Skip to main content
SpringerLink
Log in

Fatty Acids Receptors

  • Chapter
Bioactive Lipid Mediators

  • 1356 Accesses

Abstract

In the past decade, a strategy to deorphanize G protein-coupled receptors (GPCRs) has identified a series of receptors for free fatty acids (FFAs) that play significant roles in nutrition regulation. In this free fatty acid receptor family, FFAR1 (GPR40) and FFAR4 (GPR120) are activated by medium- and long-chain FFAs. FFAR1 regulates insulin secretion in pancreatic β-cells, whereas FFAR4 promotes the secretion of glucagon-like peptide-1 (GLP-1) in the intestine and also act as the lipid sensor in the adipose tissue to sense dietary fat and control energy balance. In this chapter, we discuss recent advances in the identification of ligands and the pharmacological characterization of FFAR1 and FFAR4, and we present a summary of the current understanding of their physiological roles and potential as drug targets.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Briscoe CP, Tadayyon M, Andrews JL, Benson WG, Chambers JK, Eilert MM, Ellis C, Elshourbagy NA, Goetz AS, Minnick DT, Murdock PR, Sauls HR, Shabon U, Spinage LD, Strum JC, Szekeres PG, Tan KB, Way JM, Ignar DM, Wilson S, Muir AI (2003) The orphan G protein-coupled receptor GPR40 is activated by medium and long chain fatty acids. J Biol Chem 278(13):11303–11311

    Article  CAS  PubMed  Google Scholar 

  2. Briscoe CP, Peat AJ, McKeown SC, Corbett DF, Goetz AS, Littleton TR, McCoy DC, Kenakin TP, Andrews JL, Ammala C, Fornwald JA, Ignar DM, Jenkinson S (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):619–628

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Brown AJ, Goldsworthy SM, Barnes AA, Eilert MM, Tcheang L, Daniels D, Muir AI, Wigglesworth MJ, Kinghorn I, Fraser NJ, Pike NB, Sturm 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 278:11312–11319

    Article  CAS  PubMed  Google Scholar 

  4. Catchen JM, Conery JS, Postlethwait JH (2009) Automated identification of conserved synteny after whole-genome duplication. Genome Res 19(8):1497–1505

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Chawla A, Repa JJ, Evans RM, Mangelsdorf DJ (2001) Nuclear receptors and lipid physiology: opening the X-files. Science 294(5548):1866–1870

    Article  CAS  PubMed  Google Scholar 

  6. Davenport AP, Harmar AJ (2013) Evolving pharmacology of orphan GPCRs: IUPHAR commentary. Br J Pharmacol 170(4):693–695

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Dobbins RL, Chester MW, Daniels MB, McGarry JD, Stein DT (1998) Circulating fatty acids are essential for efficient glucose-stimulated insulin secretion after prolonged fasting in humans. Diabetes 47(10):1613–1618

    Article  CAS  PubMed  Google Scholar 

  8. Dobbins RL, Chester MW, Stevenson BE, Daniels MB, Stein DT, McGarry JD (1998) A fatty acid-dependent step is critically important for both glucose- and non-glucose-stimulated insulin secretion. J Clin Invest 101(11):2370–2376

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Feng DD, Luo Z, Roh SG, Hernandez M, Tawadros N, Keating DJ, Chen C (2006) Reduction in voltage-gated K+ currents in primary cultured rat pancreatic beta-cells by linoleic acids. Endocrinology 147(2):674–682

    Article  CAS  PubMed  Google Scholar 

  10. Fujiwara K, Maekawa F, Yada T (2005) Oleic acid interacts with GPR40 to induce Ca2+ signaling in rat islet beta-cells: mediation by PLC and L-type Ca2+ channel and link to insulin release. Am J Physiol Endocrinol Metab 289(4):E670–E677

    Article  CAS  PubMed  Google Scholar 

  11. 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

    Article  CAS  PubMed  Google Scholar 

  12. Garrido DM, Corbett DF, Dwornik KA, Goetz AS, Littleton TR, McKeown SC, Mills WY, Smalley TL, Briscoe CP, Peat AJ (2006) Synthesis and activity of small molecule GPR40 agonists. Bioorg Med Chem Lett 16(7):1840–1845

    Article  CAS  PubMed  Google Scholar 

  13. Gravena C, Mathias PC, Ashcroft SJ (2002) Acute effects of fatty acids on insulin secretion from rat and human islets of Langerhans. J Endocrinol 173(1):73–80

    Article  CAS  PubMed  Google Scholar 

  14. Halder S, Kumar S, Sharma R (2013) The therapeutic potential of GPR120: a patent review. Expert Opin Ther Pat 23(12):1581–1590

    Article  CAS  PubMed  Google Scholar 

  15. Hamid YH, Vissing H, Holst B, Urhammer SA, Pyke C, Hansen SK, Glumer C, Borch-Johnsen K, Jørgensen T, Schwartz TW, Pedersen O, Hansen T (2005) Studies of relationships between variation of the human G protein-coupled receptor 40 gene and type 2 diabetes and insulin release. Diabet Med 22(1):74–80

    Article  CAS  PubMed  Google Scholar 

  16. Hara T, Hirasawa A, Sun Q, Koshimizu TA, Itsubo C, Sadakane K, Awaji T, Tsujimoto G (2009) Flow cytometry-based binding assay for GPR40 (FFAR1; free fatty acid receptor 1). Mol Pharmacol 75(1):85–91

    Article  CAS  PubMed  Google Scholar 

  17. Hara T, Hirasawa A, Sun Q, Sadakane K, Itsubo C, Iga T, Adachi T, Koshimizu TA, Hashimoto T, Asakawa Y, Tsujimoto G (2009) Novel selective ligands for free fatty acid receptors GPR120 and GPR40. Naunyn Schmiedebergs Arch Pharmacol 380(3):247–255

    Article  CAS  PubMed  Google Scholar 

  18. Hirasawa A, Tsumaya K, Awaji T, Katsuma S, Adachi T, Yamada M, Sugimoto Y, Miyazaki S, Tsujimoto G (2005) Free fatty acids regulate gut incretin glucagon-like peptide-1 secretion through GPR120. Nat Med 11(1):90–94

    Article  CAS  PubMed  Google Scholar 

  19. Hu H, He LY, Gong Z, Li N, Lu YN, Zhai QW, Liu H, Jiang HL, Zhu WL, Wang HY (2009) A novel class of antagonists for the FFAs receptor GPR40. Biochem Biophys Res Commun 390(3):557–563

    Article  CAS  PubMed  Google Scholar 

  20. Hudson BD, Shimpukade B, Mackenzie AE, Butcher AJ, Pediani JD, Christiansen E, Heathcote H, Tobin AB, Ulven T, Milligan G (2013) The pharmacology of TUG-891, a potent and selective agonist of the free fatty acid receptor 4 (FFA4/GPR120), demonstrates both potential opportunity and possible challenges to therapeutic agonism. Mol Pharmacol 84(5):710–725

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Hudson BD, Shimpukade B, Milligan G, Ulven T (2014) The molecular basis of ligand interaction at free fatty acid receptor 4 (FFA4/GPR120). J Biol Chem 289(29):20345–20358

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Humphries PS, Benbow JW, Bonin PD, Boyer D, Doran SD, Frisbie RK, Piotrowski DW, Balan G, Bechle BM, Conn EL, Dirico KJ, Oliver RM, Soeller WC, Southers JA, Yang X (2009) Synthesis and SAR of 1,2,3,4-tetrahydroisoquinolin-1-ones as novel G-protein-coupled receptor 40 (GPR40) antagonists. Bioorg Med Chem Lett 19(9):2400–2403

    Article  CAS  PubMed  Google Scholar 

  23. Ichimura A, Hirasawa A, Poulain-Godefroy O, Bonnefond A, Hara T, Yengo L, Kimura I, Leloire A, Liu N, Iida K, Choquet H, Besnard P, Lecoeur C, Vivequin S, Ayukawa K, Takeuchi M, Ozawa K, Tauber M, Maffeis C, Morandi A, Buzzetti R, Elliott P, Pouta A, Jarvelin MR, Korner A, Kiess W, Pigeyre M, Caiazzo R, Van Hul W, Van Gaal L, Horber F, Balkau B, Levy-Marchal C, Rouskas K, Kouvatsi A, Hebebrand J, Hinney A, Scherag A, Pattou F, Meyre D, Koshimizu TA, Wolowczuk I, Tsujimoto G, Froguel P (2012) Dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human. Nature 483(7389):350–354

    Article  CAS  PubMed  Google Scholar 

  24. Itoh Y, Kawamata Y, Harada M, Kobayashi M, Fujii R, Fukusumi S, Ogi K, Hosoya M, Tanaka Y, Uejima H, Tanaka H, Maruyama M, Satoh R, Okubo S, Kizawa H, Komatsu H, Matsumura F, Noguchi Y, Shinohara T, Hinuma S, Fujisawa Y, Fujino M (2003) Free fatty acids regulate insulin secretion from pancreatic beta cells through GPR40. Nature 422(6928):173–176

    Article  CAS  PubMed  Google Scholar 

  25. Katsuma S, Hatae N, Yano T, Ruike Y, Kimura M, Hirasawa A, Tsujimoto G (2005) Free fatty acids inhibit serum deprivation-induced apoptosis through GPR120 in a murine enteroendocrine cell line STC-1. J Biol Chem 280(20):19507–19515

    Article  CAS  PubMed  Google Scholar 

  26. 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):8030–8035

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Kotarsky K, Nilsson NE, Flodgren E, Owman C, Olde B (2003) A human cell surface receptor activated by free fatty acids and thiazolidinedione drugs. Biochem Biophys Res Commun 301(2):406–410

    Article  CAS  PubMed  Google Scholar 

  28. Louet JF, Chatelain F, Decaux JF, Park EA, Kohl C, Pineau T, Girard J, Pegorier JP (2001) Long-chain fatty acids regulate liver carnitine palmitoyl-transferase I gene (L-CPT I) expression through a peroxisome-proliferator-activated receptor alpha (PPARalpha)-independent pathway. Biochem J 354(pt 1):189–197

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Maslowski KM, Vieira AT, Ng A, Kranich J, Sierro F, Yu D, Schilter HC, Rolph MS, Mackay F, Artis D, Xavier RJ, Teixeira MM, Mackay CR (2009) Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature 461(7268):1282–1286

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Matsumura S, Mizushige T, Yoneda T, Iwanaga T, Inoue K, Tsuzuki S, Fushiki T (2007) GPR expression in the rat taste bud relating to fatty acid sensing. Biomed Res 28(1):49–55

    Article  CAS  PubMed  Google Scholar 

  31. Miyauchi S, Hirasawa A, Iga T, Liu N, Itsubo C, Sadakane K, Hara T, Tsujimoto G (2009) Distribution and regulation of protein expression of the free fatty acid receptor GPR120. Naunyn Schmiedebergs Arch Pharmacol 379(4):427–434

    Article  CAS  PubMed  Google Scholar 

  32. Miyauchi S, Hirasawa A, Ichimura A, Hara T, Tsujimoto G (2010) New frontiers in gut nutrient sensor research: free fatty acid sensing in the gastrointestinal tract. J Pharmacol Sci 112(1):19–24

    Google Scholar 

  33. Nagasumi K, Esaki R, Iwachidow K, Yasuhara Y, Ogi K, Tanaka H, Nakata M, Yano T, Shimakawa K, Taketomi S, Takeuchi K, Odaka H, Kaisho Y (2009) Overexpression of GPR40 in pancreatic beta-cells augments glucose-stimulated insulin secretion and improves glucose tolerance in normal and diabetic mice. Diabetes 58(5):1067–1076

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Ogawa T, Hirose H, Miyashita K, Saito I, Saruta T (2005) GPR40 gene Arg211His polymorphism may contribute to the variation of insulin secretory capacity in Japanese men. Metab Clin Exp 54(3):296–299

    Article  CAS  PubMed  Google Scholar 

  35. Ohda Y, Walenta E, Akiyama TE, Lagakos WS, Lackey D, Pessentheiner AR, Sasik R, Hah N, Chi TJ, Cox JM, Powels MA, Di Salvo J, Sinz C, Watkins SM, Armando AM, Chung H, Evans RM, Quehenberger O, McNelis J, Bogner-Strauss JG, Olefsky JM (2014) A Gpr120-selective agonist improves insulin resistance and chronic inflammation in obese mice. Nat Med 20(8):942–947

    Article  Google Scholar 

  36. Oh DY, Talukdar S, Bae EJ, Imamura T, Morinaga H, Fan W, Li P, Lu WJ, Watkins SM, Olefsky JM (2010) GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell 142(5):687–698

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Papadopoulos JS, Agarwala R (2007) COBALT: constraint-based alignment tool for multiple protein sequences. Bioinformatics 23(9):1073–1079

    Article  CAS  PubMed  Google Scholar 

  38. Remely M, Aumueller E, Merold C, Dworzak S, Hippe B, Zanner J, Pointner A, Brath H, Haslberger AG (2014) Effects of short chain fatty acid producing bacteria on epigenetic regulation of FFAR3 in type 2 diabetes and obesity. Gene 537(1):85–92

    Article  CAS  PubMed  Google Scholar 

  39. Sasaki S, Kitamura S, Negoro N, Suzuki M, Tsujihata Y, Suzuki N, Santou T, Kanzaki N, Harada M, Tanaka Y, Kobayashi M, Tada N, Funami M, Tanaka T, Yamamoto Y, Fukatsu K, Yasuma T, Momose Y (2011) Design, synthesis, and biological activity of potent and orally available G protein-coupled receptor 40 agonists. J Med Chem 54(5):1365–1378

    Article  CAS  PubMed  Google Scholar 

  40. Sauer LA, Dauchy RT, Blask DE (2000) Mechanism for the antitumor and anticachectic effects of n-3 fatty acids. Cancer Res 60(18):5289–5295

    CAS  PubMed  Google Scholar 

  41. Shah BP, Liu P, Yu T, Hansen DR, Gilbertson TA (2012) TRPM5 is critical for linoleic acid-induced CCK secretion from the enteroendocrine cell line, STC-1. Am J Physiol Cell Physiol 302(1):C210–C219

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  42. 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(7516):124–127

    Article  CAS  PubMed  Google Scholar 

  43. Stein DT, Esser V, Stevenson BE, Lane KE, Whiteside JH, Daniels MB, Chen S, McGarry JD (1996) Essentiality of circulating fatty acids for glucose- stimulated insulin secretion in the fasted rat. J Clin Invest 97(12):2728–2735

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  44. Steneberg P, Rubins N, Bartoov-Shifman R, Walker MD, Edlund H (2005) The FFA receptor GPR40 links hyperinsulinemia, hepatic steatosis, and impaired glucose homeostasis in mouse. Cell Metab 1(4):245–258

    Article  CAS  PubMed  Google Scholar 

  45. Stoddart LA, Smith NJ, Milligan G (2008) International Union of Pharmacology. LXXI. Free fatty acid receptors FFA1, -2, and -3: pharmacology and pathophysiological functions. Pharmacol Rev 60(4):405–417

    Article  CAS  PubMed  Google Scholar 

  46. Suckow AT, Polidori D, Yan W, Chon S, Ma JY, Leonard J, Briscoe CP (2014) Alteration of the glucagon axis in GPR120 (FFAR4) knockout mice: a role for GPR120 in glucagon secretion. J Biol Chem 289(22):15751–15763

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  47. Sun Q, Hirasawa A, Hara T, Kimura I, Adachi T, Awaji T, Ishiguro M, Suzuki T, Miyata N, Tsujimoto G (2010) Structure–activity relationships of GPR120 agonists based on a docking simulation. Mol Pharmacol 78(5):804–810

    Article  CAS  PubMed  Google Scholar 

  48. Suzuki T, Igari S, Hirasawa A, Hata M, Ishiguro M, Fujieda H, Itoh Y, Hirano T, Nakagawa H, Ogura M, Makishima M, Tsujimoto G, Miyata N (2008) Identification of G protein-coupled receptor 120-selective agonists derived from PPARgamma agonists. J Med Chem 51(23):7640–7644

    Article  CAS  PubMed  Google Scholar 

  49. Takeuchi M, Hirasawa A, Hara T, Kimura I, Hirano T, Suzuki T, Miyata N, Awaji T, Ishiguro M, Tsujimoto G (2013) FFA1-selective agonistic activity based on docking simulation using FFA1 and GPR120 homology models. Br J Pharmacol 168(7):1570–1583

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. Tanaka T, Katsuma S, Adachi T, Koshimizu TA, Hirasawa A, Tsujimoto G (2008) Free fatty acids induce cholecystokinin secretion through GPR120. Naunyn Schmiedebergs Arch Pharmacol 377(4-6):523–527

    Article  CAS  PubMed  Google Scholar 

  51. Taneera J, Lang S, Sharma A, Fadista J, Zhou Y, Ahlqvist E, Jonsson A, Lyssenko V, Vikman P, Hansson O, Parikh H, Korsgren O, Soni A, Krus U, Zhang E, Jing XJ, Esguerra JL, Wollheim CB, Salehi A, Rosengren A, Renstrom E, Groop L (2012) A systems genetics approach identifies genes and pathways for type 2 diabetes in human islets. Cell Metab 16(1):122–134

    Article  CAS  PubMed  Google Scholar 

  52. Vettor R, Granzotto M, De Stefani D, Trevellin E, Rossato M, Farina MG, Milan G, Pilon C, Nigro A, Federspil G, Vigneri R, Vitiello L, Rizzuto R, Baratta R, Frittitta L (2008) Loss-of-function mutation of the GPR40 gene associates with abnormal stimulated insulin secretion by acting on intracellular calcium mobilization. J Clin Endocrinol Metab 93(9):3541–3550

    Google Scholar 

  53. Zhang X, Yan G, Li Y, Zhu W, Wang H (2010) DC2601 in obese Zucker rats. Biomed Pharmacother 64(9):647–651

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Genomic Drug Discovery Science, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, 606-8501, Japan

    Akira Hirasawa, Masato Takeuchi, Takafumi Hara, Ayako Hirata, Soshi Tanabe & Naoya Umeda

  2. Institute for Integrated Medical Sciences, Tokyo Women’s Medical University, Tokyo, 162-8666, Japan

    Akira Hirasawa

Authors
  1. Akira Hirasawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Masato Takeuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Takafumi Hara
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ayako Hirata
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Soshi Tanabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Naoya Umeda
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Akira Hirasawa .

Editor information

Editors and Affiliations

  1. Department of Biochemistry, Juntendo University Graduate School of Medicine, Tokyo, Japan

    Takehiko Yokomizo

  2. Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

    Makoto Murakami

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer Japan

About this chapter

Cite this chapter

Hirasawa, A., Takeuchi, M., Hara, T., Hirata, A., Tanabe, S., Umeda, N. (2015). Fatty Acids Receptors. In: Yokomizo, T., Murakami, M. (eds) Bioactive Lipid Mediators. Springer, Tokyo. https://doi.org/10.1007/978-4-431-55669-5_10

Download citation

Publish with us

Policies and ethics

Search

Navigation