FFA4/GPR120: Pharmacology and Therapeutic Opportunities

Trends in Pharmacological Sciences

Volumn 38, Issue 9, 2017, Pages 809-821

  Milligan, Graeme ^a   Alvarez Curto, Elisa ^a   Hudson, Brian D ^a   Prihandoko, Rudi ^a   Tobin, Andrew B ^a  

^a UNIVERSITY OF GLASGOW   (United Kingdom)

Author keywords

cancer; diabetes; free fatty acid; G protein coupled receptor; lung function inflammation

Indexed keywords

4 METHYL N 9H XANTHEN 9 YL BENZENESULFONAMIDE; 4 [[(3 PHENOXYPHENYL)METHYL]AMINO]BENZENEPROPANOIC ACID; 4 [[4 FLUORO 40 METHYL (1,10 BIPHENYL) 2 YL]METHOXY]BENZENEPROPANOIC ACID; BENZENESULFONAMIDE DERIVATIVE; CARBOXYLIC ACID; FATTY ACID; FREE FATTY ACID A1; G PROTEIN COUPLED RECEPTOR 120; GLUCAGON LIKE PEPTIDE 1; ISOTHIAZOLE DERIVATIVE; LINOLENIC ACID; PROPIONIC ACID; PYRIDINE; UNCLASSIFIED DRUG; [2 [3 (PYRIDIN 2 YLOXY)PHENYL] 2,3 DIHYDROBENZO[D]ISOTHIAZOLE 1,1 DIOXIDE]; [4 METHOXY N (2,4,6 TRIMETHYLPHENYL)BENZENESULFONAMIDE]; G PROTEIN COUPLED RECEPTOR; O3FAR1 PROTEIN, HUMAN; O3FAR1 PROTEIN, MOUSE;

CANCER THERAPY; CONDITIONED MEDIUM; DRUG EFFICACY; DRUG POTENCY; DRUG SELECTIVITY; FFA1 GENE; FFA4 GENE; GENE; GENE EXPRESSION; GLUCOSE HOMEOSTASIS; HUMAN; MOLECULARLY TARGETED THERAPY; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN SECRETION; REVIEW; SIGNAL TRANSDUCTION; AGONISTS; ANIMAL; ANTAGONISTS AND INHIBITORS;

ANIMALS; HUMANS; RECEPTORS, G-PROTEIN-COUPLED;

EID: 85024930756     PISSN: 01656147     EISSN: 18733735     Source Type: Journal    
DOI: 10.1016/j.tips.2017.06.006     Document Type: Review

References (80)

1. Blad, C.C., et al. G protein-coupled receptors for energy metabolites as new therapeutic targets. Nat. Rev. Drug Discov. 11 (2012), 603–619.
2. Milligan, G., et al. Complex pharmacology of free fatty acid receptors. Chem. Rev. 117 (2017), 67–110.
3. Ulven, T., Christiansen, E., Dietary fatty acids and their potential for controlling metabolic diseases through activation of FFA4/GPR120. Annu. Rev. Nutr. 35 (2015), 239–263.
4. Briscoe, C.P., et al. The orphan G protein-coupled receptor GPR40 is activated by medium and long chain fatty acids. J. Biol. Chem. 278 (2003), 11303–11311.
5. Hirasawa, A., et al. Free fatty acids regulate gut incretin glucagon-like peptide-1 secretion through GPR120. Nat. Med. 11 (2005), 90–94.
6. Stoddart, L.A., et al. International Union of Pharmacology. LXXI. Free fatty acid receptors FFA1, −2, and −3: pharmacology and pathophysiological functions. Pharmacol. Rev. 60 (2008), 405–417.
7. Davenport, A.P., et al. International Union of Basic and Clinical Pharmacology. LXXXVIII. G protein-coupled receptor list: recommendations for new pairings with cognate ligands. Pharmacol. Rev. 65 (2013), 967–986.
8. Leifke, E., et al. A multiple-ascending-dose study to evaluate safety, pharmacokinetics, and pharmacodynamics of a novel GPR40 agonist, TAK-875, in subjects with type 2 diabetes. Clin. Pharmacol. Ther. 92 (2012), 29–39.
9. Kaku, K., et al. Randomized, double-blind, dose-ranging study of TAK-875, a novel GPR40 agonist, in Japanese patients with inadequately controlled type 2 diabetes. Diabetes Care 36 (2013), 245–250.
10. Mayer, M., et al. Evaluation of the pharmacokinetics and safety of a single oral dose of fasiglifam in subjects with normal or varying degrees of impaired renal function. Drugs R D 14 (2014), 273–282.
11. Kaku, K., et al. Long-term safety and efficacy of fasiglifam (TAK-875), a G-protein-coupled receptor 40 agonist, as monotherapy and combination therapy in Japanese patients with type 2 diabetes: a 52-week open-label phase III study. Diabetes Obes. Metab. 18 (2016), 925–929.
12. Wolenski, F.S., et al. Fasiglifam (TAK-875) alters bile acid homeostasis in rats and dogs: a potential cause of drug induced liver injury. Toxicol. Sci. 157 (2017), 50–61.
13. Otieno, M.A., Fasiglifam (TAK-875): mechanistic investigation and retrospective identification of hazards for drug induced liver injury (DILI). Toxicol. Sci., 2017, 10.1093/toxsci/kfx040 Published online February 16, 2017.
14. Chen, C., et al. GPR40 agonists for the treatment of type 2 diabetes mellitus: the biological characteristics and the chemical space. Bioorg. Med. Chem. Lett. 26 (2016), 5603–5612.
15. Ghislain, J., Poitout, V., The role and future of FFA1 as a therapeutic target. Handb. Exp. Pharmacol. 236 (2017), 159–180.
16. Sharma, N., et al. Recent advances in development of GPR40 modulators (FFA1/FFAR1): an emerging target for type 2 diabetes. Mini Rev. Med. Chem. 17 (2017), 947–958.
17. Chen, Y., et al. A selective GPR40 (FFAR1) agonist LY2881835 provides immediate and durable glucose control in rodent models of type 2 diabetes. Pharmacol. Res. Perspect., 4, 2016, e00278.
18. Jurica, E.A., et al. Discovery of pyrrolidine-containing GPR40 agonists: stereochemistry effects a change in binding mode. J. Med. Chem. 60 (2017), 1417–1431.
19. Agarwal, S., et al. Identification of an orally efficacious GPR40/FFAR1 receptor agonist. ACS Med. Chem. Lett. 7 (2016), 1134–1138.
20. Christiansen, E., et al. Activity of dietary fatty acids on FFA1 and FFA4 and characterisation of pinolenic acid as a dual FFA1/FFA4 agonist with potential effect against metabolic diseases. Br. J. Nutr. 113 (2015), 1677–1688.
21. Oh, D.Y., et al. GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell 142 (2010), 687–698.
22. Li, X., et al. Cyclooxygenase-2 induction in macrophages is modulated by docosahexaenoic acid via interactions with free fatty acid receptor 4 (FFA4). FASEB J. 27 (2013), 4987–4997.
23. Wellhauser, L., Belsham, D.D., Activation of the omega-3 fatty acid receptor GPR120 mediates anti-inflammatory actions in immortalized hypothalamic neurons. J. Neuroinflamm., 11, 2014, 60.
24. Lager, S., et al. Expression and localization of the omega-3 fatty acid receptor GPR120 in human term placenta. Placenta 35 (2014), 523–525.
25. Kim, N., et al. Endogenous ligand for GPR120, docosahexaenoic acid, exerts benign metabolic effects on the skeletal muscles via AMP-activated protein kinase pathway. J. Biol. Chem. 290 (2015), 20438–20447.
26. Furutani, A., et al. Fish oil accelerates diet-induced entrainment of the mouse peripheral clock via GPR120. PLoS One, 10, 2015, e0132472.
27. Arantes, E.L., et al. Topical docosahexaenoic acid (DHA) accelerates skin wound healing in rats and activates GPR120. Biol. Res. Nurs. 18 (2016), 411–419.
28. Della Corte, C., et al. Docosahexaenoic acid and Its role in G-protein-coupled receptor 120 activation in children affected by nonalcoholic fatty liver disease. Endocr. Dev. 30 (2016), 29–36.
29. Bjursell, M., et al. The beneficial effects of n-3 polyunsaturated fatty acids on diet induced obesity and impaired glucose control do not require Gpr120. PLoS One, 9, 2014, e114942.
30. Chung, H., et al. Omega-3 fatty acids reduce obesity-induced tumor progression independent of GPR120 in a mouse model of postmenopausal breast cancer. Oncogene 34 (2015), 3504–3513.
31. Belchior, T., et al. Omega-3 fatty acids protect from diet-induced obesity, glucose intolerance, and adipose tissue inflammation through PPARγ-dependent and PPARγ-independent actions. Mol. Nutr. Food Res. 59 (2015), 957–967.
32. Pærregaard, S.I., et al. FFAR4 (GPR120) Signaling is not required for anti-inflammatory and insulin-sensitizing effects of omega-3 fatty acids. Mediators Inflamm., 2016, 2016, 1536047.
33. Shewale, S.V., et al. In vivo activation of leukocyte GPR120/FFAR4 by PUFAs has minimal impact on atherosclerosis in LDL receptor knockout mice. J. Lipid Res. 58 (2017), 236–246.
34. Li, X., et al. Endogenously generated omega-3 fatty acids attenuate vascular inflammation and neointimal hyperplasia by interaction with free fatty acid receptor 4 in mice. J. Am. Heart Assoc., 4, 2015, e001856.
35. O'Connell, T.D., et al. ω3-Polyunsaturated fatty acids for heart failure: effects of dose on efficacy and novel signaling through free fatty acid receptor 4. J. Mol. Cell Cardiol. 103 (2016), 74–92.
36. Houthuijzen, J.M., et al. Fatty acid 16:4(n-3) stimulates a GPR120-induced signaling cascade in splenic macrophages to promote chemotherapy resistance. FASEB J. 31 (2017), 2195–2209.
37. Yore, M.M., et al. Discovery of a class of endogenous mammalian lipids with anti-diabetic and anti-inflammatory effects. Cell 159 (2014), 318–332.
38. Briscoe, C.P., et al. 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 (2006), 619–628.
39. Watson, S.J., et al. Differential signaling by splice variants of the human free fatty acid receptor GPR120. Mol. Pharmacol. 81 (2012), 631–642.
40. Hudson, B.D., et al. 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 (2013), 710–725.
41. Alvarez-Curto, E., et al. Targeted elimination of G proteins and arrestins defines their specific contributions to both intensity and duration of G protein-coupled receptor signaling. J. Biol. Chem. 291 (2016), 27147–27159.
42. Engelstoft, M.S., et al. Seven transmembrane G protein-coupled receptor repertoire of gastric ghrelin cells. Mol. Metab. 2 (2013), 376–392.
43. Stone, V.M., et al. GPR120 (FFAR4) is preferentially expressed in pancreatic delta cells and regulates somatostatin secretion from murine islets of Langerhans. Diabetologia 57 (2014), 1182–1191.
44. Segerstolpe, Å., et al. Single-cell transcriptome profiling of human pancreatic islets in health and type 2 diabetes. Cell. Metab. 24 (2016), 593–607.
45. Talukdar, S., et al. Targeting GPR120 and other fatty acid-sensing GPCRs ameliorates insulin resistance and inflammatory diseases. Trends Pharmacol. Sci. 32 (2011), 543–550.
46. 35 7 in the C-terminal tail. Biochem. Pharmacol. 87 (2014), 650–659.
47. Butcher, A.J., et al. Concomitant action of structural elements and receptor phosphorylation determines arrestin-3 interaction with the free fatty acid receptor FFA4. J. Biol. Chem. 289 (2014), 18451–18465.
48. Prihandoko, R., et al. Distinct phosphorylation clusters determine the signaling outcome of free fatty acid receptor 4/G protein-coupled receptor 120. Mol. Pharmacol. 89 (2016), 505–520.
49. Moore, K., et al. Cloning, expression, and pharmacological characterization of the GPR120 free fatty acid receptor from cynomolgus monkey: comparison with human GPR120 splice variants. Comp. Biochem. Physiol. B Biochem. Mol. Biol. 154 (2009), 419–426.
50. Suzuki, T., et al. Identification of G protein-coupled receptor 120-selective agonists derived from PPARgamma agonists. J. Med. Chem. 51 (2008), 7640–7644.
51. Sun, Q., et al. Structure-activity relationships of GPR120 agonists based on a docking simulation. Mol. Pharmacol. 78 (2010), 804–810.
52. Shimpukade, B., et al. Discovery of a potent and selective GPR120 agonist. J. Med. Chem. 55 (2012), 4511–4515.
53. Suckow, A.T., Briscoe, C.P., Key questions for translation of FFA receptors: from pharmacology to medicines. Handb. Exp. Pharmacol. 236 (2017), 101–131.
54. Adams, G.L., et al. Discovery of chromane propionic acid analogues as selective agonists of GPR120 with in vivo activity in rodents. ACS Med. Chem. Lett. 8 (2016), 96–101.
55. Sparks, S.M., et al. Exploration of phenylpropanoic acids as agonists of the free fatty acid receptor 4 (FFA4): Identification of an orally efficacious FFA4 agonist. Bioorg. Med. Chem. Lett. 27 (2017), 1278–1283.
56. Sparks, S.M., et al. Identification of diarylsulfonamides as agonists of the free fatty acid receptor 4 (FFA4/GPR120). Bioorg. Med. Chem. Lett. 24 (2014), 3100–3103.
57. Azevedo, C.M., et al. Non-acidic free fatty acid receptor 4 agonists with antidiabetic activity. J. Med. Chem. 59 (2016), 8868–8878.
58. Hansen, S.V., Ulven, T., Pharmacological tool compounds for the free fatty acid receptor 4 (FFA4/GPR120). Handb. Exp. Pharmacol. 236 (2017), 33–56.
59. Scheen, A.J., Investigational insulin secretagogues for type 2 diabetes. Expert Opin. Investig. Drugs 25 (2016), 405–422.
60. Watterson, K.R., et al. Probe-dependent negative allosteric modulators of the long-chain free fatty acid receptor FFA4. Mol. Pharmacol. 91 (2017), 630–641.
61. Quesada-López, T., et al. The lipid sensor GPR120 promotes brown fat activation and FGF21 release from adipocytes. Nat. Commun., 7, 2016, 13479.
62. Villegas-Comonfort, S., et al. Effects of arachidonic acid on FFA4 receptor: signaling, phosphorylation and internalization. Prostaglandins Leukot. Essent. Fatty Acids 117 (2017), 1–10.
63. Tran, D.Q., et al. Induction of Gnrh mRNA expression by the ω-3 polyunsaturated fatty acid docosahexaenoic acid and the saturated fatty acid palmitate in a GnRH-synthesizing neuronal cell model, mHypoA-GnRH/GFP. Mol. Cell Endocrinol. 426 (2016), 125–135.
64. Paillamanque, J., et al. Arachidonic acid triggers [Ca2+]i increases in rat round spermatids by a likely GPR activation, ERK signalling and ER/acidic compartments Ca2+ release. PLoS One, 12, 2017, e0172128.
65. Houthuijzen, J.M., For better or worse: FFAR1 and FFAR4 signaling in cancer and diabetes. Mol. Pharmacol. 90 (2017), 738–743.
66. Roodhart, J.M., et al. Mesenchymal stem cells induce resistance to chemotherapy through the release of platinum-induced fatty acids. Cancer Cell 20 (2011), 370–383.
67. Houthuijzen, J.M., et al. Lysophospholipids secreted by splenic macrophages induce chemotherapy resistance via interference with the DNA damage response. Nat. Commun., 5, 2014, 5275.
68. Liu, Z., et al. Omega-3 fatty acids and other FFA4 agonists inhibit growth factor signaling in human prostate cancer cells. J. Pharmacol. Exp. Ther. 352 (2015), 380–394.
69. Hopkins, M.M., et al. Eicosopentaneoic acid and other free fatty acid receptor agonists inhibit lysophosphatidic acid- and epidermal growth factor-induced proliferation of human breast cancer cells. J. Clin. Med., 5, 2016, E16.
70. Miyauchi, S., et al. Distribution and regulation of protein expression of the free fatty acid receptor GPR120. Naunyn Schmiedebergs Arch. Pharmacol. 379 (2009), 427–434.
71. Freedman, S.D., et al. Association of cystic fibrosis with abnormalities in fatty acid metabolism. N. Eng. J. Med. 350 (2004), 560–569.
72. Lee, K.P., et al. ω-3 polyunsaturated fatty acids accelerate airway repair by activating FFA4 in club cells. Am. J. Physiol. Lung Cell. Mol. Physiol. 312 (2017), L835–L844.
73. Wiedegmann, H.P., Fish oil is not the fix for acute lung injury. Crit. Care Med. 39 (2011), 1829–1830.
74. Cintra, D.E., et al. Unsaturated fatty acids revert diet-induced hypothalamic inflammation in obesity. PLoS One, 7, 2012, e30571.
75. Lu, X., et al. Postprandial inhibition of gastric ghrelin secretion by long-chain fatty acid through GPR120 in isolated gastric ghrelin cells and mice. Am. J. Physiol. Gastrointest. Liver Physiol. 303 (2012), G367–G376.
76. Bradley, S.J., et al. Mapping physiological G protein-coupled receptor signaling pathways reveals a role for receptor phosphorylation in airway contraction. Proc. Natl. Acad. Sci. U. S. A. 113 (2016), 4524–4529.
77. Susuki, M., et al. Medium-chain fatty acid-sensing receptor, GPR84, is a proinflammatory receptor. J. Biol. Chem. 288 (2013), 10684–10689.
78. Lee, J., et al. Branched fatty acid esters of hydroxy fatty acids (FAHFAs) protect against colitis by regulating gut innate and adaptive immune responses. J. Biol. Chem. 291 (2016), 22207–22217.
79. Yore, M.M., et al. Discovery of a class of endogenous mammalian lipids with anti-diabetic and anti-inflammatory effects. Cell 159 (2014), 318–332.
80. Oh, D.Y., Olefsky, J.M., Omega 3 fatty acids and GPR120. Cell Metab. 15 (2012), 564–565.