signaling downstream of FFAR4. The Journal of biological chemistry 23 32647011
2019 Activation of GPR120 promotes the metastasis of breast cancer through the PI3K/Akt/NF-κB signaling pathway. Anti-cancer drugs 23 30520776
2019 Aberrant fatty acid profile and FFAR4 signaling confer endocrine resistance in breast cancer. Journal of experimental & clinical cancer research : CR 23 30795784
2016 Different effects of GPR120 and GPR40 on cellular functions stimulated by 12-O-tetradecanoylphorbol-13-acetate in melanoma cells. Biochemical and biophysical research communications 23 27163640
2016 In vivo activation of leukocyte GPR120/FFAR4 by PUFAs has minimal impact on atherosclerosis in LDL receptor knockout mice. Journal of lipid research 22 27811230
2016 Insulinotropic effects of GPR120 agonists are altered in obese diabetic and obese non-diabetic states. Clinical science (London, England : 1979) 22 27980130
2024 Activation of free fatty acid receptors, FFAR1 and FFAR4, ameliorates ulcerative colitis by promote fatty acid metabolism and mediate macrophage polarization. International immunopharmacology 21 38432147
2022 Effects of dietary omega-3 fatty acids on orthotopic prostate cancer progression, tumor associated macrophages, angiogenesis and T-cell activation-dependence on GPR120. Prostate cancer and prostatic diseases 21 35075215
2019 Novel GPR120 agonist TUG891 modulates fat taste perception and preference and activates tongue-brain-gut axis in mice. Journal of lipid research 21 31806728
2018 FFAR1-and FFAR4-dependent activation of Hippo pathway mediates DHA-induced apoptosis of androgen-independent prostate cancer cells. Biochemical and biophysical research communications 21 30366669
2016 Functional and genetic epidemiological characterisation of the FFAR4 (GPR120) p.R270H variant in the Danish population. Journal of medical genetics 21 27068006
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2021 Anti-Atherosclerotic Potential of Free Fatty Acid Receptor 4 (FFAR4). Biomedicines 20 33923318
2021 GPR120 Inhibits RANKL-Induced Osteoclast Formation and Resorption by Attenuating Reactive Oxygen Species Production in RAW264.7 Murine Macrophages. International journal of molecular sciences 20 34638884
2015 Discovery of novel FFA4 (GPR120) receptor agonists with β-arrestin2-biased characteristics. Future medicinal chemistry 20 26653412
2014 Expression of the long-chain fatty acid receptor GPR120 in the gonadotropes of the mouse anterior pituitary gland. Histochemistry and cell biology 20 25112963
2020 DHA Sensor GPR120 in Host Defense Exhibits the Dual Characteristics of Regulating Dendritic Cell Function and Skewing the Balance of Th17/Tregs. International journal of biological sciences 19 32015675
2017 GPR120: Mechanism of action, role and potential for medical applications. Postepy higieny i medycyny doswiadczalnej (Online) 19 29176006
2023 Central activation of the fatty acid sensor GPR120 suppresses microglia reactivity and alleviates sickness- and anxiety-like behaviors. Journal of neuroinflammation 18 38111048
2021 Docosahexaenoic acid ameliorates autoimmune inflammation by activating GPR120 signaling pathway in dendritic cells. International immunopharmacology 18 33932699
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2019 Agonism of GPR120 prevents ox-LDL-induced attachment of monocytes to endothelial cells. Chemico-biological interactions 17 31870843