Advertisement

Ligands at the Free Fatty Acid Receptors 2/3 (GPR43/GPR41)

  • Graeme MilliganEmail author
  • Daniele Bolognini
  • Eugenia Sergeev
Chapter
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 236)

Abstract

A large number of reviews and commentaries have highlighted the potential role of the short-chain fatty acid receptors GPR41 (FFA3) and, particularly, GPR43 (FFA2) as an interface between the intestinal microbiota and metabolic and inflammatory disorders. However, short-chain fatty acids have very modest potency and display limited selectivity between these two receptors, and studies on receptor knockout mice have resulted in non-uniform conclusions; therefore, selective and high-potency/high-affinity synthetic ligands are required to further explore the contribution of these receptors to health and disease. Currently no useful orthosteric ligands of FFA3 have been reported and although a number of orthosteric FFA2 agonists and antagonists have been described, a lack of affinity of different chemotypes of FFA2 antagonists at the mouse and rat orthologs of this receptor has hindered progress. Selective allosteric regulators of both FFA2 and FFA3 have provided tools to address a number of basic questions in both in vitro and ex vivo preparations, but at least some of the positive modulators appear to be biased and able to regulate only a subset of the functional capabilities of the short-chain fatty acids. Significant further progress is required to provide improved tool compounds to better assess potential translational opportunities of these receptors for short-chain fatty acids.

Keywords

Diabetes Free fatty acids Inflammation Microbiota 

References

  1. Agus A, Denizot J, Thévenot J, Martinez-Medina M, Massier S, Sauvanet P, Bernalier-Donadille A, Denis S, Hofman P, Bonnet R, Billard E, Barnich N (2016) Western diet induces a shift in microbiota composition enhancing susceptibility to adherent-invasive E. coli infection and intestinal inflammation. Sci Rep 6:19032Google Scholar
  2. Ang Z, Ding JL (2016) GPR41 and GPR43 in obesity and inflammation – protective or causative? Front Immunol 7:28CrossRefPubMedPubMedCentralGoogle Scholar
  3. Ballesteros JA, Weinstein H (1995) Integrated methods for modeling G-protein coupled receptors. Methods Neurosci 25:366–428CrossRefGoogle Scholar
  4. Bolognini D, Tobin AB, Milligan G, Moss CE (2016a) The pharmacology and function of short chain fatty acid receptors. Mol Pharmacol 89:388–398Google Scholar
  5. Bolognini D, Moss CE, Nilsson K, Petersson AU, Donnelly I, Sergeev E, König GM, Kostenis E, Kurowska-Stolarska M, Miller A, Dekker N, Tobin AB, Milligan G (2016b) A novel allosteric activator of free fatty acid 2 receptor displays unique Gi-functional bias. J Biol Chem 291:18915–18931CrossRefPubMedPubMedCentralGoogle Scholar
  6. Brantis C, Ooms F, Bernard J (2011) Novel amino acid derivatives and their use as gpr43 receptor modulators. PCT Int Appl WO2011092284Google Scholar
  7. Brown AJ, Goldsworthy SM, Barnes AA, Eilert MM, Tcheang L, Daniels D, Muir AI, Wigglesworth MJ, Kinghorn I, Fraser NJ, Pike NB, Strum JC, Steplewski KM, Murdock PR, Holder JC, Marshall FH, Szekeres PG, Wilson S, Ignar DM, Foord SM, Wise A, Dowell SJ (2003) The Orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids. J Biol Chem 278:11312–11319CrossRefPubMedGoogle Scholar
  8. Brown AJ, Tsoulou C, Ward E, Gower E, Bhudia N, Chowdhury F, Dean TW, Faucher N, Gangar A, Dowell SJ (2015) Pharmacological properties of acid N-thiazolylamide FFA2 agonists. Pharmacol Res Perspect 3, e00141CrossRefPubMedPubMedCentralGoogle Scholar
  9. Engelstoft MS, Park WM, Sakata I, Kristensen LV, Husted AS, Osborne-Lawrence S, Piper PK, Walker AK, Pedersen MH, Nohr MK, Pan J, Sinz CJ, Carrington PE, Akiyama TE, Jones RM, Tang C, Ahmed K, Offermanns S, Egerod KL, Zigman JM, Schwartz TW (2013) Seven transmembrane G protein-coupled receptor repertoire of gastric ghrelin cells. Mol Metab 2:376–392CrossRefPubMedPubMedCentralGoogle Scholar
  10. Forbes S, Stafford S, Coope G, Heffron H, Real K, Newman R, Davenport R, Barnes M, Grosse J, Cox H (2015) Selective FFA2 agonism appears to act via intestinal PYY to reduce transit and food intake but does not improve glucose tolerance in mouse models. Diabetes 64:3763–3771CrossRefPubMedGoogle Scholar
  11. Grundmann M, Tikhonova IG, Hudson BD, Smith NJ, Mohr K, Ulven T, Milligan G, Kenakin T, Kostenis E (2016) A molecular mechanism for sequential activation of a G protein-coupled receptor. Cell Chem Biol 23:392–403CrossRefPubMedGoogle Scholar
  12. Hoveyda H, Brantis CE, Dutheuil G, Zoute L, Schils D, Bernard J (2010) Compounds, pharmaceutical composition and methods for use in treating metabolic disorders. PCT Int Appl WO2011076732Google Scholar
  13. Hoveyda H, Brantis CE, Dutheuil G, Zoute L, Schils D, Bernard J (2011a) Compounds, pharmaceutical composition and methods for use in treating inflammatory diseases. PCT Int Appl WO2011076734Google Scholar
  14. Hoveyda H, Brantis CE, Dutheuil G, Zoute L, Schils D, Fraser G (2011b) Compounds, pharmaceutical composition and methods for use in treating for use in the treatment of gastrointestinal disorders. PCT Int Appl WO2011076732Google Scholar
  15. Hoveyda H, Schils D, Zoute L, Parcq J (2011c) Pyrrolidine or thiazolidine carboxylic acid derivatives, pharmaceutical compositions and methods for use as in treating metabolic disorders as agonists of G-protein coupled receptor 43 (GPR43). PCT Int Appl WO2011073376Google Scholar
  16. Hoveyda H, Zoute L, Lenoir F (2011d) Azepanes, azocanes and related compounds as GPR43 modulators and their preparation and use for the treatment of inflammatory, gastrointestinal and metabolic disorders. PCT Int Appl WO2011151436Google Scholar
  17. Hudson BD, Christiansen E, Murdoch H, Jenkins L, Hansen AH, Madsen O, Ulven T, Milligan G (2014) Complex pharmacology of novel allosteric free fatty acid 3 receptor ligands. Mol Pharmacol 86:200–210CrossRefPubMedGoogle Scholar
  18. Hudson BD, Due-Hansen ME, Christiansen E, Hansen AM, Mackenzie AE, Murdoch H, Pandey SK, Ward RJ, Marquez R, Tikhonova IG, Ulven T, Milligan G (2013) Defining the molecular basis for the first potent and selective orthosteric agonists of the FFA2 free fatty acid receptor. J Biol Chem 288:17296–17312CrossRefPubMedPubMedCentralGoogle Scholar
  19. 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 287:41195–41209CrossRefPubMedPubMedCentralGoogle Scholar
  20. Kenakin T (2015) The effective application of biased signaling to new drug discovery. Mol Pharmacol 88:1055–1061CrossRefPubMedGoogle Scholar
  21. 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 108:8030–8035CrossRefPubMedPubMedCentralGoogle Scholar
  22. Kimura I, Ozawa K, Inoue D, Imamura T, Kimura K, Maeda T, Terasawa K, Kashihara D, Hirano K, Tani T, Takahashi T, Miyauchi S, Shioi G, Inoue H, Tsujimoto G (2013) The gut microbiota suppresses insulin-mediated fat accumulation via the short-chain fatty acid receptor GPR43. Nat Commun 4:1829CrossRefPubMedPubMedCentralGoogle Scholar
  23. Lane JR, Sexton PM, Christopoulos A (2013) Bridging the gap: bitopic ligands of G-protein-coupled receptors. Trends Pharmacol Sci 34:59–66CrossRefPubMedGoogle Scholar
  24. Lee SU, In HJ, Kwon MS, Park BO, Jo M, Kim MO, Cho S, Lee S, Lee HJ, Kwak YS, Kim S (2013) beta-Arrestin 2 mediates G protein-coupled receptor 43 signals to nuclear factor-kappaB. Biol Pharm Bull 36:1754–1759Google Scholar
  25. Lee T, Schwandner R, Swaminath G, Weiszmann J, Cardozo M, Greenberg J, Jaeckel P, Ge H, Wang Y, Jiao X, Liu J, Kayser F, Tian H, Li Y (2008) Identification and functional characterization of allosteric agonists for the G protein-coupled receptor FFA2. Mol Pharmacol 74:1599–1609CrossRefPubMedGoogle Scholar
  26. Leonard JN, Chu ZL, Bruce MA, Boatman PD (2006) GPR41 and modulators thereof for the treatment of insulin-related disorders. PCT Int Appl WO 2006052566Google Scholar
  27. Le Poul E, Loison C, Struyf S, Springael JY, Lannoy V, Decobecq ME, Brezillon S, Duprie V, Vassart G, Van Damme J, Parmentier M, Detheux M (2003) Functional characterization of human receptors for short chain fatty acids and their role in polymorphonuclear cell activation. J Biol Chem 278:25481–25489CrossRefPubMedGoogle Scholar
  28. Nilsson NE, Kotarsky K, Owman C, Olde B (2003) Identification of a free fatty acid receptor, FFA2R, expressed on leukocytes and activated by short-chain fatty acids. Biochem Biophys Res Commun 303:1047–1052CrossRefPubMedGoogle Scholar
  29. McNelis JC, Lee YS, Mayoral R, van der Kant R, Johnson AM, Wollam J, Olefsky JM (2015) GPR43 potentiates β-cell function in obesity. Diabetes 64:3203–3217CrossRefPubMedPubMedCentralGoogle Scholar
  30. Ma L, Wang T, Shi M, Fu P, Pei H, Ye H (2016) Synthesis, activity and docking study of novel phenylthiazole-carboxamido acid derivatives as FFA2 agonists. Chem Biol Drug Des 88:26–37Google Scholar
  31. Milligan G, Shimpukade B, Ulven T, Hudson BD (2016) Complex pharmacology of the free fatty acid receptors. Chem Rev (in press)Google Scholar
  32. Milligan G, Stoddart LA, Smith NJ (2009) Agonism and allosterism: the pharmacology of the free fatty acid receptors FFA2 and FFA3. Br J Pharmacol 158:146–153CrossRefPubMedPubMedCentralGoogle Scholar
  33. Mohr K, Schmitz J, Schrage R, Tränkle C, Holzgrabe U (2013) Molecular alliance-from orthosteric and allosteric ligands to dualsteric/bitopic agonists at G protein coupled receptors. Angew Chem Int Ed Engl 52:508–516CrossRefPubMedGoogle Scholar
  34. Namour F, Galien R, Van Kaem T, Van der Aa A, Vanhoutte F, Beetens J, Van’t Klooster G (2016) Safety, pharmacokinetics and pharmacodynamics of GLPG0974, a potent and selective FFA2 antagonist, in healthy male subjects. Br J Clin Pharmacol 82:139–148Google Scholar
  35. Nohr MK, Pedersen MH, Gille A, Egerod KL, Engelstoft MS, Husted AS, Sichlau RM, Grunddal KV, Poulsen SS, Han S, Jones RM, Offermanns S, Schwartz TW et al (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 154:3552–3564CrossRefPubMedGoogle Scholar
  36. Park BO, Kim SH, Kong GY, da Kim H, Kwon MS, Lee SU, Kim MO, Cho S, Lee S, Lee HJ, Han SB, Kwak YS, Lee SB, Kim S (2016) Selective novel inverse agonists for human GPR43 augment GLP-1 secretion. Eur J Pharmacol 771:1–9CrossRefPubMedGoogle Scholar
  37. Pizzonero M, Dupont S, Babel M, Beaumont S, Bienvenu N, Blanqué R, Cherel L, Christophe T, Crescenzi B, De Lemos E, Delerive P, Deprez P, De Vos S, Djata F, Fletcher S, Kopiejewski S, L’Ebraly C, Lefrançois JM, Lavazais S, Manioc M, Nelles L, Oste L, Polancec D, Quénéhen V, Soulas F, Triballeau N, van der Aar EM, Vandeghinste N, Wakselman E, Brys R, Saniere L (2014) Discovery and optimization of an azetidine chemical series as a free fatty acid receptor 2 (FFA2) antagonist: from hit to clinic. J Med Chem 57:10044–10057CrossRefPubMedGoogle Scholar
  38. Priyadarshini M, Villa SR, Fuller M, Wicksteed B, Mackay CR, Alquier T, Poitout V, Mancebo H, Mirmira RG, Gilchrist A, Layden BT (2015) An acetate-specific GPCR, FFAR2, regulates insulin secretion. Mol Endocrinol 29:1055–1066CrossRefPubMedPubMedCentralGoogle Scholar
  39. Saniere LRM, Pizzonero MR, Triballeau N, Vandeghinste NER, De VSIJ, Brys RCX, Pourbaix-L’ebraly CD (2012) Preparation of azetidine derivatives as GPR43 antagonists useful in the treatment of metabolic and inflammatory diseases. PCT Int Appl WO2012098033Google Scholar
  40. Schmidt J, Smith NJ, Christiansen E, Tikhonova IG, Grundmann M, Hudson BD, Ward RJ, Drewke C, Milligan G, Kostenis E, Ulven T (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 286:10628–10640CrossRefPubMedPubMedCentralGoogle Scholar
  41. Schrage R, Schmitz AL, Gaffal E, Annala S, Kehraus S, Wenzel D, Büllesbach KM, Bald T, Inoue A, Shinjo Y, Galandrin S, Shridhar N, Hesse M, Grundmann M, Merten N, Charpentier TH, Martz M, Butcher AJ, Slodczyk T, Armando S, Effern M, Namkung Y, Jenkins L, Horn V, Stößel A, Dargatz H, Tietze D, Imhof D, Galés C, Drewke C, Müller CE, Hölzel M, Milligan G, Tobin AB, Gomeza J, Dohlman HG, Sondek J, Harden TK, Bouvier M, Laporte SA, Aoki J, Fleischmann BK, Mohr K, König GM, Tüting T, Kostenis E (2015) The experimental power of FR900359 to study Gq-regulated biological processes. Nat Commun 6:10156CrossRefPubMedPubMedCentralGoogle Scholar
  42. Sergeev E, Hansen H, Pandey SK, MacKenzie AE, Hudson BD, Ulven T, Milligan G (2016) Non-equivalence of key positively charged residues of the free fatty acid 2 receptor in the recognition and function of agonist versus antagonist ligands. J Biol Chem 291:303–317CrossRefPubMedGoogle Scholar
  43. Smith NJ, Stoddart LA, Devine NM, Jenkins L, Milligan G (2009) The action and mode of binding of thiazolidinedione ligands at free fatty acid receptor 1. J Biol Chem 284:17527–31759CrossRefPubMedPubMedCentralGoogle Scholar
  44. Smith NJ, Ward RJ, Stoddart LA, Hudson BD, Kostenis E, Ulven T, Morris JC, Tränkle C, Tikhonova IG, Adams DR, Milligan G (2011) Extracellular loop 2 of the free fatty acid receptor 2 mediates allosterism of a phenylacetamide ago-allosteric modulator. Mol Pharmacol 80:163–173CrossRefPubMedPubMedCentralGoogle Scholar
  45. Srivastava A, Yano J, Hirozane Y, Kefala G, Gruswitz F, Snell G, Lane W, Ivetac A, Aertgeerts K, Nguyen J, Jennings A, Okada K (2014) High-resolution structure of the human GPR40 receptor bound to allosteric agonist TAK-875. Nature 513:124–127CrossRefPubMedGoogle Scholar
  46. Stoddart L, Smith NJ, Milligan G (2008a) International Union of Pharmacology. LXXI. Free fatty acid receptors FFA1, -2, and -3: pharmacology and pathophysiological functions. Pharmacol Rev 60:405–417CrossRefPubMedGoogle Scholar
  47. Stoddart LA, Smith NJ, Jenkins L, Brown AJ, Milligan G (2008b) Conserved polar residues in transmembrane domains V, VI, and VII of free fatty acid receptor 2 and free fatty acid receptor 3 are required for the binding and function of short chain fatty acids. J Biol Chem 283:32913–32924CrossRefPubMedGoogle Scholar
  48. Sum CS, Tikhonova IG, Neumann S, Engel S, Raaka BM, Costanzi S, Gershengorn MC (2007) Identification of residues important for agonist recognition and activation in GPR40. J Biol Chem 282:29248–29255CrossRefPubMedGoogle Scholar
  49. Swaminath G, Jaeckel P, Guo Q, Cardozo M, Weiszmann J, Lindberg R, Wang Y, Schwandner R, Li Y (2011) Mutational analysis of G-protein coupled receptor--FFA2. Biochem Biophys Res Commun 405:122–127CrossRefPubMedGoogle Scholar
  50. Tang C, Ahmed K, Gille A, Lu S, Gröne HJ, Tunaru S, Offermanns S (2015) Loss of FFA2 and FFA3 increases insulin secretion and improves glucose tolerance in type 2 diabetes. Nat Med 21:173–177CrossRefPubMedGoogle Scholar
  51. Ulven T (2012) Short-chain free fatty acid receptors FFA2/GPR43 and FFA3/GPR41 as new potential therapeutic targets. Front Endocrinol (Lausanne) 3:111Google Scholar
  52. Vinolo MA, Ferguson GJ, Kulkarni S, Damoulakis G, Anderson K, Bohlooly-Y M, Stephens L, Hawkins PT, Curi R (2011) SCFAs induce mouse neutrophil chemotaxis through the GPR43 receptor. PLoS One 6, e21205CrossRefPubMedPubMedCentralGoogle Scholar
  53. Wang Y, Jiao X, Kayser F, Liu J, Wang Z, Wanska M, Greenberg J, Weiszmann J, Ge H, Tian H, Wong S, Schwandner R, Lee T, Li Y (2010) The first synthetic agonists of FFA2: discovery and SAR of phenylacetamides as allosteric modulators. Bioorg Med Chem Lett 20:493–498CrossRefPubMedGoogle Scholar
  54. Won YJ, Lu VB, Puhl HL 3rd, Ikeda SR (2013) Beta-hydroxybutyrate modulates N-type calcium channels in rat sympathetic neurons by acting as an agonist for the G-protein-coupled receptor FFA3. J Neurosci 33:19314–19325CrossRefPubMedPubMedCentralGoogle Scholar
  55. 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 584:2381–2386CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Graeme Milligan
    • 1
    Email author
  • Daniele Bolognini
    • 1
  • Eugenia Sergeev
    • 1
  1. 1.Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life SciencesUniversity of GlasgowGlasgowUK

Personalised recommendations