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FFA4 receptor

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Target id: 127

Nomenclature: FFA4 receptor

Family: Free fatty acid receptors

Contents:

Gene and Protein Information Click here for help
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 361 10q23.33 FFAR4 free fatty acid receptor 4 11,17
Mouse 7 361 19 C2 Ffar4 free fatty acid receptor 4 11
Rat 7 361 1q53 Ffar4 free fatty acid receptor 4 49
Previous and Unofficial Names Click here for help
PGR4 | GPR120 | GPR129 | G-protein-coupled receptor GT01 | GT01 | G protein-coupled receptor 120 | G protein-coupled receptor 129 | omega-3 fatty acid receptor 1 | O3FAR1 | G-protein coupled receptor GT01
Database Links Click here for help
Specialist databases
GPCRdb ffar4_human (Hs), ffar4_mouse (Mm), ffar4_rat (Rn)
Other databases
Alphafold Q5NUL3 (Hs), Q7TMA4 (Mm), Q2AC31 (Rn)
ChEMBL Target CHEMBL5339 (Hs), CHEMBL2052036 (Mm), CHEMBL3309099 (Rn)
Ensembl Gene ENSG00000186188 (Hs), ENSMUSG00000054200 (Mm), ENSRNOG00000021763 (Rn)
Entrez Gene 338557 (Hs), 107221 (Mm), 294075 (Rn)
Human Protein Atlas ENSG00000186188 (Hs)
KEGG Gene hsa:338557 (Hs), mmu:107221 (Mm), rno:294075 (Rn)
OMIM 609044 (Hs)
Pharos Q5NUL3 (Hs)
RefSeq Nucleotide NM_181745 (Hs), NM_181748 (Mm), NM_001047088 (Rn)
RefSeq Protein NP_859529 (Hs), NP_861413 (Mm), NP_001040553 (Rn)
UniProtKB Q5NUL3 (Hs), Q7TMA4 (Mm), Q2AC31 (Rn)
Wikipedia FFAR4 (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Cryo-EM structure of the 9-hydroxystearic acid bound GPR120-Gi complex
PDB Id:  8ID3
Ligand:  9-hydroxystearic acid   This ligand is endogenous
Resolution:  3.1Å
Species:  Human
References:  27
Image of receptor 3D structure from RCSB PDB
Description:  Cryo-EM structure of the TUG891 bound GPR120-Giq complex
PDB Id:  8G59
Ligand:  TUG-891
Resolution:  2.64Å
Species:  Human
References:  27
Natural/Endogenous Ligands Click here for help
linoleic acid
α-linolenic acid
myristic acid
oleic acid
Free fatty acids

Download all structure-activity data for this target as a CSV file go icon to follow link

Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
grifolic acid methyl ether Small molecule or natural product Hs Partial agonist 5.0 pA2 16,45
⤷ pA2 5.0 [16,45]
grifolic acid Small molecule or natural product Hs Partial agonist 4.9 pA2 16
⤷ pA2 4.9 [16]
compound A [PMID 24997608] Small molecule or natural product Primary target of this compound Hs Agonist 7.6 pEC50 35
⤷ pEC50 7.6 [35]
Description: Fluorometric calcium assay using FLIPR methodology.
TUG-891 Small molecule or natural product Ligand has a PDB structure ? Full agonist 7.0 pEC50 43
⤷ pEC50 7.0 [43]
TUG-1197 Small molecule or natural product Mm Agonist 6.8 pEC50 2
⤷ pEC50 6.8 (EC50 1.48x10-7 M) [2]
Description: Determined in a Ca2+ mobilization assay.
TUG-1197 Small molecule or natural product Hs Agonist 6.6 pEC50 2
⤷ pEC50 6.6 (EC50 2.34x10-7 M) [2]
Description: Determined in a Ca2+ mobilization assay.
NCG21 Small molecule or natural product Hs Full agonist 5.9 pEC50 46
⤷ pEC50 5.9 (EC50 1.2x10-6 M) [46]
linoleic acid Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Hs Full agonist 5.9 pEC50 3
⤷ pEC50 5.9 [3]
α-linolenic acid Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Hs Full agonist 5.5 pEC50 43
⤷ pEC50 5.5 [43]
GW9508 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Partial agonist 5.5 pEC50 3,17
⤷ pEC50 5.5 [3,17]
myristic acid Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Hs Full agonist 5.2 pEC50 50
⤷ pEC50 5.2 [50]
α-linolenic acid Small molecule or natural product Ligand is endogenous in the given species Ligand has a PDB structure Rn Full agonist 5.1 pEC50 49
⤷ pEC50 5.1 [49]
oleic acid Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Hs Full agonist 4.7 pEC50 50
⤷ pEC50 4.7 [50]
View species-specific agonist tables
Agonist Comments
The FFA4 receptor is a specific receptor for long-chain endogenous FFAs (α-linolenic acid, palmitoleic acid and docosahexaenoic acid) and can potently regulate the secretion of incretin hormone GLP-1 from the gastrointestinal tract [1,17]. For human and mouse FFA4 receptors isolated from DNA fragments, stimulatory activities were detected for saturated FFAs with chain length of C14 to C18, and for unsaturated FFAs with chain length of C16 to C22 [17].

FFA4 receptors can be activated by various saturated free fatty acids ranging in chain length from C14 to C18, as well as by both mono- and poly-unsaturated free fatty acids with chain lengths of between 16 and 22 carbon atoms [33]. Agonism with α-linolenic acid and docosahexaenoic acid mediates phosphorylation of both the short and long isoforms of the human FFA4 receptor in HEK293 cells. Both receptor isoforms are phosphorylated to the same extent over a range of stimulation times, although the long isoform exhibits a lower basal level of phosphorylation [4]. A selective partial agonist has been identified among a series of natural compounds derived from fruiting bodies of Albatrellus ovinu. This compound could activate the FFA4 receptor in both FFA4 receptor overexpressing cells and STC-1 cells, which express FFA4 receptors endogenously [15]. A docking simulation approach using FFA1 and FFA4 receptor homology models could be useful in predicting the FFA1-selective agonistic activity of compounds [47].

A close analogue of 4-{4-[2-(phenyl-2-pyridinylamino)ethoxy]phenyl}butyric acid, 3-(4-{2-[phenyl(pyridin-2-yl)amino]ethoxy}phenyl)propanoic acid (compound 10), is also shown to be a weak non-selective agonist at FFA4 receptors [46], while synthetic ligand NCG120 has been shown to be an agonist for FFA4 receptors [15,45].
Antagonist Comments
EPA is thought to bind to FFA4 receptors in the intestine inhibiting GLP-1 secretion, with potential as an anti-diabetic [34]. NCG21 activates extracellular signal-regulated kinase in a cloned FFA4 receptor system, and furthermore activated ERK, intracellular calcium responses and GLP-1 secretion in murine enteroendocrine STC-1 cells that express FFA4 receptors endogenously. Administration of NCG21 into the mouse colon caused an increase in plasma GLP-1 levels. Docking simulation using a GPR120 homology model might be useful to predict the agonistic activity of compounds [45].
Immunopharmacology Comments
FFA4 has been identified as a drug target in asthma and COPD [39]. A selective FFA4 agonist, TUG-1197 [2], reduced airway resistance in preclinical models of lung inflammation.
Immuno Process Associations
Immuno Process:  Inflammation
Immuno Process:  Immune regulation
Immuno Process:  Cytokine production & signalling
Primary Transduction Mechanisms Click here for help
Transducer Effector/Response
Gq/G11 family
Comments:  Linolenic acid-mediated inhibition of Caspase-3 activity is mediated through the Gq pathway, but not the Gi nor the Gs pathway. Results suggest that FFA4 receptor activation leads to association of β-arrestin2 with the receptor and that this complex subsequently internalizes, whereupon β-arrestin2 can bind to TAB1 [37].
References:  15,17,22
Tissue Distribution Click here for help
Intestinal tract
Species:  Human
Technique:  RT-PCR
References:  18
Stomach
Species:  Human
Technique:  Expressed sequence tag
References:  11
Colonic intraepithelial neuroendocrine cells, GLP-1 positive cells
Species:  Human
Technique:  in situ hybridisation
References:  18
Rectum, spleen, adrenal gland, caecum
Expression level:  Medium
Species:  Mouse
Technique:  RT-PCR
References:  18
Spleen, thymus
Expression level:  Low
Species:  Mouse
Technique:  RT-PCR
References:  18
Large intestine, lung, adipose tissue
Species:  Mouse
Technique:  Immunohistochemistry
References:  32
Glucose-dependent insulinotropic polypeptide- secreting K cells
Species:  Mouse
Technique:  RT-PCR
References:  38
Intestinal tract
Species:  Mouse
Technique:  RT-PCR
References:  18
MIN6 cells, isolated mouse islets
Species:  Mouse
Technique:  RT-PCR
References:  24
Type II taste cells
Species:  Mouse
Technique:  Double immunostaining
References:  29
Type II taste cells
Species:  Mouse
Technique:  Immunohistochemistry
References:  5
Stromal vascular cells
Expression level:  Medium
Species:  Mouse
Technique:  Semi-quantitative RT-PCR analysis
References:  14
Adipocytes
Expression level:  High
Species:  Mouse
Technique:  Semi-quantitative RT-PCR analysis
References:  14
Gastrointestinal tract (preferential in mucosa), increasing expression along the longitudinal axis with highest expression in the proximal colon
Species:  Mouse
Technique:  RT-PCR
References:  21
Tongue (epithelium of the circumvallate papillae)
Species:  Rat
Technique:  RT-PCR and Western blot
References:  30
Enteroendocrine cells of the colon
Species:  Rat
Technique:  Immunohistochemistry
References:  30
Intestinal tract
Species:  Rat
Technique:  RT-PCR
References:  49
Adipose tissue macrophages, adipocytes, Kupffer cells, monocytic RAW 264.7 cells, enteroendocrine L cells
Species:  None
Technique:  Western blot; qPCR
References:  37
Lung, colon
Expression level:  High
Species:  None
Technique:  RT-PCR
References:  18
Tissue Distribution Comments
FFA4 receptors are also reported to be present in enteroendocrine cells (technique not specified) [40]. QPCR analysis show that pure L cells express the long chain fatty acid receptors GPR40, in addition to FFA4 receptors [10]. A high fat diet significantly up-regulates FFA4 receptor gene transcripts in rat cardiac tissue and extensor digitorum longus skeletal muscle [7]. Also rats sensitive to diet induced obesity show upregulation of FFA4 receptor, compared to resistant rats [9], and this is mirrored in humans [20]. A high-fat diet also increases the expression of this receptor on macrophages in mice [42]. FFA4 receptor expression displays a diurnal rhythm in the gustatory circumvallate papillae [28]. FFA4 receptor expression has also been found to be upregulated in obese humans [52].

Morgan and Dhayal found that FFA4 receptor is expressed in islets cells (data not published) [33].

In addition to numerous tissue distribution studies, the FFA4 receptor has also been shown to be expressed in various cells lines:

Mouse GLUTag cells by RT-PCR analysis [41].
Human RAW264.7 cells by RT-PCR analysis [8].
Rat β-cell lines (INS-1, BRIN-BD11) (unpublished data) [33].
Breast cancer cell lines: Human MDA-MB-231 breast cancer cells, detected by flow cytometry [34]; human MCF-7 cells, MCF10A cells, also detected by flow cytometry [44]

Despite expression in human epithelial breast cancer lines it is thought that the FFA4 receptor does not participate in the signal transduction pathways and in the cellular processes induced by arachidonic acid [34], or oleic acid in MCF10A cells [44]. Expression of FFA4 receptor protein and mRNA is up-regulated during the adipogenic differentiation of 3T3-L1 cells [32]. It seems likely that the shorter form of the FFA4 receptor is the major isoforms present in the endocrine pancreas, although FFA4 receptor agonists on insulin secretion are likely to be mediated mainly by indirect actions on the intestine [33].
Expression Datasets Click here for help

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Log average relative transcript abundance in mouse tissues measured by qPCR from Regard, J.B., Sato, I.T., and Coughlin, S.R. (2008). Anatomical profiling of G protein-coupled receptor expression. Cell, 135(3): 561-71. [PMID:18984166] [Raw data: website]

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Functional Assays Click here for help
Acute and long term administration of α-linoleic acid significantly increase plasma GLP-1 and insulin concentrations in vivo
Species:  Rat
Tissue:  Intestinal tract
Response measured:  Increased GLP-1 and insulin secretion
References:  49
DHA and EPA reverse insulin resistance caused by the high-fat diet in mice
Species:  Mouse
Tissue: 
Response measured:  Insulin sensitisation
References:  37
Free Fatty Acids Enhance Cell Survival of Serum-starved STC-1 Cells via FFA4
Species:  Human
Tissue:  STC-1 cells
Response measured:  Free fatty acid linolenic acid mediated inhibition of caspase-3 activity and DNA fragmentation, and promote ERK activation, promoting survival
References:  22
Activation of FFA4 by DHA antagonizes the proinflammatory effects of TNFα and lipopolysaccharide in a macrophage cell line. DHA blocks the NFκB and JNK pathways and prevents expression of cytokines
Species:  Mouse
Tissue:  Macrophage
Response measured: 
References:  37,42
A FFA4 agonist mimics the antiosteoclastogenic actions of the fatty acids, identifying FFA4 as a likely mediator of the antiosteoclastogenic actions of C16 and C18 fatty acids
Species:  Human
Tissue:  RAW264.7 cells
Response measured:  Stimulate osteoblastic cell proliferation and inhibition of osteoclastogenesis without affecting bone resorbtion
References:  8
Free fatty acids stimulate cholecystokinin secretion in STC-1 cells and in mice in vivo
Species:  Mouse
Tissue:  SCT-1 cells
Response measured:  Free fatty acids activate FFA4 in SCT-1 cells, causing cholecystokinin secretion dependent on activation of L-type calcium channels
References:  48
Acute hypothalamic injection of ω3 and ω9 fatty acids activate signal transduction through the recently identified FFA4 unsaturated fatty acid receptor.
Species:  Mouse
Tissue:  Hypothalamus
Response measured:  Revert diet-induced inflammation and reducing body adiposity
References:  6
Meal-related increases in gastric mucosal LCFA interact with FFA4 on ghrelin cells to inhibit ghrelin secretion
Species:  Mouse
Tissue:  Gastric mucosa
Response measured:  High level of expression of the long-chain fatty acid (LCFA) receptor FFA4 and significantly increased mRNA levels of lipoprotein lipase, glycosylphosphatidylinositol-anchored HDL-binding protein 1, and peroxisome proliferator-activated receptor-γ in postprandial gastric mucosa
References:  26
FFA4 mRNA is elevated in mice fed a high fat diet
Species:  Mouse
Tissue:  Adipose tissue
Response measured:  Increased receptor expression
References:  14
Ligand-stimulated FFA4 exerts anti-inflammatory effects
Species:  Mouse
Tissue:  RAW 264.7 cells
Response measured:  GW9508 treatment broadly and markedly repressed the ability of the TLR4 ligand LPS to stimulate inflammatory responses in RAW 264.7 cells
References:  37
Ligand-stimulation of leads to an increase in glucose transport and translocation of GLUT4 to the plasma membrane in adipocytes
Species:  Mouse
Tissue:  Apidocytes
Response measured:  Enhanced glucose uptake
References:  37
Functional Assay Comments
Cell-based fluorescence imaging system successfully monitored the internalization of the FFA4 receptor [12]. Mice receiving bone marrow transplants from the FFA4 receptor-deficient mice are also resistant to the beneficial properties of DHA and EPA [42]. Although the FFA4 receptor has been characterized in LβT2 cells, it does not mediate the effects of unsaturated fatty acids on LH release [13].
Physiological Functions Click here for help
FFA4 indirectly promotes free fatty acid mediated- glucose-stimulated insulin secretion
Species:  Mouse
Tissue:  Pancreas and intestine
References:  17
GLP-1 secretion and CCK secretion
Species:  Human
Tissue:  Intestinal tract
References:  15
In a diabetic and insulin-resistant state, ω-3 PUFAs bind to the G-protein coupled receptor, FFA4, resulting in reduced cytokine production from inflammatory macrophages and improved signaling in adipocytes, leading to a reduction in insulin resistance.
Species:  Human
Tissue:  Adipocytes
References:  23
Physiological Functions Comments
There is a suggested role for FFA4 in sensing dietary fat, based on expression in the taste cells of the circumvallate papillae and enteroendocrine cells [30]. FFA4 triggers release of incretins from intestinal endocrine cells, and so indirectly enhances insulin secretion and promote satiety. FFA4 signaling in adipocytes and macrophages also results in insulin sensitizing and beneficial anti-inflammatory effects [19].
Physiological Consequences of Altering Gene Expression Click here for help
Application of α-linolenic acid to SCN-1 cells provoked a rapid rise in [Ca2+]i, which was eliminated by siRNA knockdown of O3FAR1, causing reduced secretion of GLP-1
Species:  Mouse
Tissue:  SCN-1
Technique:  RNA interference (RNAi)
References:  18
Disruption of the O3FAR1 gene abolishes the benefits of ω-3 fatty acids on glucose homeostasis and insulin sensitivity in mice
Species:  Mouse
Tissue: 
Technique: 
References:  37,42
There is a diminished preference for linoleic acid in 48 hours bottle tests in O3FAR1 knockout mice, and lick tests indicate diminished ability of knockout mice to detect linoleic acid and oleic acid. Nerve responses to both agonists were also reduced.
Species:  Mouse
Tissue:  Taste II cells
Technique:  Gene knockouts
References:  5
DHA- and α-linolenic acid-mediated ERK phosphorylation were abolished by O3FAR1 knockdown
Species:  Mouse
Tissue:  HEK 293 cells
Technique:  RNA interference (RNAi)
References:  37
FFA4-deficient mice fed a high-fat diet develop obesity, glucose intolerance and fatty liver with decreased adipocyte differentiation and lipogenesis and enhanced hepatic lipogenesis.
Species:  Mouse
Tissue:  Adipocytes
Technique:  Gene knockouts
References:  20
Knock out animals exhibited a 30% decrease in GIR compared to the ω-3 fatty acid supplemented bone marrow transplant wild types, explained by skeletal muscle insulin resistance and hepatic insulin resistance in the O3FAR1 knockout. The benefits of increased hepatic and muscle insulin sensitivity, and decreased hepatic steatosis seen in ω-3 fatty acid diets are not seen in knock out mice. Receptor knockout also reduces inflammatory macrophages in adipose tissue
Species:  Mouse
Tissue:  Macrophages and hamatopoietic cells
Technique:  Adoptive transfer
References:  37
Stimulatory effect of DHA and GW9508 on glucose uptake is blocked when O3FAR1 or Gαq/11 is depleted by siRNA knockdown
Species:  Mouse
Tissue:  Adipocytes
Technique:  RNA interference (RNAi)
References:  37
GW9508 and DHA, strongly inhibit LPS-induced phosphorylation of JNK and IKKβ, IκB degradation, cytokine secretion and inflammatory gene expression level in RAW 264.7 cells. These effects are inhibited by siRNA knockdown of O3FAR1
Species:  Mouse
Tissue:  RAW 264.7 cells and primary intraperitoneal macrophages
Technique:  RNA interference (RNAi)
References:  37
Physiological Consequences of Altering Gene Expression Comments
It is possible that the relative levels of O3FAR1 expression in STC-1 cells does not necessarily reflect the levels expressed in the native I cell, and further studies on native I cells will be necessary to exclude a potential role of FFA4 on CCK secretion [25]. O3FAR1 gene inactivation leads to a decrease in the preference for lipids [28].
Phenotypes, Alleles and Disease Models Click here for help Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Gpr120tm1Sdmk Gpr120tm1Sdmk/Gpr120tm1Sdmk
C57BL/6J-Gpr120		 MGI:2147577  MP:0001985 abnormal gustatory system physiology PMID: 20573884 
Gpr120tm1Sdmk Gpr120tm1Sdmk/Gpr120tm1Sdmk
C57BL/6J-Gpr120		 MGI:2147577  MP:0010055 abnormal sensory neuron physiology PMID: 20573884 
Gpr120tm1Sdmk Gpr120tm1Sdmk/Gpr120tm1Sdmk
C57BL/6J-Gpr120		 MGI:2147577  MP:0001986 abnormal taste sensitivity PMID: 20573884 
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Body mass index quantitative trait locus 10; BMIQ10
OMIM: 607514
Role:  Increased risk of obesity shown in individuals with a missense mutation in FFAR4
References:  20,36
Click column headers to sort
Type Species Amino acid change Nucleotide change Description Reference
Missense Human R270H 20,36
Disease:  Diabetes mellitus, noninsulin-dependent; NIDDM
Synonyms: Diabetes mellitus, Type II; T2D [OMIM: 125853]
Maturity onset diabetes
Type 2 diabetes mellitus [Disease Ontology: DOID:9352]
Disease Ontology: DOID:9352
OMIM: 125853
Comments:  FFA4 is a potential drug target in type 2 diabetes mellitus.
References:  20,36
Clinically-Relevant Mutations and Pathophysiology Comments
O3FAR1 exon sequencing in obese subjects reveals a deleterious non-synonymous mutation (p.R270H) that inhibits FFA4 signalling activity. Furthermore, the p.R270H variant increases the risk of obesity in european populations [20,31].
Biologically Significant Variants Click here for help
Type:  Single nucleotide polymorphism
Species:  Human
Amino acid change:  Q257R
Global MAF (%):  1
Subpopulation MAF (%):  ASN|EUR: 2|1
Minor allele count:  G=0.007/16
Comment on frequency:  Low frequency (<10% in all tested populations)
SNP accession:  rs115724324
Validation:  1000 Genomes, Frequency
Type:  Single nucleotide polymorphism
Species:  Human
Amino acid change:  R67C
Global MAF (%):  15
Subpopulation MAF (%):  AFR|AMR|ASN|EUR: 5|16|36|5
Minor allele count:  T=0.149/326
SNP accession:  VAR_067799, rs61866610
Validation:  1000 Genomes, Frequency, Multiple observations
Type:  Single nucleotide polymorphism
Species:  Human
Amino acid change:  R254H
Global MAF (%):  1
Subpopulation MAF (%):  AMR|EUR: 1|1
Minor allele count:  A=0.007/16
Comment on frequency:  Low frequency (<10% in all tested populations)
SNP accession:  VAR_067800, rs116454156
Validation:  Frequency
Biologically Significant Variant Comments
Long (L, Q5NUL3-1) and short (S, Q5NUL3-2) human FFA4 splice variants, differ by insertion of 16 amino acids in the third intracellular loop. The third intracellular loop insertion in FFA4L prevents G protein-dependent intracellular calcium and DMR responses, but this receptor isoform remains functionally coupled to the β-arrestin pathway, providing one of the first examples of a native β-arrestin-biased receptor [50].
General Comments
The Arg, Asn/His, and Arg residues at the top of TM5, TM6, and TM7, anchoring the carboxylate group in FFA1-3 receptors are absent in the FFA4 receptor, suggesting that the binding mode of FFAs in the FFA4 receptor is different from FFA1-3 receptors [51].

The FFA4 receptor regulates the secretion of glucagon-like peptide-1 in the intestine, as well as insulin sensitivity in macrophages [15].

References

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1. Adachi T, Yanaka H, Kanai H, Nozaki M, Takahara Y, Tsuda M, Jonouchi T, Tsuda K, Hirasawa A, Tsujimoto G. (2008) Administration of perilla oil coated with Calshell increases glucagon-like peptide secretion. Biol Pharm Bull, 31 (5): 1021-3. [PMID:18451539]

2. Azevedo CM, Watterson KR, Wargent ET, Hansen SV, Hudson BD, Kępczyńska MA, Dunlop J, Shimpukade B, Christiansen E, Milligan G et al.. (2016) Non-Acidic Free Fatty Acid Receptor 4 Agonists with Antidiabetic Activity. J Med Chem, 59 (19): 8868-8878. [PMID:27570890]

3. Briscoe CP, Peat AJ, McKeown SC, Corbett DF, Goetz AS, Littleton TR, McCoy DC, Kenakin TP, Andrews JL, Ammala C et al.. (2006) Pharmacological regulation of insulin secretion in MIN6 cells through the fatty acid receptor GPR40: identification of agonist and antagonist small molecules. Br J Pharmacol, 148 (5): 619-28. [PMID:16702987]

4. Burns RN, Moniri NH. (2010) Agonism with the omega-3 fatty acids alpha-linolenic acid and docosahexaenoic acid mediates phosphorylation of both the short and long isoforms of the human GPR120 receptor. Biochem Biophys Res Commun, 396 (4): 1030-5. [PMID:20471368]

5. Cartoni C, Yasumatsu K, Ohkuri T, Shigemura N, Yoshida R, Godinot N, le Coutre J, Ninomiya Y, Damak S. (2010) Taste preference for fatty acids is mediated by GPR40 and GPR120. J Neurosci, 30 (25): 8376-82. [PMID:20573884]

6. Cintra DE, Ropelle ER, Moraes JC, Pauli JR, Morari J, Souza CT, Grimaldi R, Stahl M, Carvalheira JB, Saad MJ et al.. (2012) Unsaturated fatty acids revert diet-induced hypothalamic inflammation in obesity. PLoS ONE, 7 (1): e30571. [PMID:22279596]

7. Cornall LM, Mathai ML, Hryciw DH, McAinch AJ. (2011) Diet-induced obesity up-regulates the abundance of GPR43 and GPR120 in a tissue specific manner. Cell Physiol Biochem, 28 (5): 949-58. [PMID:22178946]

8. Cornish J, MacGibbon A, Lin JM, Watson M, Callon KE, Tong PC, Dunford JE, van der Does Y, Williams GA, Grey AB, Naot D, Reid IR. (2008) Modulation of osteoclastogenesis by fatty acids. Endocrinology, 149 (11): 5688-95. [PMID:18617622]

9. Duca FA, Swartz TD, Sakar Y, Covasa M. (2013) Decreased intestinal nutrient response in diet-induced obese rats: role of gut peptides and nutrient receptors. Int J Obes (Lond.), 37 (3): 375-81. [PMID:22546775]

10. Engelstoft MS, Egerod KL, Holst B, Schwartz TW. (2008) A gut feeling for obesity: 7TM sensors on enteroendocrine cells. Cell Metab, 8 (6): 447-9. [PMID:19041758]

11. Fredriksson R, Höglund PJ, Gloriam DE, Lagerström MC, Schiöth HB. (2003) Seven evolutionarily conserved human rhodopsin G protein-coupled receptors lacking close relatives. FEBS Lett, 554 (3): 381-8. [PMID:14623098]

12. Fukunaga S, Setoguchi S, Hirasawa A, Tsujimoto G. (2006) Monitoring ligand-mediated internalization of G protein-coupled receptor as a novel pharmacological approach. Life Sci, 80 (1): 17-23. [PMID:16978657]

13. Garrel G, Simon V, Denoyelle C, Cruciani-Guglielmacci C, Migrenne S, Counis R, Magnan C, Cohen-Tannoudji J. (2011) Unsaturated fatty acids stimulate LH secretion via novel PKCepsilon and -theta in gonadotrope cells and inhibit GnRH-induced LH release. Endocrinology, 152 (10): 3905-16. [PMID:21862612]

14. Gotoh C, Hong YH, Iga T, Hishikawa D, Suzuki Y, Song SH, Choi KC, Adachi T, Hirasawa A, Tsujimoto G, Sasaki S, Roh SG. (2007) The regulation of adipogenesis through GPR120. Biochem Biophys Res Commun, 354 (2): 591-7. [PMID:17250804]

15. Hara T, Hirasawa A, Ichimura A, Kimura I, Tsujimoto G. (2011) Free fatty acid receptors FFAR1 and GPR120 as novel therapeutic targets for metabolic disorders. J Pharm Sci, 100 (9): 3594-601. [PMID:21618241]

16. Hara T, Hirasawa A, Sun Q, Sadakane K, Itsubo C, Iga T, Adachi T, Koshimizu TA, Hashimoto T, Asakawa Y et al.. (2009) Novel selective ligands for free fatty acid receptors GPR120 and GPR40. Naunyn Schmiedebergs Arch Pharmacol, 380 (3): 247-55. [PMID:19471906]

17. Hirasawa A, Hara T, Katsuma S, Adachi T, Tsujimoto G. (2008) Free fatty acid receptors and drug discovery. Biol Pharm Bull, 31 (10): 1847-51. [PMID:18827341]

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