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FFA3 receptor

Family: Free fatty acid receptors

Contents:
Gene and Protein Information
Previous and Unofficial Names
Database Links
Agonists
Antagonists
Allosteric Regulators
Transduction Mechanisms
Tissue Distribution
Expression Datasets
Functional Assays
Physiological Functions
Physiological Consequences of Altering Gene Expression
Phenotypes, Alleles and Disease Models
References
Gene and Protein Information
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 346 19q13.1 FFAR3 free fatty acid receptor 3 12
Mouse 7 319 7 A3 Ffar3 free fatty acid receptor 3 6
Rat 7 646 1q21 Ffar3 free fatty acid receptor 3 2
Previous and Unofficial Names
Names References
GPR41 12
FFAR3
FFA3R
GPCR41
LSSIG 15
G protein-coupled receptor 41
Gpr41_predicted
LOC365228
G protein-coupled receptor 41 (predicted)
free fatty acid receptor 3
LOC233080
Gm478
Database Links
ChEMBL Target CHEMBL5201 (Hs)
Ensembl ENSG00000185897 (Hs), ENSMUSG00000019429 (Mm), ENSRNOG00000037467 (Rn)
Entrez Gene 2865 (Hs), 233080 (Mm), 365228 (Rn)
GeneCards FFAR3 (Hs)
GenitoUrinary Development Molecular Anatomy Project Ffar3 (Mm)
HomoloGene 82482 (Hs)
Human Protein Reference Database 04823 (Hs)
InterPro O14843 (Hs), Q3UFD7 (Mm), B2GV46 (Rn)
KEGG Gene hsa:2865 (Hs), mmu:233080 (Mm), rno:365228 (Rn)
OMIM 603821 (Hs)
PharmGKB Gene PA28888 (Hs)
Protein Ontology (PRO) PRO:000001584 (Hs)
RefSeq Nucleotide NM_005304 (Hs), NM_001033316 (Mm), NM_001108912 (Rn)
RefSeq Protein NP_005295 (Hs), NP_001028488 (Mm), NP_001102382 (Rn)
TreeFam ENSG00000185897 (Hs), ENSMUSG00000019429 (Mm), ENSRNOG00000037467 (Rn)
UniGene Hs. 291167 (Hs)
UniProt O14843 (Hs), Q3UFD7 (Mm), B2GV46 (Rn)
Wikipedia FFA3 receptor
Free fatty acid receptors
Search for 3D structures on the PDB
Search by keyword: Free fatty acid receptors FFA3 receptor Search by accession number: O14843, B2GV46, Q3UFD7
Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
propanoic acid Hs Full agonist 3.9 – 5.7 pEC50 3,20
pentanoic acid Hs Full agonist 3.8 – 5.4 pEC50 3,20
isobutyric acid Hs Full agonist 4.3 – 4.8 pEC50 3,20
butyric acid Hs Full agonist 3.8 – 4.9 pEC50 3,20
acetic acid Hs Full agonist 3.0 – 3.9 pEC50 3,20
Agonist Comments
A series of short chain fatty acids with varying degrees of selectivity for FFA3 over FFA2 have been reported [13]. Species orthologs of FFA2 have been found to have different rank orders of potencies for short chain fatty acids compared ot the human receptor [5].
Antagonist Comments
To date the only reported antagonist for FFA3 is β-hydroxybutyrate [8]. In this study the short-chain fatty acid propionate promoted sympathetic outflow via FFA3, whereas the ketone body β-hydroxybutyrate (which can be present in the circulation as a result of starvation or diabetes) antagonized FFA3, thus suppressing sympathetic nervous system activity. This is proposed as a mechanism whereby short-chain fatty acids and ketone bodies are able to directly regulate sympathetic nervous system activity and thereby control body energy expenditure and maintain metabolic homeostasis.
Allosteric Regulator Comments
To date no compounds that act as allosteric modulators at FFA3 have been reported in the peer reviewed literature, but FFA3 allosteric modulators have been described in patent applications [18].

Explore drug-target interactions for this set of compounds using iPHACE

Primary Transduction Mechanisms
Transducer Effector/Response
Gi/Go family Adenylate cyclase inhibition
References:  20
Tissue Distribution
Spleen, lymph node, bone marrow, peripheral blood monuclear cells, adipose tissue.
Species:  Human
Technique:  RT-PCR.
References:  3,9
Duodenal enteroendocrine L-cells.
Species:  Human
Technique:  Immunohistochemistry.
References:  16
PYY containing enteroendocrine cells of the colonic mucosa.
Species:  Human
Technique:  Immunohistochemistry, RT-PCR.
References:  17
Pancreatic islets.
Species:  Mouse
Technique:  RT-PCR.
References:  7
Sympathetic ganglia.
Species:  Mouse
Technique:  RT-PCR.
References:  8
Tissue Distribution Comments
Expression of FFA3 in adipose tissue is a contentious issue, with some studies detecting expression in adipose tissue [3,20] and others failing to find any FFA3 expression [4,21].
FFA3 expression has been described in bovine rumen epithelium but not islet of Langerhans cells [19].
Expression Datasets

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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
Measurement of leptin production in Ob-Luc cells endogenously expressing the FFA3 receptor.
Species:  Mouse
Tissue:  Ob-Luc cells.
Response measured:  Leptin production.
References:  20
Measurement of cAMP levels in CHO-K1 cells transfected with the human FFA3 receptor.
Species:  Human
Tissue:  CHO-K1 cells.
Response measured:  Inhibition of cAMP accumulation.
References:  9,20
Measurement of Ca2+ levels in CHO-K1 cells transfected with the human FFA3 receptor and chimeric G proteins.
Species:  Human
Tissue:  CHO-K1 cells.
Response measured:  Increase in intracellular Ca2+ concentration.
References:  9
Stimulation of [35S]GTPγS binding in HEK293 cell membranes expressing the human FFA3 receptor.
Species:  Human
Tissue:  HEK293 cells.
Response measured:  Increase in [35S]GTPγS binding.
References:  3,13
Stimulation of FUS1-LacZ and FUS1-HIS3 reporter genes in modified yeast expressing the rat Gpr41 receptor in combination with chimeric G proteins.
Species:  Rat
Tissue:  Yeast cells.
Response measured:  Yeast cell growth and/or beta-galactosidase.
References:  3
Label-free dynamic mass redistribution measured on the Coring Epic biosensor system in HEK293 cell expressing the human FFA3 receptor.
Species:  Human
Tissue:  HEK293 cells.
Response measured:  Measurement of cell mass redistribution via a change in the optical density of the cells.
References:  13
Measurement of extracellular-regulated kinase 1/2 (ERK1/2) phosphorylation in HEK293 cells expressing the human FFA3 receptor.
Species:  Human
Tissue:  HEK293 cells.
Response measured:  Phosphorylation of ERK1/2.
References:  14
Physiological Functions
Increase in leptin production.
Species:  Mouse
Tissue:  Ob-Luc cells.
References:  20
Activation of sympathetic ganglion neurons by short chain fatty acids is mediated by FFA3.
Species:  Mouse
Tissue:  Sympathetic neurons.
References:  8
Physiological Functions Comments
A general function of FFA3 in nutrient sensing in the gut to maintain energy homoeostatsis has been suggested [10].
Physiological Consequences of Altering Gene Expression
FFA3 knockout out mice have reduced adiposity and body mass. A reduction in the expression of PYY is also found.
Species:  None
Tissue:  in vivo.
Technique:  Gene knock-outs.
References:  11
Male mice lacking FFA3 are found to have increased body fat mass coupled with a reduction in energy expenditure.
Species:  Mouse
Tissue:  in vivo.
Technique:  Gene knock-outs.
References:  1
Short chain fatty acids cannot activate the sympathetic nervous system in mice lacking FFA3 expression.
Species:  Mouse
Tissue:  in vivo.
Technique:  Gene knock-outs.
References:  8
Physiological Consequences of Altering Gene Expression Comments
Expression of FFA2 is found to be reduced in FFA3 knockout mice [21] which may hamper efforts to separate the physiological function of the two short chain fatty acids receptors.
Phenotypes, Alleles and Disease Models Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Ffar3tm1Dgen Ffar3tm1Dgen/Ffar3tm1Dgen
B6.129P2-Ffar3		 MGI:2685324  MP:0005666 abnormal adipose tissue physiology PMID: 20399779 
Ffar3tm1Reh Ffar3tm1Reh/Ffar3tm1Reh
involves: 129S6/SvEvTac * C57BL/6J		 MGI:2685324  MP:0001664 abnormal digestion PMID: 18931303 
Ffar3tm1Reh Ffar3tm1Reh/Ffar3tm1Reh
involves: 129S6/SvEvTac * C57BL/6J		 MGI:2685324  MP:0005448 abnormal energy balance PMID: 18931303 
Ffar3tm1Reh Ffar3tm1Reh/Ffar3tm1Reh
involves: 129S6/SvEvTac * C57BL/6J		 MGI:2685324  MP:0003868 abnormal feces composition PMID: 18931303 
Ffar3tm1Reh Ffar3tm1Reh/Ffar3tm1Reh
involves: 129S6/SvEvTac * C57BL/6J		 MGI:2685324  MP:0006001 abnormal intestinal transit time PMID: 18931303 
Ffar3tm1Reh Ffar3tm1Reh/Ffar3tm1Reh
involves: 129S6/SvEvTac * C57BL/6J		 MGI:2685324  MP:0001262 decreased body weight PMID: 18931303 
Ffar3tm1Reh Ffar3tm1Reh/Ffar3tm1Reh
involves: 129S6/SvEvTac * C57BL/6J		 MGI:2685324  MP:0005668 decreased circulating leptin level PMID: 18931303 
Ffar3tm1Reh Ffar3tm1Reh/Ffar3tm1Reh
involves: 129S6/SvEvTac * C57BL/6J		 MGI:2685324  MP:0009289 decreased epididymal fat pad weight PMID: 18931303 
Ffar3tm1Reh Ffar3tm1Reh/Ffar3tm1Reh
involves: 129S6/SvEvTac * C57BL/6J		 MGI:2685324  MP:0005318 decreased triglyceride level PMID: 18931303 

REFERENCES

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1. Bellahcene, M; O'Dowd, JF; Wargent, ET; Zaibi, MS; Hislop, DC; Ngala, RA; Smith, DM; Cawthorne, MA; Stocker, CJ; Arch, JR. (2012) Male mice that lack the G-protein-coupled receptor GPR41 have low energy expenditure and increased body fat content. Br. J. Nutr., : 1-10 [Epub ahead of print]. [PMID:23110765]

2. Bonini, J. A., Anderson, S. M. and Steiner, D. F. (1997) Molecular cloning and tissue expression of a novel orphan G protein-coupled receptor from rat lung. Biochem Biophys Res Commun, 234: 190-193. [PMID:9168987]

3. Brown, A. J., Goldsworthy, S. M., Barnes, A. A., Eilert, M. M., Tcheang, L., Daniels, D., Muir, A. I., Wigglesworth, M. J., Kinghorn, I., Fraser, N. J., Pike, N. B., Strum, J. C., Steplewski, K. M., Murdock, P. R., Holder, J. C., Marshall, F. H., Szekeres, P. G., Wilson, S., Ignar, D. M., Foord, S. M., Wise, A. and Dowell, S. J. (2003) The Orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids. J Biol Chem, 278: 11312-11319. [PMID:12496283]

4. Hong, Y. H., Nishimura, Y., Hishikawa, D., Tsuzuki, H., Miyahara, H., Gotoh, C., Choi, K. C., Feng, D. D., Chen, C., Lee, H. G., Katoh, K., Roh, S. G. and Sasaki, S. (2005) Acetate and propionate short chain fatty acids stimulate adipogenesis via GPCR43. Endocrinology, 146: 5092-5099. [PMID:16123168]

5. Hudson, BD; Tikhonova, IG; Pandey, SK; Ulven, T; Milligan, G. (2012) Extracellular ionic locks determine variation in constitutive activity and ligand potency between species orthologs of the free fatty acid receptors FFA2 and FFA3. J. Biol. Chem., 287 (49): 41195-209. [PMID:23066016]

6. Katayama, S., Tomaru, Y., Kasukawa, T., Waki, K., Nakanishi, M., Nakamura, M., Nishida, H., Yap, C. C., Suzuki, M., Kawai, J., Suzuki, H., Carninci, P., Hayashizaki, Y., Wells, C., Frith, M., Ravasi, T., Pang, K. C., Hallinan, J., Mattick, J., Hume, D. A., Lipovich, L., Batalov, S., Engström, P. G., Mizuno, Y., Faghihi, M. A., Sandelin, A., Chalk, A. M., Mottagui-Tabar, S., Liang, Z., Lenhard, B. and Wahlestedt, C. (2005) Antisense transcription in the mammalian transcriptome. Science, 309: 1564-1566. [PMID:16141073]

7. Kebede, MA; Alquier, T; Latour, MG; Poitout, V. (2009) Lipid receptors and islet function: therapeutic implications?. Diabetes Obes Metab, 11 Suppl 4: 10-20. [PMID:19817784]

8. Kimura, I; Inoue, D; Maeda, T; Hara, T; Ichimura, A; Miyauchi, S; Kobayashi, M; Hirasawa, A; Tsujimoto, G. (2011) Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41). Proc. Natl. Acad. Sci. U.S.A., 108 (19): 8030-5. [PMID:21518883]

9. Le Poul, E., Loison, C., Struyf, S., Springael, J. Y., Lannoy, V., Decobecq, M. E., Brezillon, S., Dupriez, V., Vassart, G., Van Damme, J., Parmentier, M. and Detheux, M. (2003) Functional characterization of human receptors for short chain fatty acids and their role in polymorphonuclear cell activation. J Biol Chem, 278: 25481-25489. [PMID:12711604]

10. Rasoamanana, R; Darcel, N; Fromentin, G; Tomé, D. (2012) Nutrient sensing and signalling by the gut. Proc Nutr Soc, : 1-10 [Epub ahead of print]. [PMID:22453062]

11. Samuel, BS; Shaito, A; Motoike, T; Rey, FE; Backhed, F; Manchester, JK; Hammer, RE; Williams, SC; Crowley, J; Yanagisawa, M; et al.. (2008) Effects of the gut microbiota on host adiposity are modulated by the short-chain fatty-acid binding G protein-coupled receptor, Gpr41. Proc. Natl. Acad. Sci. U.S.A., 105 (43): 16767-72. [PMID:18931303]

12. Sawzdargo, M., George, S. R., Nguyen, T., Xu, S., Kolakowski, L. F. and O'Dowd, B. F. (1997) A cluster of four novel human G protein-coupled receptor genes occurring in close proximity to CD22 gene on chromosome 19q13.1. Biochem Biophys Res Commun, 239: 543-547. [PMID:9344866]

13. Schmidt, J; Smith, NJ; Christiansen, E; Tikhonova, IG; Grundmann, M; Hudson, BD; Ward, RJ; Drewke, C; Milligan, G; Kostenis, E; et al.. (2011) Selective orthosteric free fatty acid receptor 2 (FFA2) agonists: identification of the structural and chemical requirements for selective activation of FFA2 versus FFA3. J. Biol. Chem., 286 (12): 10628-40. [PMID:21220428]

14. Seljeset, S; Siehler, S. (2012) Receptor-specific regulation of ERK1/2 activation by members of the "free fatty acid receptor" family. J. Recept. Signal Transduct. Res., 32 (4): 196-201. [PMID:22712802]

15. Senga, T., Iwamoto, S., Yoshida, T., Yokota, T., Adachi, K., Azuma, E., Hamaguchi, M. and Iwamoto, T. (2003) LSSIG is a novel murine leukocyte-specific GPCR that is induced by the activation of STAT3. Blood, 101: 1185-1187. [PMID:12393494]

16. Sykaras, AG; Demenis, C; Case, RM; McLaughlin, JT; Smith, CP. (2012) Duodenal enteroendocrine I-cells contain mRNA transcripts encoding key endocannabinoid and fatty acid receptors. PLoS ONE, 7 (8): e42373. [PMID:22876318]

17. Tazoe, H; Otomo, Y; Karaki, S; Kato, I; Fukami, Y; Terasaki, M; Kuwahara, A. (2009) Expression of short-chain fatty acid receptor GPR41 in the human colon. Biomed. Res., 30 (3): 149-56. [PMID:19574715]

18. Ulven, T. (2012) Short-chain free fatty acid receptors FFA2/GPR43 and FFA3/GPR41 as new potential therapeutic targets. Front Endocrinol (Lausanne), 3: 111. [PMID:23060857]

19. Wang, A; Akers, RM; Jiang, H. (2012) Short communication: Presence of G protein-coupled receptor 43 in rumen epithelium but not in the islets of Langerhans in cattle. J. Dairy Sci., 95 (3): 1371-5. [PMID:22365220]

20. Xiong, Y., Miyamoto, N., Shibata, K., Valasek, M. A., Motoike, T., Kedzierski, R. M. and Yanagisawa, M. (2004) Short-chain fatty acids stimulate leptin production in adipocytes through the G protein-coupled receptor GPR41. Proc Natl Acad Sci U S A, 101: 1045-1050. [PMID:14722361]

21. Zaibi, MS; Stocker, CJ; O'Dowd, J; Davies, A; Bellahcene, M; Cawthorne, MA; Brown, AJ; Smith, DM; Arch, JR. (2010) Roles of GPR41 and GPR43 in leptin secretory responses of murine adipocytes to short chain fatty acids. FEBS Lett., 584 (11): 2381-6. [PMID:20399779]

To cite this database page, please use the following:

Leigh Stoddart.
Free fatty acid receptors: FFA3 receptor. Last modified on 01/03/2013. Accessed on 23/05/2013. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=227.


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