Metabolism meets immunity: The role of free fatty acid receptors in the immune system

Biochemical Pharmacology

Volumn 114, Issue , 2016, Pages 3-13

  Alvarez Curto, Elisa ^a   Milligan, Graeme ^a  

^a UNIVERSITY OF GLASGOW   (United Kingdom)

Author keywords

Free fatty acids (FFAs); GPCR; Immuno metabolism; Inflammation; Macrophages; Obesity

Indexed keywords

FATTY ACID; FFAR 2 PROTEIN; FFAR 3 PROTEIN; FFAR 4 PROTEIN; G PROTEIN COUPLED RECEPTOR; G PROTEIN COUPLED RECEPTOR 40; OMEGA 3 FATTY ACID; SHORT CHAIN FATTY ACID; UNCLASSIFIED DRUG;

ANTIINFLAMMATORY ACTIVITY; ASTHMA; CARBOHYDRATE DIET; HUMAN; IMMUNE RESPONSE; IMMUNE SYSTEM; IMMUNOCOMPETENT CELL; INSULIN RESISTANCE; INTESTINE FLORA; MACROPHAGE; METABOLISM; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; OBESITY; PRIORITY JOURNAL; RESPIRATORY TRACT INFLAMMATION; REVIEW; SIGNAL TRANSDUCTION; ANIMAL; IMMUNOLOGY; INFLAMMATION; INTESTINE MUCOSA; PANCREAS;

ANIMALS; FATTY ACIDS, NONESTERIFIED; FATTY ACIDS, OMEGA-3; GASTROINTESTINAL MICROBIOME; HUMANS; IMMUNE SYSTEM; INFLAMMATION; INTESTINAL MUCOSA; PANCREAS; RECEPTORS, G-PROTEIN-COUPLED;

EID: 84977119864     PISSN: 00062952     EISSN: 18732968     Source Type: Journal    
DOI: 10.1016/j.bcp.2016.03.017     Document Type: Review

References (146)

1. [1] Le Chatelier, E., Nielsen, T., Qin, J., Prifti, E., Hildebrand, F., Falony, G., et al. Richness of human gut microbiome correlates with metabolic markers. Nature 500 (2013), 541–546.
2. [2] Thorburn, A.N., Macia, L., Mackay, C.R., Diet, metabolites, and “western-lifestyle” inflammatory diseases. Immunity 40 (2014), 833–842.
3. [3] Font-Burgada, J., Sun, B., Karin, M., Obesity and cancer: the oil that feeds the flame. Cell Metab. 23 (2016), 48–62.
4. [4] Holliday, N.D., Watson, S.J., Brown, A.J., Drug discovery opportunities and challenges at g protein coupled receptors for long chain free fatty acids. Front. Endocrinol. (Lausanne), 2, 2011, 112.
5. [5] Hudson, B.D., Ulven, T., Milligan, G., The therapeutic potential of allosteric ligands for free fatty acid sensitive GPCRs. Curr. Top. Med. Chem. 13 (2013), 14–25.
6. [6] Wu, Q., Wang, H., Zhao, X., Shi, Y., Jin, M., Wan, B., et al. Identification of G-protein-coupled receptor 120 as a tumor-promoting receptor that induces angiogenesis and migration in human colorectal carcinoma. Oncogene 32 (2013), 5541–5550.
7. [7] Chung, H., Lee, Y.S., Mayoral, R., Oh, D.Y., Siu, J.T., Webster, N.J., 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.
8. [8] Yates, C.M., Calder, P.C., Ed Rainger, G., Pharmacology and therapeutics of omega-3 polyunsaturated fatty acids in chronic inflammatory disease. Pharmacol. Ther. 141 (2014), 272–282.
9. [9] Lackey, D.E., Olefsky, J.M., Regulation of metabolism by the innate immune system. Nat. Rev. Endocrinol. 12 (2016), 15–28.
10. [10] Murray, P.J., Rathmell, J., Pearce, E., SnapShot: immunometabolism. Cell Metab., 22, 2015, 190-e1.
11. [11] Rasoamanana, R., Darcel, N., Fromentin, G., Tome, D., Nutrient sensing and signalling by the gut. Proc. Nutr. Soc. 71 (2012), 446–455.
12. [12] Hara, T., Kashihara, D., Ichimura, A., Kimura, I., Tsujimoto, G., Hirasawa, A., Role of free fatty acid receptors in the regulation of energy metabolism. Biochim. Biophys. Acta 1841 (2014), 1292–1300.
13. [13] Hara, T., Kimura, I., Inoue, D., Ichimura, A., Hirasawa, A., Free fatty acid receptors and their role in regulation of energy metabolism. Rev. Physiol. Biochem. Pharmacol. 164 (2013), 77–116.
14. [14] Ichimura, A., Hirasawa, A., Hara, T., Tsujimoto, G., Free fatty acid receptors act as nutrient sensors to regulate energy homeostasis. Prostaglandins Other Lipid Mediat. 89 (2009), 82–88.
15. [15] Kimura, I., Inoue, D., Hirano, K., Tsujimoto, G., The SCFA receptor GPR43 and energy metabolism. Front. Endocrinol. (Lausanne), 5, 2014, 85.
16. [16] Stoddart, L.A., Smith, N.J., Milligan, G., International Union of Pharmacology. LXXI. Free fatty acid receptors FFA1, -2, and -3: pharmacology and pathophysiological functions. Pharmacol. Rev. 60 (2008), 405–417.
17. [17] Coope, A., Torsoni, A.S., Velloso, L., Mechanisms in endocrinology: metabolic and inflammatory pathways on the pathogenesis of type 2 diabetes. Eur. J. Endocrinol., 2015.
18. [18] Offermanns, S., Free fatty acid (FFA) and hydroxy carboxylic acid (HCA) receptors. Annu. Rev. Pharmacol. Toxicol. 54 (2014), 407–434.
19. [19] Tvrzicka, E., Kremmyda, L.S., Stankova, B., Zak, A., Fatty acids as biocompounds: their role in human metabolism, health and disease—a review. Part 1: classification, dietary sources and biological functions. Biomed. Pap. Med. Fac. Univ. Palacky Olomouc. Czech Repub. 155 (2011), 117–130.
20. [20] Kremmyda, L.S., Tvrzicka, E., Stankova, B., Zak, A., Fatty acids as biocompounds: their role in human metabolism, health and disease: a review. Part 2: fatty acid physiological roles and applications in human health and disease. Biomed. Pap. Med. Fac. Univ. Palacky Olomouc. Czech Repub. 155 (2011), 195–218.
21. [21] Macfarlane, S., Bahrami, B., Macfarlane, G.T., Mucosal biofilm communities in the human intestinal tract. Adv. Appl. Microbiol. 75 (2011), 111–143.
22. [22] Krishnan, S., Alden, N., Lee, K., Pathways and functions of gut microbiota metabolism impacting host physiology. Curr. Opin. Biotechnol. 36 (2015), 137–145.
23. [23] Hudson, B.D., Smith, N.J., Milligan, G., Experimental challenges to targeting poorly characterized GPCRs: uncovering the therapeutic potential for free fatty acid receptors. Adv. Pharmacol. 62 (2011), 175–218.
24. [24] Macia, L., Thorburn, A.N., Binge, L.C., Marino, E., Rogers, K.E., Maslowski, K.M., et al. Microbial influences on epithelial integrity and immune function as a basis for inflammatory diseases. Immunol. Rev. 245 (2012), 164–176.
25. [25] Maslowski, K.M., Mackay, C.R., Diet, gut microbiota and immune responses. Nat. Immunol. 12 (2011), 5–9.
26. [26] Sawzdargo, M., George, S.R., Nguyen, T., Xu, S., Kolakowski, L.F., O'Dowd, B.F., 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 (1997), 543–547.
27. [27] Brown, A.J., Goldsworthy, S.M., Barnes, A.A., Eilert, M.M., Tcheang, L., Daniels, D., et al. The Orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids. J. Biol. Chem. 278 (2003), 11312–11319.
28. [28] Puhl, H.L. 3rd, Won, Y.J., Lu, V.B., Ikeda, S.R., Human GPR42 is a transcribed multisite variant that exhibits copy number polymorphism and is functional when heterologously expressed. Sci. Rep., 5, 2015, 12880.
29. [29] Hirasawa, A., Tsumaya, K., Awaji, T., Katsuma, S., Adachi, T., Yamada, M., et al. Free fatty acids regulate gut incretin glucagon-like peptide-1 secretion through GPR120. Nat. Med. 11 (2005), 90–94.
30. [30] Briscoe, C.P., Tadayyon, M., Andrews, J.L., Benson, W.G., Chambers, J.K., Eilert, M.M., 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.
31. [31] Itoh, Y., Kawamata, Y., Harada, M., Kobayashi, M., Fujii, R., Fukusumi, S., et al. Free fatty acids regulate insulin secretion from pancreatic beta cells through GPR40. Nature 422 (2003), 173–176.
32. [32] Kotarsky, K., Nilsson, N.E., Flodgren, E., Owman, C., Olde, B., A human cell surface receptor activated by free fatty acids and thiazolidinedione drugs. Biochem. Biophys. Res. Commun. 301 (2003), 406–410.
33. [33] Nilsson, N.E., Kotarsky, K., Owman, C., Olde, B., Identification of a free fatty acid receptor, FFA2R, expressed on leukocytes and activated by short-chain fatty acids. Biochem. Biophys. Res. Commun. 303 (2003), 1047–1052.
34. [34] Burns, R.N., Moniri, N.H., 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 (2010), 1030–1035.
35. [35] Moore, K., Zhang, Q., Murgolo, N., Hosted, T., Duffy, R., 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.
36. [36] Galindo, M.M., Voigt, N., Stein, J., van Lengerich, J., Raguse, J.D., Hofmann, T., et al. G protein-coupled receptors in human fat taste perception. Chem. Senses. 37 (2012), 123–139.
37. [37] Smith, N.J., Low affinity GPCRs for metabolic intermediates: challenges for pharmacologists. Front. Endocrinol. (Lausanne), 3, 2012, 1.
38. [38] Cummings, J.H., Pomare, E.W., Branch, W.J., Naylor, C.P., Macfarlane, G.T., Short chain fatty acids in human large intestine, portal, hepatic and venous blood. Gut 28 (1987), 1221–1227.
39. [39] Topping, D.L., Clifton, P.M., Short-chain fatty acids and human colonic function: roles of resistant starch and nonstarch polysaccharides. Physiol. Rev. 81 (2001), 1031–1064.
40. [40] Pouteau, E., Meirim, I., Metairon, S., Fay, L.B., Acetate, propionate and butyrate in plasma: determination of the concentration and isotopic enrichment by gas chromatography/mass spectrometry with positive chemical ionization. J. Mass. Spectrom. 36 (2001), 798–805.
41. [41] Wang, Y., Liu, J.J., Dransfield, P.J., Zhu, L., Wang, Z., Du, X., et al. Discovery and optimization of potent GPR40 full agonists containing tricyclic spirocycles. ACS Med. Chem. Lett. 4 (2013), 551–555.
42. [42] Schmidt, J., Smith, N.J., Christiansen, E., Tikhonova, I.G., Grundmann, M., Hudson, B.D., et al. 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 (2011), 10628–10640.
43. [43] Bolognini, D., Tobin, A.B., Milligan, G., Moss, C.E., The pharmacology and function of short chain fatty acid receptors. Mol. Pharmacol. 89 (2015), 388–398.
44. [44] Milligan, G., Shimpukade, B., Ulven, T., Hudson, B.D., Complex pharmacology of the Free Fatty Acid receptors. Chem. Rev., 2016 (in press).
45. [45] Wang, J., Wu, X., Simonavicius, N., Tian, H., Ling, L., Medium-chain fatty acids as ligands for orphan G protein-coupled receptor GPR84. J. Biol. Chem. 281 (2006), 34457–34464.
46. [46] Wittenberger, T., Schaller, H.C., Hellebrand, S., An expressed sequence tag (EST) data mining strategy succeeding in the discovery of new G-protein coupled receptors. J. Mol. Biol. 307 (2001), 799–813.
47. [47] Le Poul, E., Loison, C., Struyf, S., Springael, J.Y., Lannoy, V., Decobecq, M.E., et al. Functional characterization of human receptors for short chain fatty acids and their role in polymorphonuclear cell activation. J. Biol. Chem. 278 (2003), 25481–25489.
48. [48] Kimura, I., Inoue, D., Maeda, T., Hara, T., Ichimura, A., Miyauchi, S., et al. 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 (2011), 8030–8035.
49. [49] Forbes, S., Stafford, S., Coope, G., Heffron, H., Real, K., Newman, R., et al. 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 (2015), 3763–3771.
50. [50] Itoh, Y., Hinuma, S., GPR40, a free fatty acid receptor on pancreatic beta cells, regulates insulin secretion. Hepatol. Res. 33 (2005), 171–173.
51. [51] Salehi, A., Flodgren, E., Nilsson, N.E., Jimenez-Feltstrom, J., Miyazaki, J., Owman, C., et al. Free fatty acid receptor 1 (FFA(1)R/GPR40) and its involvement in fatty-acid-stimulated insulin secretion. Cell Tissue Res. 322 (2005), 207–215.
52. [52] Edfalk, S., Steneberg, P., Edlund, H., Gpr40 is expressed in enteroendocrine cells and mediates free fatty acid stimulation of incretin secretion. Diabetes 57 (2008), 2280–2287.
53. [53] Liou, A.P., Lu, X., Sei, Y., Zhao, X., Pechhold, S., Carrero, R.J., et al. The G-protein-coupled receptor GPR40 directly mediates long-chain fatty acid-induced secretion of cholecystokinin. Gastroenterology 140 (2011), 903–912.
54. [54] Hauge, M., Vestmar, M.A., Husted, A.S., Ekberg, J.P., Wright, M.J., Di Salvo, J., et al. GPR40 (FFAR1) – combined Gs and Gq signaling in vitro is associated with robust incretin secretagogue action ex vivo and in vivo. Mol. Metab. 4 (2015), 3–14.
55. [55] Stone, V.M., Dhayal, S., Brocklehurst, K.J., Lenaghan, C., Sorhede Winzell, M., Hammar, 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.
56. [56] Bjursell, M., Xu, X., Admyre, T., Bottcher, G., Lundin, S., Nilsson, R., 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.
57. [57] Oh, D.Y., Talukdar, S., Bae, E.J., Imamura, T., Morinaga, H., Fan, W., et al. GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell 142 (2010), 687–698.
58. [58] Castoldi, A., Naffah de Souza, C., Camara, N.O., Moraes-Vieira, P.M., The macrophage switch in obesity development. Front. Immunol., 6, 2015, 637.
59. [59] Kratz, M., Coats, B.R., Hisert, K.B., Hagman, D., Mutskov, V., Peris, E., et al. Metabolic dysfunction drives a mechanistically distinct proinflammatory phenotype in adipose tissue macrophages. Cell Metab. 20 (2014), 614–625.
60. [60] Gordon, S., Taylor, P.R., Monocyte and macrophage heterogeneity. Nat. Rev. Immunol. 5 (2005), 953–964.
61. [61] Martinez, F.O., Helming, L., Gordon, S., Alternative activation of macrophages: an immunologic functional perspective. Annu. Rev. Immunol. 27 (2009), 451–483.
62. [62] Oh da, Y., Walenta, E., Akiyama, T.E., Lagakos, W.S., Lackey, D., Pessentheiner, A.R., et al. A Gpr120-selective agonist improves insulin resistance and chronic inflammation in obese mice. Nat. Med. 20 (2014), 942–947.
63. [63] Dranse, H.J., Kelly, M.E., Hudson, B.D., Drugs or diet? – developing novel therapeutic strategies targeting the free fatty acid family of GPCRs. Br. J. Pharmacol. 170 (2013), 696–711.
64. [64] Milligan, G., Alvarez-Curto, E., Watterson, K.R., Ulven, T., Hudson, B.D., Characterizing pharmacological ligands to study the long-chain fatty acid receptors GPR40/FFA1 and GPR120/FFA4. Br. J. Pharmacol. 172 (2015), 3254–3265.
65. [65] Milligan, G., Ulven, T., Murdoch, H., Hudson, B.D., G-protein-coupled receptors for free fatty acids: nutritional and therapeutic targets. Br. J. Nutr. 111:Suppl 1 (2014), S3–S7.
66. [66] Hudson, B.D., Shimpukade, B., Mackenzie, A.E., Butcher, A.J., Pediani, J.D., Christiansen, E., 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.
67. [67] Qian, J., Wu, C., Chen, X., Li, X., Ying, G., Jin, L., et al. Differential requirements of arrestin-3 and clathrin for ligand-dependent and -independent internalization of human G protein-coupled receptor 40. Cell. Signal. 26 (2014), 2412–2423.
68. [68] Mancini, A.D., Poitout, V., The fatty acid receptor FFA1/GPR40 a decade later: how much do we know?. Trends Endocrinol. Metab. 24 (2013), 398–407.
69. [69] Mancini, A.D., Bertrand, G., Vivot, K., Carpentier, E., Tremblay, C., Ghislain, J., et al. Beta-arrestin recruitment and biased agonism at free fatty acid receptor 1. J. Biol. Chem. 290 (2015), 21131–21140.
70. [70] Shukla, A.K., Xiao, K., Lefkowitz, R.J., Emerging paradigms of beta-arrestin-dependent seven transmembrane receptor signaling. Trends Biochem. Sci. 36 (2011), 457–469.
71. [71] Reiter, E., Ahn, S., Shukla, A.K., Lefkowitz, R.J., Molecular mechanism of beta-arrestin-biased agonism at seven-transmembrane receptors. Annu. Rev. Pharmacol. Toxicol. 52 (2012), 179–197.
72. [72] Reiter, E., Lefkowitz, R.J., GRKs and beta-arrestins: roles in receptor silencing, trafficking and signaling. Trends Endocrinol. Metab. 17 (2006), 159–165.
73. [73] Shenoy, S.K., Lefkowitz, R.J., Beta-Arrestin-mediated receptor trafficking and signal transduction. Trends Pharmacol. Sci. 32 (2011), 521–533.
74. [74] Gurevich, E.V., Gurevich, V.V., Arrestins: ubiquitous regulators of cellular signaling pathways. Genome Biol., 7, 2006, 236.
75. [75] Gurevich, V.V., Gurevich, E.V., The structural basis of arrestin-mediated regulation of G-protein-coupled receptors. Pharmacol. Ther. 110 (2006), 465–502.
76. [76] Luttrell, L.M., Arrestin pathways as drug targets. Prog. Mol. Biol. Transl. Sci. 118 (2013), 469–497.
77. [77] Rajagopal, S., Rajagopal, K., Lefkowitz, R.J., Teaching old receptors new tricks: biasing seven-transmembrane receptors. Nat. Rev. Drug Discov. 9 (2010), 373–386.
78. [78] Defea, K., Beta-arrestins and heterotrimeric G-proteins: collaborators and competitors in signal transduction. Br. J. Pharmacol. 153:Suppl 1 (2008), S298–S309.
79. [79] Sun, Y., Cheng, Z., Ma, L., Pei, G., Beta-arrestin2 is critically involved in CXCR4-mediated chemotaxis, and this is mediated by its enhancement of p38 MAPK activation. J. Biol. Chem. 277 (2002), 49212–49219.
80. [80] DeFea, K.A., Beta-arrestins as regulators of signal termination and transduction: how do they determine what to scaffold?. Cell. Signal. 23 (2011), 621–629.
81. [81] McDonald, P.H., Chow, C.W., Miller, W.E., Laporte, S.A., Field, M.E., Lin, F.T., et al. Beta-arrestin 2: a receptor-regulated MAPK scaffold for the activation of JNK3. Science 290 (2000), 1574–1577.
82. [82] Watson, S.J., Brown, A.J., Holliday, N.D., Differential signaling by splice variants of the human free fatty acid receptor GPR120. Mol. Pharmacol. 81 (2012), 631–642.
83. [83] Butcher, A.J., Hudson, B.D., Shimpukade, B., Alvarez-Curto, E., Prihandoko, R., Ulven, T., 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.
84. [84] Prihandoko, R., Alvarez-Curto, E., Hudson, B.D., Butcher, A.J., Ulven, T., Miller, A.M., Tobin, A.B., Milligan, G., Distinct phosphorylation clusters determines the signalling outcome of the free fatty acid receptor FFA4/GPR120. Mol. Pharmacol., 2016 in press.
85. [85] Engelstoft, M.S., Park, W.M., Sakata, I., Kristensen, L.V., Husted, A.S., Osborne-Lawrence, S., et al. Seven transmembrane G protein-coupled receptor repertoire of gastric ghrelin cells. Mol. Metab. 2 (2013), 376–392.
86. [86] Tolhurst, G., Heffron, H., Lam, Y.S., Parker, H.E., Habib, A.M., Diakogiannaki, E., et al. Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the G-protein-coupled receptor FFAR2. Diabetes 61 (2012), 364–371.
87. [87] Sina, C., Gavrilova, O., Forster, M., Till, A., Derer, S., Hildebrand, F., et al. G protein-coupled receptor 43 is essential for neutrophil recruitment during intestinal inflammation. J. Immunol. 183 (2009), 7514–7522.
88. [88] Smith, P.M., Howitt, M.R., Panikov, N., Michaud, M., Gallini, C.A., Bohlooly, Y.M., et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341 (2013), 569–573.
89. [89] Nohr, M.K., Pedersen, M.H., Gille, A., Egerod, K.L., Engelstoft, M.S., Husted, A.S., et al. 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 (2013), 3552–3564.
90. [90] Sykaras, A.G., Demenis, C., Case, R.M., McLaughlin, J.T., Smith, C.P., Duodenal enteroendocrine I-cells contain mRNA transcripts encoding key endocannabinoid and fatty acid receptors. PLoS One, 7, 2012, e42373.
91. [91] Lepage, P., Hasler, R., Spehlmann, M.E., Rehman, A., Zvirbliene, A., Begun, A., et al. Twin study indicates loss of interaction between microbiota and mucosa of patients with ulcerative colitis. Gastroenterology 141 (2011), 227–236.
92. [92] Manichanh, C., Rigottier-Gois, L., Bonnaud, E., Gloux, K., Pelletier, E., Frangeul, L., et al. Reduced diversity of faecal microbiota in Crohn's disease revealed by a metagenomic approach. Gut 55 (2006), 205–211.
93. [93] Pearl, D.S., Masoodi, M., Eiden, M., Brummer, J., Gullick, D., McKeever, T.M., et al. Altered colonic mucosal availability of n-3 and n-6 polyunsaturated fatty acids in ulcerative colitis and the relationship to disease activity. J. Crohns Colitis 8 (2014), 70–79.
94. [94] Maslowski, K.M., Vieira, A.T., Ng, A., Kranich, J., Sierro, F., Yu, D., et al. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature 461 (2009), 1282–1286.
95. [95] Nick, J.A., Avdi, N.J., Young, S.K., Lehman, L.A., McDonald, P.P., Frasch, S.C., et al. Selective activation and functional significance of p38alpha mitogen-activated protein kinase in lipopolysaccharide-stimulated neutrophils. J. Clin. Invest. 103 (1999), 851–858.
96. [96] Pizzonero, M., Dupont, S., Babel, M., Beaumont, S., Bienvenu, N., Blanque, R., et al. 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 (2014), 10044–10057.
97. [97] Sergeev, E., Hansen, A.H., Pandey, S.K., MacKenzie, A.E., Hudson, B.D., Ulven, T., et al. 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 (2016), 303–317.
98. [98] Vieira, A.T., Macia, L., Galvao, I., Martins, F.S., Canesso, M.C., Amaral, F.A., et al. A role for gut microbiota and the metabolite-sensing receptor GPR43 in a murine model of gout. Arthritis Rheumatol. 67 (2015), 1646–1656.
99. [99] Haslberger, A., Terkeltaub, R., Editorial: can GPR43 sensing of short-chain fatty acids unchain inflammasome-driven arthritis?. Arthritis Rheumatol. 67 (2015), 1419–1423.
100. [100] Hudson, B.D., Christiansen, E., Tikhonova, I.G., Grundmann, M., Kostenis, E., Adams, D.R., et al. Chemically engineering ligand selectivity at the free fatty acid receptor 2 based on pharmacological variation between species orthologs. FASEB J. 26 (2012), 4951–4965.
101. [101] Lee, T., Schwandner, R., Swaminath, G., Weiszmann, J., Cardozo, M., Greenberg, J., et al. Identification and functional characterization of allosteric agonists for the G protein-coupled receptor FFA2. Mol. Pharmacol. 74 (2008), 1599–1609.
102. [102] Trompette, A., Gollwitzer, E.S., Yadava, K., Sichelstiel, A.K., Sprenger, N., Ngom-Bru, C., et al. Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis. Nat. Med. 20 (2014), 159–166.
103. [103] Mirkovic, B., Murray, M.A., Lavelle, G.M., Molloy, K., Azim, A.A., Gunaratnam, C., et al. The role of short-chain fatty acids, produced by anaerobic bacteria, in the cystic fibrosis airway. Am. J. Respir. Crit. Care Med. 192 (2015), 1314–1324.
104. [104] Ghorbani, P., Santhakumar, P., Hu, Q., Djiadeu, P., Wolever, T.M., Palaniyar, N., et al. Short-chain fatty acids affect cystic fibrosis airway inflammation and bacterial growth. Eur. Respir. J. 46 (2015), 1033–1045.
105. [105] Yousefi, S., Cooper, P.R., Potter, S.L., Mueck, B., Jarai, G., Cloning and expression analysis of a novel G-protein-coupled receptor selectively expressed on granulocytes. J. Leukoc. Biol. 69 (2001), 1045–1052.
106. [106] Lattin, J.E., Schroder, K., Su, A.I., Walker, J.R., Zhang, J., Wiltshire, T., et al. Expression analysis of G Protein-Coupled Receptors in mouse macrophages. Immunome Res., 4, 2008, 5.
107. [107] Bouchard, C., Page, J., Bedard, A., Tremblay, P., Vallieres, L., G protein-coupled receptor 84, a microglia-associated protein expressed in neuroinflammatory conditions. Glia 55 (2007), 790–800.
108. [108] Nagasaki, H., Kondo, T., Fuchigami, M., Hashimoto, H., Sugimura, Y., Ozaki, N., et al. Inflammatory changes in adipose tissue enhance expression of GPR84, a medium-chain fatty acid receptor: TNFalpha enhances GPR84 expression in adipocytes. FEBS Lett. 586 (2012), 368–372.
109. [109] Talukdar, S., Olefsky, J.M., Osborn, O., Targeting GPR120 and other fatty acid-sensing GPCRs ameliorates insulin resistance and inflammatory diseases. Trends Pharmacol. Sci. 32 (2011), 543–550.
110. [110] Suzuki, M., Takaishi, S., Nagasaki, M., Onozawa, Y., Iino, I., Maeda, H., et al. Medium-chain fatty acid-sensing receptor, GPR84, is a proinflammatory receptor. J. Biol. Chem. 288 (2013), 10684–10691.
111. [111] Venkataraman, C., Kuo, F., The G-protein coupled receptor, GPR84 regulates IL-4 production by T lymphocytes in response to CD3 crosslinking. Immunol. Lett. 101 (2005), 144–153.
112. [112] Nicol, L.S., Dawes, J.M., La Russa, F., Didangelos, A., Clark, A.K., Gentry, C., et al. The role of G-protein receptor 84 in experimental neuropathic pain. J. Neurosci. 35 (2015), 8959–8969.
113. [113] Christiansen, E., Watterson, K.R., Stocker, C.J., Sokol, E., Jenkins, L., Simon, K., 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.
114. [114] Stulnig, T.M., Immunomodulation by polyunsaturated fatty acids: mechanisms and effects. Int. Arch. Allergy Immunol. 132 (2003), 310–321.
115. [115] Calder, P.C., Omega-3 polyunsaturated fatty acids and inflammatory processes: nutrition or pharmacology?. Br. J. Clin. Pharmacol. 75 (2013), 645–662.
116. [116] Calder, P.C., N-3 fatty acids, inflammation and immunity: new mechanisms to explain old actions. Proc. Nutr. Soc. 72 (2013), 326–336.
117. [117] Shi, H., Kokoeva, M.V., Inouye, K., Tzameli, I., Yin, H., Flier, J.S., TLR4 links innate immunity and fatty acid-induced insulin resistance. J. Clin. Invest. 116 (2006), 3015–3025.
118. [118] Serhan, C.N., Yacoubian, S., Yang, R., Anti-inflammatory and proresolving lipid mediators. Annu. Rev. Pathol. 3 (2008), 279–312.
119. [119] Oh, D.Y., Olefsky, J.M., Omega 3 fatty acids and GPR120. Cell Metab. 15 (2012), 564–565.
120. [120] Im, D.S., Functions of omega-3 fatty acids and FFA4 (GPR120) in macrophages. Eur. J. Pharmacol., S0014–2999(15), 2015 00458-6.
121. [121] Suckow, A.T., Polidori, D., Yan, W., Chon, S., Ma, J.Y., Leonard, J., et al. Alteration of the glucagon axis in GPR120 (FFAR4) knockout mice: a role for GPR120 in glucagon secretion. J. Biol. Chem. 289 (2014), 15751–15763.
122. [122] Ichimura, A., Hirasawa, A., Poulain-Godefroy, O., Bonnefond, A., Hara, T., Yengo, L., et al. Dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human. Nature 483 (2012), 350–354.
123. [123] Bonnefond, A., Lamri, A., Leloire, A., Vaillant, E., Roussel, R., Levy-Marchal, C., et al. Contribution of the low-frequency, loss-of-function p. R270H mutation in FFAR4 (GPR120) to increased fasting plasma glucose levels. J. Med. Genet. 52 (2015), 595–598.
124. [124] Weisberg, S.P., McCann, D., Desai, M., Rosenbaum, M., Leibel, R.L., Ferrante, A.W. Jr., Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Invest. 112 (2003), 1796–1808.
125. [125] Morinaga, H., Mayoral, R., Heinrichsdorff, J., Osborn, O., Franck, N., Hah, N., et al. Characterization of distinct subpopulations of hepatic macrophages in HFD/obese mice. Diabetes 64 (2015), 1120–1130.
126. [126] Wang, Y., Huang, F., N-3 polyunsaturated fatty acids and inflammation in obesity: local effect and systemic benefit. Biomed. Res. Int., 2015, 2015, 581469.
127. [127] Odegaard, J.I., Chawla, A., The immune system as a sensor of the metabolic state. Immunity 38 (2013), 644–654.
128. [128] Debnath, M., Agrawal, S., Agrawal, A., Dubey, G.P., Metaflammatory responses during obesity: pathomechanism and treatment. Obes. Res. Clin. Pract., 2015 S1871-403X(15)00180-5.
129. [129] Calder, P.C., Mechanisms of action of (n-3) fatty acids. J. Nutr. 142 (2012), 592S–599S.
130. [130] Saltiel, A.R., Fishing out a sensor for anti-inflammatory oils. Cell 142 (2010), 672–674.
131. [131] Cinti, S., Mitchell, G., Barbatelli, G., Murano, I., Ceresi, E., Faloia, E., et al. Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J. Lipid. Res. 46 (2005), 2347–2355.
132. [132] Hofmann, C., Lorenz, K., Braithwaite, S.S., Colca, J.R., Palazuk, B.J., Hotamisligil, G.S., et al. Altered gene expression for tumor necrosis factor-alpha and its receptors during drug and dietary modulation of insulin resistance. Endocrinology 134 (1994), 264–270.
133. [133] Hotamisligil, G.S., Spiegelman, B.M., Tumor necrosis factor alpha: a key component of the obesity-diabetes link. Diabetes 43 (1994), 1271–1278.
134. [134] Osborn, O., Olefsky, J.M., The cellular and signaling networks linking the immune system and metabolism in disease. Nat. Med. 18 (2012), 363–374.
135. [135] Shoelson, S.E., Lee, J., Yuan, M., Inflammation and the IKK beta/I kappa B/NF-kappa B axis in obesity- and diet-induced insulin resistance. Int. J. Obes. Relat. Metab. Disord. 27:Suppl. 3 (2003), S49–S52.
136. [136] Hirosumi, J., Tuncman, G., Chang, L., Gorgun, C.Z., Uysal, K.T., Maeda, K., et al. A central role for JNK in obesity and insulin resistance. Nature 420 (2002), 333–336.
137. [137] Arkan, M.C., Hevener, A.L., Greten, F.R., Maeda, S., Li, Z.W., Long, J.M., et al. IKK-beta links inflammation to obesity-induced insulin resistance. Nat. Med. 11 (2005), 191–198.
138. [138] Olefsky, J.M., Glass, C.K., Macrophages, inflammation, and insulin resistance. Annu. Rev. Physiol. 72 (2010), 219–246.
139. [139] Lumeng, C.N., Deyoung, S.M., Bodzin, J.L., Saltiel, A.R., Increased inflammatory properties of adipose tissue macrophages recruited during diet-induced obesity. Diabetes 56 (2007), 16–23.
140. [140] Yan, Y., Jiang, W., Spinetti, T., Tardivel, A., Castillo, R., Bourquin, C., et al. Omega-3 fatty acids prevent inflammation and metabolic disorder through inhibition of NLRP3 inflammasome activation. Immunity 38 (2013), 1154–1163.
141. [141] Schroder, K., Zhou, R., Tschopp, J., The NLRP3 inflammasome: a sensor for metabolic danger?. Science 327:5963 (2010), 296–300.
142. [142] Konno, Y., Ueki, S., Takeda, M., Kobayashi, Y., Tamaki, M., Moritoki, Y., et al. Functional analysis of free fatty acid receptor GPR120 in human eosinophils: implications in metabolic homeostasis. PLoS One, 10, 2015, e0120386.
143. [143] Molofsky, A.B., Nussbaum, J.C., Liang, H.E., Van Dyken, S.J., Cheng, L.E., Mohapatra, A., et al. Innate lymphoid type 2 cells sustain visceral adipose tissue eosinophils and alternatively activated macrophages. J. Exp. Med. 210 (2013), 535–549.
144. [144] Lloyd, C.M., Saglani, S., Eosinophils in the spotlight: Finding the link between obesity and asthma. Nat. Med. 19 (2013), 976–977.
145. [145] Possa, S.S., Leick, E.A., Prado, C.M., Martins, M.A., Tiberio, I.F., Eosinophilic inflammation in allergic asthma. Front. Pharmacol., 4, 2013, 46.
146. [146] Fukunaga, S., Setoguchi, S., Hirasawa, A., Tsujimoto, G., Monitoring ligand-mediated internalization of G protein-coupled receptor as a novel pharmacological approach. Life Sci. 80 (2006), 17–23.