FFA2 and FFA3 in metabolic regulation

Handbook of Experimental Pharmacology

Volumn 236, Issue , 2017, Pages 205-220

  Tang, Cong ^a   Offermanns, Stefan ^b,c  

^a NOVARTIS PHARMA AG   (Switzerland)

^b MAX PLANCK INSTITUTE FOR HEART AND LUNG RESEARCH   (Germany)

^c GOETHE UNIVERSITY   (Germany)

Author keywords

Acetate; Butyrate; Diabetes; Propionate; Short chain fatty acids

Indexed keywords

ACETIC ACID; BUTYRIC ACID; CYTOKINE RECEPTOR ANTAGONIST; G PROTEIN COUPLED RECEPTOR; G PROTEIN COUPLED RECEPTOR 41; G PROTEIN COUPLED RECEPTOR 43; GLPG 0974; INSULIN; PLACEBO; PROPIONIC ACID; UNCLASSIFIED DRUG; CELL SURFACE RECEPTOR; FFAR3 PROTEIN, HUMAN; G-PROTEIN COUPLED RECEPTOR 43, HUMAN;

ADIPOCYTE; ADIPOSE TISSUE; ASTHMA; BODY WEIGHT; COLITIS; DIET INDUCED OBESITY; DIETARY FIBER; DRUG TARGETING; DYSLIPIDEMIA; ENTEROENDOCRINE CELL; GOUT; HUMAN; IMMUNOCOMPETENT CELL; INFLAMMATION; INFLAMMATORY BOWEL DISEASE; INFLAMMATORY DISEASE; INSULIN RELEASE; INSULIN RESISTANCE; METABOLIC REGULATION; NERVE CELL; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; PANCREAS ISLET BETA CELL; PATHOPHYSIOLOGY; PROTEIN EXPRESSION; ANIMAL; DRUG EFFECTS; METABOLISM; PHYSIOLOGY;

ADIPOSE TISSUE; ANIMALS; ENTEROENDOCRINE CELLS; HUMANS; INSULIN-SECRETING CELLS; RECEPTORS, CELL SURFACE; RECEPTORS, G-PROTEIN-COUPLED;

EID: 85014089635     PISSN: 01712004     EISSN: 18650325     Source Type: Book Series    
DOI: 10.1007/164_2016_50     Document Type: Chapter

References (64)

1. Anderson JW, Baird P, Davis RH Jr, Ferreri S, Knudtson M, Koraym A, Waters V, Williams CL (2009) Health benefits of dietary fiber. Nutr Rev 67:188-205
2. Bahar Halpern K, Veprik A, Rubins N, Naaman O, Walker MD (2012) GPR41 gene expression is mediated by internal ribosome entry site (IRES)-dependent translation of bicistronic mRNA encoding GPR40 and GPR41 proteins. J Biol Chem 287:20154-20163
3. Bellahcene M, O’Dowd JF, Wargent ET, Zaibi MS, Hislop DC, Ngala RA, Smith DM, Cawthorne MA, Stocker CJ, Arch JRS (2012) Male mice that lack the G-protein-coupled receptor GPR41 have low energy expenditure and increased body fat content. Br J Nutr 109:1755-1764
4. Bjursell M, Admyre T, Goransson M, Marley AE, Smith DM, Oscarsson J, Bohlooly YM (2011) Improved glucose control and reduced body fat mass in free fatty acid receptor 2-deficient mice fed a high-fat diet. Am J Physiol Endocrinol Metab 300:E211-E220
5. Blad CC, Tang C, Offermanns S (2012) G protein-coupled receptors for energy metabolites as new therapeutic targets. Nat Rev Drug Discov 11:603-619
6. Briscoe CP, Tadayyon M, Andrews JL, Benson WG, Chambers JK, Eilert MM, Ellis C, Elshourbagy NA, Goetz AS, Minnick DT, Murdock PR, Sauls HR Jr, Shabon U, Spinage LD, Strum JC, Szekeres PG, Tan KB, Way JM, Ignar DM, Wilson S et al (2003) The orphan G protein-coupled receptor GPR40 is activated by medium and long chain fatty acids. J Biol Chem 278:11303-11311
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 et al (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
8. Campbell AP (2001) Health benefits of dietary fiber for people with diabetes. Diabetes Educ 27:511-514
9. Cox MA, Jackson J, Stanton M, Rojas-Triana A, Bober L, Laverty M, Yang X, Zhu F, Liu J, Wang S, Monsma F, Vassileva G, Maguire M, Gustafson E, Bayne M, Chou CC, Lundell D, Jenh CH (2009) Short-chain fatty acids act as antiinflammatory mediators by regulating prostaglandin E(2) and cytokines. World J Gastroenterol 15:5549-5557
10. De Vadder F, Kovatcheva-Datchary P, Goncalves D, Vinera J, Zitoun C, Duchampt A, Backhed F, Mithieux G (2014) Microbiota-generated metabolites promote metabolic benefits via gut-brain neural circuits. Cell 156:84-96
11. Eberle JA, Widmayer P, Breer H (2014) Receptors for short-chain fatty acids in brush cells at the “gastric groove”. Front Physiol 5:152
12. Engelstoft MS, Egerod KL, Lund ML, Schwartz TW (2013a) Enteroendocrine cell types revisited. Curr Opin Pharmacol 13:912-921
13. 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 et al (2013b) Seven transmembrane G protein-coupled receptor repertoire of gastric ghrelin cells. Mol Metab 2:376-392
14. Flint HJ, Bayer EA, Rincon MT, Lamed R, White BA (2008) Polysaccharide utilization by gut bacteria: potential for new insights from genomic analysis. Nat Rev Microbiol 6:121-131
15. Furness JB, Rivera LR, Cho HJ, Bravo DM, Callaghan B (2013) The gut as a sensory organ. Nat Rev Gastroenterol Hepatol 10:729-740
16. Ge H, Li X, Weiszmann J, Wang P, Baribault H, Chen JL, Tian H, Li Y (2008) Activation of G protein-coupled receptor 43 in adipocytes leads to inhibition of lipolysis and suppression of plasma free fatty acids. Endocrinology 149:4519-4526
17. Gribble FM, Reimann F (2016) Enteroendocrine cells: chemosensors in the intestinal epithelium. Annu Rev Physiol 78:277-299
18. Hong YH, Nishimura Y, Hishikawa D, Tsuzuki H, Miyahara H, Gotoh C, Choi KC, Feng DD, Chen C, Lee HG, Katoh K, Roh SG, Sasaki S (2005) Acetate and propionate short chain fatty acids stimulate adipogenesis via GPCR43. Endocrinology 146:5092-5099
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 287:41195-41209
20. Inoue D, Kimura I, Wakabayashi M, Tsumoto H, Ozawa K, Hara T, Takei Y, Hirasawa A, Ishihama Y, Tsujimoto G (2012) Short-chain fatty acid receptor GPR41-mediated activation of sympathetic neurons involves synapsin 2b phosphorylation. FEBS Lett 586:1547-1554
21. Karaki S, Mitsui R, Hayashi H, Kato I, Sugiya H, Iwanaga T, Furness JB, Kuwahara A (2006) Short-chain fatty acid receptor, GPR43, is expressed by enteroendocrine cells and mucosal mast cells in rat intestine. Cell Tissue Res 324:353-360
22. 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 108:8030-8035
23. 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 4:1829
24. Kuwahara A (2014) Contributions of colonic short-chain Fatty Acid receptors in energy homeostasis. Front Endocrinol 5:144
25. Le Poul E, Loison C, Struyf S, Springael JY, Lannoy V, Decobecq ME, Brezillon S, Dupriez 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 278:25481-25489
26. Lee T, Schwandner R, Swaminath G, Weiszmann J, Cardozo M, Greenberg J, Jaeckel P, Ge HF, Wang YC, Jiao XY, 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 74:1599-1609
27. Liaw CW, Connolly DT (2009) Sequence polymorphisms provide a common consensus sequence for GPR41 and GPR42. DNA Cell Biol 28:555-560
28. Lin HV, Frassetto A, Kowalik EJ Jr, Nawrocki AR, Lu MM, Kosinski JR, Hubert JA, Szeto D, Yao X, Forrest G, Marsh DJ (2012) Butyrate and propionate protect against diet-induced obesity and regulate gut hormones via free fatty acid receptor 3-independent mechanisms. PLoS One 7, e35240
29. Macia L, Tan J, Vieira AT, Leach K, Stanley D, Luong S, Maruya M, Ian McKenzie C, Hijikata A, Wong C, Binge L, Thorburn AN, Chevalier N, Ang C, Marino E, Robert R, Offermanns S, Teixeira MM, Moore RJ, Flavell RA et al (2015) Metabolite-sensing receptors GPR43 and GPR109A facilitate dietary fibre-induced gut homeostasis through regulation of the inflammasome. Nat Commun 6:6734
30. Manning S, Batterham RL (2014) The role of gut hormone peptide YY in energy and glucose homeostasis: twelve years on. Annu Rev Physiol 76:585-608
31. 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 461:1282-1286
32. Masui R, Sasaki M, Funaki Y, Ogasawara N, Mizuno M, Iida A, Izawa S, Kondo Y, Ito Y, Tamura Y, Yanamoto K, Noda H, Tanabe A, Okaniwa N, Yamaguchi Y, Iwamoto T, Kasugai K (2013) G protein-coupled receptor 43 moderates gut inflammation through cytokine regulation from mononuclear cells. Inflamm Bowel Dis 19:2848-2856
33. McNelis JC, Lee YS, Mayoral R, van der Kant R, Johnson AM, Wollam J, Olefsky JM (2015) GPR43 potentiates beta-cell function in obesity. Diabetes 64:3203-3217
34. Mudgil D, Barak S (2013) Composition, properties and health benefits of indigestible carbohydrate polymers as dietary fiber: a review. Int J Biol Macromol 61:1-6
35. Nilsson NE, Kotarsky K, Owman C, Olde B (2003) Identification of a free fatty acid receptor, FFA (2)R, expressed on leukocytes and activated by short-chain fatty acids. Biochem Biophys Res Commun 303:1047-1052
36. Nilsson AC, Ostman EM, Knudsen KE, Holst JJ, Bjorck IM (2010) A cereal-based evening meal rich in indigestible carbohydrates increases plasma butyrate the next morning. J Nutr 140:1932-1936
37. 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 (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 154:3552-3564
38. Nohr MK, Egerod KL, Christiansen SH, Gille A, Offermanns S, Schwartz TW, Moller M (2015) Expression of the short chain fatty acid receptor GPR41/FFAR3 in autonomic and somatic sensory ganglia. Neuroscience 290:126-137
39. 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 142:687-698
40. Park BO, Kim SH, Kong GY, Kim DH, Kwon MS, Lee SU, Kim MO, Cho S, Lee S, Lee HJ, Han SB, Kwak YS, Lee SB, Kim S (2015) Selective novel inverse agonists for human GPR43 augment GLP-1 secretion. Eur J Pharmacol 771:1-9
41. Peti-Peterdi J, Kishore BK, Pluznick JL (2015) Regulation of vascular and renal function by metabolite receptors. Annu Rev Physiol 78:391-414
42. Pouteau E, Meirim I, Metairon S, Fay LB (2001) 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 36:798-805
43. Priyadarshini M, Layden BT (2015) FFAR3 modulates insulin secretion and global gene expression in mouse islets. Islets: e1045182
44. 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 29:1055-1066
45. Puhl HL 3rd, Won YJ, Lu VB, Ikeda SR (2015) Human GPR42 is a transcribed multisite variant that exhibits copy number polymorphism and is functional when heterologously expressed. Sci Rep 5:12880
46. Regard JB, Kataoka H, Cano DA, Camerer E, Yin L, Zheng YW, Scanlan TS, Hebrok M, Coughlin SR (2007) Probing cell type-specific functions of Gi in vivo identifies GPCR regulators of insulin secretion. J Clin Invest 117:4034-4043
47. Regard JB, Sato IT, Coughlin SR (2008) Anatomical profiling of G protein-coupled receptor expression. Cell 135:561-571
48. Samuel BS, Shaito A, Motoike T, Rey FE, Backhed F, Manchester JK, Hammer RE, Williams SC, Crowley J, Yanagisawa M, Gordon JI (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 105:16767-16772
49. Shimazu T, Hirschey MD, Huang JY, Ho LT, Verdin E (2010) Acetate metabolism and aging: an emerging connection. Mech Ageing Dev 131:511-516
50. Sina C, Gavrilova O, Forster M, Till A, Derer S, Hildebrand F, Raabe B, Chalaris A, Scheller J, Rehmann A, Franke A, Ott S, Hasler R, Nikolaus S, Folsch UR, Rose-John S, Jiang HP, Li J, Schreiber S, Rosenstiel P (2009) G protein-coupled receptor 43 is essential for neutrophil recruitment during intestinal inflammation. J Immunol 183:7514-7522
51. Smith PM, Howitt MR, Panikov N, Michaud M, Gallini CA, Bohlooly YM, Glickman JN, Garrett WS (2013) The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341:569-573
52. 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 60:405-417
53. Tang C, Ahmed K, Gille A, Lu S, Grone HJ, Tunaru S, Offermanns S (2015) Loss of FFA2 and FFA3 increases insulin secretion and improves glucose tolerance in type 2 diabetes. Nat Med 21:173-177
54. Tarini J, Wolever TM (2010) The fermentable fibre inulin increases postprandial serum short- chain fatty acids and reduces free-fatty acids and ghrelin in healthy subjects. Appl Physiol Nutr Metab 35:9-16
55. Tiengo A, Valerio A, Molinari M, Meneghel A, Lapolla A (1981) Effect of ethanol, acetaldehyde, and acetate on insulin and glucagon secretion in the perfused rat pancreas. Diabetes 30:705-709
56. Tolhurst G, Heffron H, Lam YS, Parker HE, Habib AM, Diakogiannaki E, Cameron J, Grosse J, Reimann F, Gribble FM (2012) Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the G-protein-coupled receptor FFAR2. Diabetes 61:364-371
57. Trompette A, Gollwitzer ES, Yadava K, Sichelstiel AK, Sprenger N, Ngom-Bru C, Blanchard C, Junt T, Nicod LP, Harris NL, Marsland BJ (2014) Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis. Nat Med 20:159-166
58. Vermeire S, Kojecky´ V, Knoflícek V, Reinisch W, Van Kaem T, Namour F, Beetens J, Vanhoutte F (2015) DOP030. GLPG0974, an FFA2 antagonist, in ulcerative colitis: efficacy and safety in a multicenter proof-of-concept study. J Crohns Colitis 9:S39
59. Vieira AT, Macia L, Galvao I, Martins FS, Canesso MC, Amaral FA, Garcia CC, Maslowski KM, De Leon E, Shim D, Nicoli JR, Harper JL, Teixeira MM, Mackay CR (2015) A role for gut microbiota and the metabolite-sensing receptor GPR43 in a murine model of gout. Arthritis Rheumatol 67:1646-1656
60. Vinolo MA, Ferguson GJ, Kulkarni S, Damoulakis G, Anderson K, Bohlooly YM, Stephens L, Hawkins PT, Curi R (2011) SCFAs induce mouse neutrophil chemotaxis through the GPR43 receptor. PLoS One 6, e21205
61. 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 33:19314-19325
62. Ximenes HM, Hirata AE, Rocha MS, Curi R, Carpinelli AR (2007) Propionate inhibits glucose- induced insulin secretion in isolated rat pancreatic islets. Cell Biochem Funct 25:173-178
63. Xiong Y, Miyamoto N, Shibata K, Valasek MA, Motoike T, Kedzierski RM, Yanagisawa M (2004) Short-chain fatty acids stimulate leptin production in adipocytes through the G proteincoupled receptor GPR41. Proc Natl Acad Sci U S A 101:1045-1050
64. 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 584:2381-2386