Drugs or diet? - Developing novel therapeutic strategies targeting the free fatty acid family of GPCRs

British Journal of Pharmacology

Volumn 170, Issue 4, 2013, Pages 696-711

  Dranse, H J ^a   Kelly, M E M ^a   Hudson, B D ^b  

^a DALHOUSIE UNIVERSITY   (Canada)

^b UNIVERSITY OF GLASGOW   (United Kingdom)

Author keywords

diet; free fatty acid; free fatty acid receptor; glucose homeostasis; gut microbiota; inflammation; metabolism; therapeutics

Indexed keywords

CARBOHYDRATE; CARBOXYLIC ACID DERIVATIVE; FASIGLIFAM; FATTY ACID; FREE FATTY ACID RECEPTOR 1 AGONIST; FREE FATTY ACID RECEPTOR 2; FREE FATTY ACID RECEPTOR 2 AGONIST; FREE FATTY ACID RECEPTOR 3; FREE FATTY ACID RECEPTOR 3 AGONIST; FREE FATTY ACID RECEPTOR 4; FREE FATTY ACID RECEPTOR 4 AGONIST; G PROTEIN COUPLED RECEPTOR; GASTROINTESTINAL HORMONE; GLUCAGON; INSULIN; LONG CHAIN FATTY ACID; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR; SHORT CHAIN FATTY ACID; TUG 891; UNCLASSIFIED DRUG;

DIET; DIETARY INTAKE; DRUG TARGETING; ENERGY RESOURCE; FATTY ACID BLOOD LEVEL; FERMENTATION; GLUCAGON RELEASE; HORMONE RELEASE; HUMAN; INFLAMMATION; INFLAMMATORY DISEASE; INSULIN RELEASE; INTESTINE FLORA; METABOLIC DISORDER; METABOLISM; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; PRIORITY JOURNAL; PROTEIN FAMILY; PROTEIN FUNCTION; REVIEW; SIGNAL TRANSDUCTION; STRUCTURE ACTIVITY RELATION;

DIET; FREE FATTY ACID; FREE FATTY ACID RECEPTOR; GLUCOSE HOMEOSTASIS; GUT MICROBIOTA; INFLAMMATION; METABOLISM; THERAPEUTICS;

ANIMALS; ANTI-INFLAMMATORY AGENTS; DIETARY FATS; DRUG DESIGN; FATTY ACIDS, NONESTERIFIED; HUMANS; INFLAMMATION; LIGANDS; METABOLIC DISEASES; MOLECULAR TARGETED THERAPY; RECEPTORS, G-PROTEIN-COUPLED; SIGNAL TRANSDUCTION;

EID: 84885169779     PISSN: 00071188     EISSN: 14765381     Source Type: Journal    
DOI: 10.1111/bph.12327     Document Type: Review

References (157)

1. Akanji AO, Peterson DB, Humphreys S, Hockaday TD, (1989). Change in plasma acetate levels in diabetic subjects on mixed high fiber diets. Am J Gastroenterol 84: 1365-1370.
2. Alexander SPH, Mathie A, Peters JA, (2011). Guide to receptors and channels (GRAC), 5th edition. Br J Pharmacol 164 (Suppl. 1): S1-324.
3. Alquier T, Peyot ML, Latour MG, Kebede M, Sorensen CM, Gesta S, et al. (2009). Deletion of GPR40 impairs glucose-induced insulin secretion in vivo in mice without affecting intracellular fuel metabolism in islets. Diabetes 58: 2607-2615.
4. Andreasen AS, Larsen N, Pedersen-Skovsgaard T, Berg RM, Moller K, Svendsen KD, et al. (2010). Effects of Lactobacillus acidophilus NCFM on insulin sensitivity and the systemic inflammatory response in human subjects. Br J Nutr 104: 1831-1838.
5. Araki T, Hirayama M, Hiroi S, Kaku K, (2012). GPR40-induced insulin secretion by the novel agonist TAK-875: first clinical findings in patients with type 2 diabetes. Diabetes Obes Metab 14: 271-278.
6. Bharate SB, Nemmani KV, Vishwakarma RA, (2009). Progress in the discovery and development of small-molecule modulators of G-protein-coupled receptor 40 (GPR40/FFA1/FFAR1): an emerging target for type 2 diabetes. Expert Opin Ther Pat 19: 237-264.
7. Bjursell M, Admyre T, Goransson M, Marley AE, Smith DM, Oscarsson J, et al. (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.
8. Briscoe CP, Tadayyon M, Andrews JL, Benson WG, Chambers JK, Eilert MM, 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.
9. Briscoe CP, Peat AJ, McKeown SC, Corbett DF, Goetz AS, Littleton TR, et al. (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: 619-628.
10. Brown AJ, Goldsworthy SM, Barnes AA, Eilert MM, Tcheang L, Daniels D, 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.
11. Burant CF, Viswanathan P, Marcinak J, Cao C, Vakilynejad M, Xie B, et al. (2012). TAK-875 versus placebo or glimepiride in type 2 diabetes mellitus: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet 379: 1403-1411.
12. Burns RN, Moniri NH, (2010). 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: 1030-1035.
13. Calder PC, (2004). n-3 Fatty acids and cardiovascular disease: evidence explained and mechanisms explored. Clin Sci (Lond) 107: 1-11.
14. Cani PD, Dewever C, Delzenne NM, (2004). Inulin-type fructans modulate gastrointestinal peptides involved in appetite regulation (glucagon-like peptide-1 and ghrelin) in rats. Br J Nutr 92: 521-526.
15. Cascio G, Schiera G, Di Liegro I, (2012). Dietary fatty acids in metabolic syndrome, diabetes and cardiovascular diseases. Curr Diab Rev 8: 2-17.
16. Christiansen E, Due-Hansen ME, Urban C, Grundmann M, Schroder R, Hudson BD, et al. (2012). Free fatty acid receptor 1 (FFA1/GPR40) agonists: mesylpropoxy appendage lowers lipophilicity and improves ADME properties. J Med Chem 55: 6624-6628.
17. Christiansen E, Due-Hansen ME, Urban C, Grundmann M, Schmidt J, Hansen SV, et al. (2013). Discovery of a potent and selective free fatty acid receptor 1 agonist with low lipophilicity and high oral bioavailability. J Med Chem 56: 982-992.
18. Cintra DE, Ropelle ER, Moraes JC, Pauli JR, Morari J, Souza CT, et al. (2012). Unsaturated fatty acids revert diet-induced hypothalamic inflammation in obesity. PLoS ONE 7: e30571.
19. Cook SI, Shellin JH, (1998). Short chain fatty acids in health and disease. Aliment Pharmacol Ther 12: 499-507.
20. Cuomo R, D'Alessandro A, Andreozzi P, Vozzella L, Sarnelli G, (2011). Gastrointestinal regulation of food intake: do gut motility, enteric nerves and entero-hormones play together? Minerva Endocrinol 36: 281-293.
21. Danaei G, Finucane MM, Lu Y, Singh GM, Cowan MJ, Paciorek CJ, et al. (2011). National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2.7 million participants. Lancet 378: 31-40.
22. Davenport AP, Alexander SPH, Sharman JL, Pawson AJ, Benson HE, Monaghan AE, et al. (2013). International Union of Basic and Clinical Pharmacology. LXXXVIII. G protein-coupled receptor list: recommendations for new pairings with cognate ligands. Pharmacol Rev 65: 967-986.
23. Deacon CF, Ahren B, (2011). Physiology of incretins in health and disease. Rev Diabet Stud 8: 293-306.
24. Del Guerra S, Bugliani M, D'Aleo V, Del Prato S, Boggi U, Mosca F, et al. (2010). G-protein-coupled receptor 40 (GPR40) expression and its regulation in human pancreatic islets: the role of type 2 diabetes and fatty acids. Nutr Metab Cardiovasc Dis 20: 22-25.
25. Delzenne NM, Cani PD, Daubioul C, Neyrinck AM, (2005). Impact of inulin and oligofructose on gastrointestinal peptides. Br J Nutr 93 (Suppl. 1): S157-S161.
26. 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: 2370-2376.
27. Doshi LS, Brahma MK, Sayyed SG, Dixit AV, Chandak PG, Pamidiboina V, et al. (2009). Acute administration of GPR40 receptor agonist potentiates glucose-stimulated insulin secretion in vivo in the rat. Metabolism 58: 333-343.
28. Doyle L, Jewell C, Mullen A, Nugent AP, Roche HM, Cashman KD, (2005). Effect of dietary supplementation with conjugated linoleic acid on markers of calcium and bone metabolism in healthy adult men. Eur J Clin Nutr 59: 432-440.
29. Edfalk S, Steneberg P, Edlund H, (2008). Gpr40 is expressed in enteroendocrine cells and mediates free fatty acid stimulation of incretin secretion. Diabetes 57: 2280-2287.
30. van Eijk HMH, Bloemen JG, Dejong CHC, (2009). Application of liquid chromatorgraphy-mass spectrometry to measure short chain fatty acids in blood. J Chromatogr B Analyt Technol Biomed Life Sci 877: 719-724.
31. El-Kaissi S, Sherbeeni S, (2011). Pharmacological management of type 2 diabetes mellitus: an update. Curr Diab Rev 7: 392-405.
32. Ferdaoussi M, Bergeron V, Zarrouki B, Kolic J, Cantley J, Fielitz J, et al. (2012). G protein-coupled receptor (GPR)40-dependent potentiation of insulin secretion in mouse islets is mediated by protein kinase D1. Diabetologia 55: 2682-2692.
33. Flodgren E, Olde B, Meidute-Abaraviciene S, Winzell MS, Ahren B, Salehi A, (2007). GPR40 is expressed in glucagon producing cells and affects glucagon secretion. Biochem Biophys Res Commun 354: 240-245.
34. Francois IE, Lescroart O, Veraverbeke WS, Marzorati M, Possemiers S, Evenepoel P, et al. (2012). Effects of a wheat bran extract containing arabinoxylan oligosaccharides on gastrointestinal health parameters in healthy adult human volunteers: a double-blind, randomised, placebo-controlled, cross-over trial. Br J Nutr 108: 2229-2242.
35. Ge H, Li X, Weiszmann J, Wang P, Baribault H, Chen JL, et al. (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.
36. Gehrmann W, Elsner M, Lenzen S, (2010). Role of metabolically generated reactive oxygen species for lipotoxicity in pancreatic beta-cells. Diabetes Obes Metab 12 (Suppl. 2): 149-158.
37. Gillingham LG, Harris-Janz S, Jones PJ, (2011). Dietary monounsaturated fatty acids are protective against metabolic syndrome and cardiovascular disease risk factors. Lipids 46: 209-228.
38. Gotoh C, Hong YH, Iga T, Hishikawa D, Suzuki Y, Song SH, et al. (2007). The regulation of adipogenesis through GPR120. Biochem Biophys Res Commun 354: 591-597.
39. Goupil E, Laporte SA, Hebert TE, (2012). Functional selectivity in GPCR signaling: understanding the full spectrum of receptor conformations. Mini Rev Med Chem 12: 817-830.
40. Gras D, Chanez P, Urbach V, Vachier I, Godard P, Bonnans C, (2009). Thiazolidinediones induce proliferation of human bronchial epithelial cells through the GPR40 receptor. Am J Physiol Lung Cell Mol Physiol 296: L970-L978.
41. Grimaldi PA, (2010). Metabolic and nonmetabolic regulatory functions of peroxisome proliferator-activated receptor beta. Curr Opin Lipidol 21: 186-191.
42. Gu JJ, Gao FY, Zhao TY, (2012). A preliminary investigation of the mechanisms underlying the effect of berberine in preventing high-fat diet-induced insulin resistance in rats. J Physiol Pharmacol 63: 505-513.
43. Haber EP, Ximenes HM, Procopio J, Carvalho CR, Curi R, Carpinelli AR, (2003). Pleiotropic effects of fatty acids on pancreatic beta-cells. J Cell Physiol 194: 1-12.
44. Habib AM, Richards P, Rogers GJ, Reimann F, Gribble FM, (2013). Co-localisation and secretion of glucagon-like peptide 1 and peptide YY from primary cultured human L cells. Diabetologia 56: 1413-1416.
45. Hara T, Hirasawa A, Ichimura A, Kimura I, Tsujimoto G, (2011). Free fatty acid receptors FFAR1 and GPR120 as novel therapeutic targets for metabolic disorders. J Pharm Sci 100: 3594-3601.
46. Hardy SS, Onge GG, Joly E, Langelier Y, Prentki M, (2005). Oleate promotes the proliferation of breast cancer cells via the G protein-coupled receptor GPR40. J Biol Chem 280: 13285-13291.
47. Hirasawa A, Tsumaya K, Awaji T, Katsuma S, Adachi T, Yamada M, et al. (2005). Free fatty acids regulate gut incretin glucagon-like peptide-1 secretion through GPR120. Nat Med 11: 90-94.
48. Hirasawa A, Hara T, Katsuma S, Adachi T, Tsujimoto G, (2008). Free fatty acid receptors and drug discovery. Biol Pharm Bull 31: 1847-1851.
49. Hong YH, Nishimura Y, Hishikawa D, Tsuzuki H, Miyahara H, Gotoh C, et al. (2005). Acetate and propionate short chain fatty acids stimulate adipogenesis via GPCR43. Endocrinology 146: 5092-5099.
50. Honore JC, Kooli A, Hamel D, Alquier T, Rivera JC, Quiniou C, et al. (2013). Fatty acid receptor gpr40 mediates neuromicrovascular degeneration induced by transarachidonic acids in rodents. Arterioscler Thromb Vasc Biol 33: 954-961.
51. Hoveyda H, Brantis C, Dutheuil G, Zoute L, Schils D, Bernard J, (2010). Compounds, pharmaceutical composition and methods for use in treating metabolic disorders. International patent application WO2011076734.
52. Hudson BD, Smith NJ, Milligan G, (2011). Experimental challenges to targeting poorly characterized GPCRs: uncovering the therapeutic potential for free fatty acid receptors. Adv Pharmacol 62: 175-218.
53. Hudson BD, Christiansen E, Tikhonova IG, Grundmann M, Kostenis E, Adams DR, et al. (2012a). Chemically engineering ligand selectivity at the free fatty acid receptor 2 based on pharmacological variation between species orthologs. FASEB J 26: 4951-4965.
54. Hudson BD, Tikhonova IG, Pandey SK, Ulven T, Milligan G, (2012b). 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.
55. Hudson BD, Due-Hansen ME, Christiansen E, Hansen AM, Mackenzie AE, Murdoch H, et al. (2013a). Defining the molecular basis for the first potent and selective orthosteric agonists of the FFA2 free fatty acid receptor. J Biol Chem 288: 17296-17312.
56. Hudson BD, Murdoch H, Milligan G, (2013b). Minireview: the effects of species ortholog and SNP variation on receptors for free fatty acids. Mol Endocrinol 27: 1177-1187.
57. Hudson BD, Ulven T, Milligan G, (2013c). The therapeutic potential of allosteric ligands for free fatty acid sensitive GPCRs. Curr Top Med Chem 13: 14-25.
58. Ichimura A, Hirasawa A, Poulain-Godefroy O, Bonnefond A, Hara T, Yengo L, et al. (2012). Dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human. Nature 483: 350-354.
59. Itoh Y, Hinuma S, (2005). GPR40, a free fatty acid receptor on pancreatic beta cells, regulates insulin secretion. Hepatol Res 33: 171-173.
60. Itoh Y, Kawamata Y, Harada M, Kobayashi M, Fujii R, Fukusumi S, et al. (2003). Free fatty acids regulate insulin secretion from pancreatic beta cells through GPR40. Nature 422: 173-176.
61. Jouven X, Charles M-A, Desnos M, Ducimetière P, (2001). Circulating nonesterified fatty acid level as a predictive risk factor for sudden death in the population. Circulation 104: 756-761.
62. Kadooka Y, Sato M, Imaizumi K, Ogawa A, Ikuyama K, Akai Y, et al. (2010). Regulation of abdominal adiposity by probiotics (Lactobacillus gasseri SBT2055) in adults with obese tendencies in a randomized controlled trial. Eur J Clin Nutr 64: 636-643.
63. Karaki S, Mitsui R, Hayashi H, Kato I, Sugiya H, Iwanaga T, et al. (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.
64. Karaki S, Tazoe H, Hayashi H, Kashiwabara H, Tooyama K, Suzuki Y, et al. (2008). Expression of the short-chain fatty acid receptor, GPR43, in the human colon. J Mol Histol 39: 135-142.
65. Katsuma S, Hatae N, Yano T, Ruike Y, Kimura M, Hirasawa A, et al. (2005). Free fatty acids inhibit serum deprivation-induced apoptosis through GPR120 in a murine enteroendocrine cell line STC-1. J Biol Chem 280: 19507-19515.
66. Kebede M, Alquier T, Latour MG, Semache M, Tremblay C, Poitout V, (2008). The fatty acid receptor GPR40 plays a role in insulin secretion in vivo after high-fat feeding. Diabetes 57: 2432-2437.
67. Kebede MA, Alquier T, Latour MG, Poitout V, (2009). Lipid receptors and islet function: therapeutic implications? Diabetes Obes Metab 11 (Suppl. 4): 10-20.
68. Khoruts A, Dicksved J, Jansson JK, Sadowsky MJ, (2010). Changes in the composition of the human fecal microbiome after bacteriotherapy for recurrent Clostridium difficile-associated diarrhea. J Clin Gastroenterol 44: 354-360.
69. Kim MH, Kang SG, Park JH, Yanagisawa M, Kim CH, (2013). Short-chain fatty acids activate GPR41 and GPR43 on intestinal epithelial cells to promote inflammatory responses in mice. Gastroenterology 145: 396-406.
70. Kimura I, Ozawa K, Inoue D, Imamura T, Kimura K, Maeda T, et al. (2013). The gut microbiota suppresses insulin-mediated fat accumulation via the short-chain fatty acid receptor GPR43. Nat Commun 4: 1829.
71. Kotarsky K, Nilsson NE, Flodgren E, Owman C, Olde B, (2003a). A human cell surface receptor activated by free fatty acids and thiazolidinedione drugs. Biochem Biophys Res Commun 301: 406-410.
72. Kotarsky K, Nilsson NE, Olde B, Owman C, (2003b). Progress in methodology. Improved reporter gene assays used to identify ligands acting on orphan seven-transmembrane receptors. Pharmacol Toxicol 93: 249-258.
73. Kremmyda LS, Tvrzicka E, Stankova B, Zak A, (2011). 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: 195-218.
74. Kuda O, Jelenik T, Jilkova Z, Flachs P, Rossmeisl M, Hensler M, et al. (2009). n-3 Fatty acids and rosiglitazone improve insulin sensitivity through additive stimulatory effects on muscle glycogen synthesis in mice fed a high-fat diet. Diabetologia 52: 941-951.
75. Lan H, Hoos LM, Liu L, Tetzloff G, Hu W, Abbondanzo SJ, et al. (2008). Lack of FFAR1/GPR40 does not protect mice from high-fat diet-induced metabolic disease. Diabetes 57: 2999-3006.
76. Latour MG, Alquier T, Oseid E, Tremblay C, Jetton TL, Luo J, et al. (2007). GPR40 is necessary but not sufficient for fatty acid stimulation of insulin secretion in vivo. Diabetes 56: 1087-1094.
77. Le Poul E, Loison C, Struyf S, Springael JY, Lannoy V, Decobecq ME, et al. (2003). Functional characterization of human receptors for short chain fatty acids and their role in polymorphonuclear cell activation. J Biol Chem 278: 25481-25489.
78. Lee T, Schwandner R, Swaminath G, Weiszmann J, Cardozo M, Greenberg J, et al. (2008). Identification and functional characterization of allosteric agonists for the G protein-coupled receptor FFA2. Mol Pharmacol 74: 1599-1609.
79. Lehto HR, Parkka J, Borra R, Tuunanen H, Lepomaki V, Parkkola R, et al. (2012). Effects of acute and one-week fatty acid lowering on cardiac function and insulin sensitivity in relation with myocardial and muscle fat and adiponectin levels. J Clin Endocrinol Metab 97: 3277-3284.
80. Leifke E, Naik H, Wu J, Viswanathan P, Demanno D, Kipnes M, et al. (2012). 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: 29-39.
81. Leonard JN, Chu ZL, Bruce MA, Boatman PD, (2006). GPR41 and modulators there of for the treatment of insulin-related disorders. International patent application WO2006052566.
82. Lin DC, Zhang J, Zhuang R, Li F, Nguyen K, Chen M, et al. (2011). AMG 837: a novel GPR40/FFA1 agonist that enhances insulin secretion and lowers glucose levels in rodents. PLoS ONE 6: e27270.
83. Lin DC, Guo Q, Luo J, Zhang J, Nguyen K, Chen M, et al. (2012). Identification and pharmacological characterization of multiple allosteric binding sites on the free fatty acid 1 receptor. Mol Pharmacol 82: 843-859.
84. Liou AP, Lu X, Sei Y, Zhao X, Pechhold S, Carrero RJ, et al. (2011). The G-protein-coupled receptor GPR40 directly mediates long-chain fatty acid-induced secretion of cholecystokinin. Gastroenterology 140: 903-912.
85. Liou AP, Paziuk M, Luevano J-M, Machineni S, Turnbaugh PJ, Kaplan LM, (2013). Conserved shifts in the gut microbiota due to gastric bypass reduce host weight and adiposity. Sci Transl Med 5: 178ra41.
86. Lu X, Zhao X, Feng J, Liou AP, Anthony S, Pechhold S, et al. (2012). 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: G367-G376.
87. Lumeng CN, Saltiel AR, (2011). Inflammatory links between obesity and metabolic disease. J Clin Invest 121: 2111-2117.
88. Macfarlane GT, Macfarlane S, (2011). Fermentation in the human large intestine: its physiologic consequences and the potential contribution of prebiotics. J Clin Gastroenterol 45 (Suppl.): S120-S127.
89. Maslowski KM, Vieira AT, Ng A, Kranich J, Sierro F, Yu D, et al. (2009). Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature 461: 1282-1286.
90. May LT, Leach K, Sexton PM, Christopoulos A, (2007). Allosteric modulation of G protein-coupled receptors. Annu Rev Pharmacol Toxicol 47: 1-51.
91. Medina V, Edmonds B, Young GP, James R, Appleton S, Zalewski PD, (1997). Induction of caspase-3 protease activity and apoptosis by butyrate and trichostatin A (inhibitors of histone deacetylase): dependence on protein synthesis and synergy with a mitochondrial/cytochrome c-dependent pathway. Cancer Res 57: 3697-3707.
92. Miller SJ, (2004). Cellular and physiological effects of short-chain fatty acids. Mini Rev Med Chem 4: 839-845.
93. Miyauchi S, Hirasawa A, Iga T, Liu N, Itsubo C, Sadakane K, et al. (2009). Distribution and regulation of protein expression of the free fatty acid receptor GPR120. Naunyn Schmiedebergs Arch Pharmacol 379: 427-434.
94. Monteiro R, Azevedo I, (2010). Chronic inflammation in obesity and the metabolic syndrome. Mediators Inflamm 2010: 289645.
95. Moussavi N, Gavino V, Receveur O, (2008). Could the quality of dietary fat, and not just its quantity, be related to risk of obesity? Obesity (Silver Spring) 16: 7-15.
96. Musso G, Gambino R, Cassader M, (2010). Obesity, diabetes, and gut microbiota: the hygiene hypothesis expanded? Diabetes Care 33: 2277-2284.
97. Na LX, Li Y, Pan HZ, Zhou XL, Sun DJ, Meng M, et al. (2012). Curcuminoids exert glucose-lowering effect in type 2 diabetes by decreasing serum free fatty acids: a double-blind, placebo-controlled trial. Mol Nutr Food Res 56: 1-9.
98. Nagasumi K, Esaki R, Iwachidow K, Yasuhara Y, Ogi K, Tanaka H, et al. (2009). Overexpression of GPR40 in pancreatic beta-cells augments glucose-stimulated insulin secretion and improves glucose tolerance in normal and diabetic mice. Diabetes 58: 1067-1076.
99. Negoro N, Sasaki S, Mikami S, Ito M, Suzuki M, Tsujihata Y, et al. (2010). Discovery of TAK-875: a potent, selective and orally bioavailable GPR40 agonist. ACS Med Chem Lett 1: 290-294.
100. 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: 1047-1052.
101. Oh DY, Talukdar S, Bae EJ, Imamura T, Morinaga H, Fan W, et al. (2010). GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell 142: 687-698.
102. Ouchi N, Parker JL, Lugus JJ, Walsh K, (2011). Adipokines in inflammation and metabolic disease. Nat Rev Immunol 11: 85-97.
103. Parnell JA, Reimer RA, (2009). Weight loss during oligofructose supplementation is associated with decreased ghrelin and increased peptide YY in overweight and obese adults. Am J Clin Nutr 89: 1751-1759.
104. Poudyal H, Panchal SK, Diwan V, Brown L, (2011). Omega-3 fatty acids and metabolic syndrome: effects and emerging mechanisms of action. Prog Lipid Res 50: 372-387.
105. Pouteau E, Meirim I, Metairon S, Fay L-B, (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: 788-805.
106. Ratnayake WM, Galli C, (2009). Fat and fatty acid terminology, methods of analysis and fat digestion and metabolism: a background review paper. Ann Nutr Metab 55: 8-43.
107. Rayasam GV, Tulasi VK, Sundaram S, Singh W, Kant R, Davis JA, et al. (2010). Identification of berberine as a novel agonist of fatty acid receptor GPR40. Phytother Res 24: 1260-1263.
108. Rustan AC, Hustvedt BE, Drevon CA, (1998). Postprandial decrease in plasma unesterified fatty acids during n-3 fatty acid feeding is not caused by accumulation of fatty acids in adipose tissue. Biochim Biophys Acta 1390: 245-257.
109. Salehi A, Flodgren E, Nilsson NE, Jimenez-Feltstrom J, Miyazaki J, Owman C, et al. (2005). Free fatty acid receptor 1 (FFA(1)R/GPR40) and its involvement in fatty-acid-stimulated insulin secretion. Cell Tissue Res 322: 207-215.
110. Samuel BS, Shaito A, Motoike T, Rey FE, Backhed F, Manchester JK, et al. (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.
111. Saniere PR, Triballeau N, Vandeghinste NER, De VSIJ, Brys RCX, et al. (2012). Preparation of azetidine derivatives as GPR43 antagonists useful in the treatment of metabolic and inflammatory diseases. International patent application WO2012098033.
112. Santomauro AT, Boden G, Silva ME, Rocha DM, Santos RF, Ursich MJ, et al. (1999). Overnight lowering of free fatty acids with Acipimox improves insulin resistance and glucose tolerance in obese diabetic and nondiabetic subjects. Diabetes 48: 1836-1841.
113. Sawzdargo M, George SR, Nguyen T, Xu S, Kolakowski LF, O'Dowd BF, (1997). 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: 543-547.
114. Schmidt J, Liebscher K, Merten N, Grundmann M, Mielenz M, Sauerwein H, et al. (2011a). Conjugated linoleic acids mediate insulin release through islet G protein-coupled receptor FFA1/GPR40. J Biol Chem 286: 11890-11894.
115. Schmidt J, Smith NJ, Christiansen E, Tikhonova IG, Grundmann M, Hudson BD, et al. (2011b). 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: 10628-10640.
116. Sealy L, Chalkley R, (1978). The effect of sodium butyrate on histone modification. Cell 14: 115-121.
117. Senga T, Iwamoto S, Yoshida T, Yokota T, Adachi K, Azuma E, et al. (2003). LSSIG is a novel murine leukocyte-specific GPCR that is induced by the activation of STAT3. Blood 101: 1185-1187.
118. Shimpukade B, Hudson BD, Hovgaard CK, Milligan G, Ulven T, (2012). Discovery of a potent and selective GPR120 agonist. J Med Chem 55: 4511-4515.
119. Shreiner A, Huffnagle GB, Noverr MC, (2008). The 'Microflora Hypothesis' of allergic disease. Adv Exp Med Biol 635: 113-134.
120. Simpson K, Parker J, Plumer J, Bloom S, (2012). CCK, PYY and PP: the control of energy balance. Handb Exp Pharmacol 209: 209-230.
121. Sina C, Gavrilova O, Forster M, Till A, Derer S, Hildebrand F, et al. (2009). G protein-coupled receptor 43 is essential for neutrophil recruitment during intestinal inflammation. J Immunol 183: 7514-7522.
122. Smith NJ, (2012). Low affinity GPCRs for metabolic intermediates: challenges for pharmacologists. Front Endocrinol (Lausanne) 3: 1.
123. Smith NJ, Ward RJ, Stoddart LA, Hudson BD, Kostenis E, Ulven T, et al. (2011). Extracellular loop 2 of the free fatty acid receptor 2 mediates allosterism of a phenylacetamide ago-allosteric modulator. Mol Pharmacol 80: 163-173.
124. 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: 245-258.
125. 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.
126. Suzuki T, Igari S, Hirasawa A, Hata M, Ishiguro M, Fujieda H, et al. (2008). Identification of G protein-coupled receptor 120-selective agonists derived from PPARgamma agonists. J Med Chem 51: 7640-7644.
127. Talukdar S, Olefsky JM, Osborn O, (2011). Targeting GPR120 and other fatty acid-sensing GPCRs ameliorates insulin resistance and inflammatory diseases. Trends Pharmacol Sci 32: 543-550.
128. Tan CP, Feng Y, Zhou YP, Eiermann GJ, Petrov A, Zhou C, et al. (2008). Selective small-molecule agonists of G protein-coupled receptor 40 promote glucose-dependent insulin secretion and reduce blood glucose in mice. Diabetes 57: 2211-2219.
129. Tanaka T, Katsuma S, Adachi T, Koshimizu TA, Hirasawa A, Tsujimoto G, (2008a). Free fatty acids induce cholecystokinin secretion through GPR120. Naunyn Schmiedebergs Arch Pharmacol 377: 523-527.
130. Tanaka T, Yano T, Adachi T, Koshimizu TA, Hirasawa A, Tsujimoto G, (2008b). Cloning and characterization of the rat free fatty acid receptor GPR120: in vivo effect of the natural ligand on GLP-1 secretion and proliferation of pancreatic beta cells. Naunyn Schmiedebergs Arch Pharmacol 377: 515-522.
131. Taneera J, Lang S, Sharma A, Fadista J, Zhou Y, Ahlqvist E, et al. (2012). A systems genetics approach identifies genes and pathways for type 2 diabetes in human islets. Cell Metab 16: 122-134.
132. Tazoe H, Otomo Y, Kaji I, Tanaka R, Karaki SI, Kuwahara A, (2008). Roles of short-chain fatty acids receptors, GPR41 and GPR43 on colonic functions. J Physiol Pharmacol 59 (Suppl. 2): 251-262.
133. Tolhurst G, Heffron H, Lam YS, Parker HE, Habib AM, Diakogiannaki E, et al. (2012). Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the G-protein-coupled receptor FFAR2. Diabetes 61: 364-371.
134. Tsujihata Y, Ito R, Suzuki M, Harada A, Negoro N, Yasuma T, et al. (2011). TAK-875, an orally available G protein-coupled receptor 40/free fatty acid receptor 1 agonist, enhances glucose-dependent insulin secretion and improves both postprandial and fasting hyperglycemia in type 2 diabetic rats. J Pharmacol Exp Ther 339: 228-237.
135. Tvrzicka E, Kremmyda LS, Stankova B, Zak A, (2011). 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: 117-130.
136. Ulven T, (2012). Short-chain free fatty acid receptors FFA2/GPR43 and FFA3/GPR41 as new potential therapeutic targets. Front Endocrinol (Lausanne) 3: 111.
137. Vandal M, Freemantle E, Tremblay-Mercier J, Plourde M, Fortier M, Bruneau J, et al. (2008). Plasma omega-3 fatty acid response to a fish oil supplement in the healthy elderly. Lipids 43: 1085-1089.
138. Varga T, Czimmerer Z, Nagy L, (2011). PPARs are a unique set of fatty acid regulated transcription factors controlling both lipid metabolism and inflammation. Biochim Biophys Acta 1812: 1007-1022.
139. Vinolo MA, Ferguson GJ, Kulkarni S, Damoulakis G, Anderson K, Bohlooly YM, et al. (2011). SCFAs induce mouse neutrophil chemotaxis through the GPR43 receptor. PLoS ONE 6: e21205.
140. Vrieze A, Van Nood E, Holleman F, Salojarvi J, Kootte RS, Bartelsman JF, et al. (2012). Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology 143: 913-916 e917.
141. Wagner R, Kaiser G, Gerst F, Christiansen E, Due-Hansen ME, Grundmann M, et al. (2013). Reevaluation of fatty acid receptor 1 (FFAR1/GPR40) as drug target for the stimulation of insulin secretion in humans. Diabetes 62: 2106-2111.
142. Waldecker M, Kautenburger T, Daumann H, Busch C, Schrenk D, (2008). Inhibition of histone-deacetylase activity by short-chain fatty acids and some polyphenol metabolites formed in the colon. J Nutr Biochem 19: 587-593.
143. Walker CG, Goff L, Bluck LJ, Griffin BA, Jebb SA, Lovegrove JA, et al. (2011). Variation in the FFAR1 gene modifies BMI, body composition and beta-cell function in overweight subjects: an exploratory analysis. PLoS ONE 6: e19146.
144. Wang J, Wu X, Simonavicius N, Tian H, Ling L, (2006). Medium-chain fatty acids as ligands for orphan G protein-coupled receptor GPR84. J Biol Chem 281: 34457-34464.
145. Wang L, Zhao Y, Gui B, Fu R, Ma F, Yu J, et al. (2011). Acute stimulation of glucagon secretion by linoleic acid results from GPR40 activation and [Ca2+]i increase in pancreatic islet {alpha}-cells. J Endocrinol 210: 173-179.
146. Warzecha Z, Dembinski A, (2012). Protective and therapeutic effects of ghrelin in the gut. Curr Med Chem 19: 118-125.
147. Watson SJ, Brown AJ, Holliday ND, (2012). Differential signaling by splice variants of the human free fatty acid receptor GPR120. Mol Pharmacol 81: 631-642.
148. Wauquier F, Philippe C, Leotoing L, Mercier S, Davicco MJ, Lebecque P, et al. (2013). The free fatty acid receptor G protein-coupled receptor 40 (GPR40) protects from bone loss through inhibition of osteoclast differentiation. J Biol Chem 288: 6542-6551.
149. WHO (2013). Obesity and Overweight Fact sheet No 311, World Health Organization.
150. Wu J, Sun P, Zhang X, Liu H, Jiang H, Zhu W, et al. (2012). Inhibition of GPR40 protects MIN6 beta cells from palmitate-induced ER stress and apoptosis. J Cell Biochem 113: 1152-1158.
151. Wu P, Yang L, Shen X, (2010). The relationship between GPR40 and lipotoxicity of the pancreatic beta-cells as well as the effect of pioglitazone. Biochem Biophys Res Commun 403: 36-39.
152. 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.
153. Yashiro H, Tsujihata Y, Takeuchi K, Hazama M, Johnson PR, Rorsman P, (2012). The effects of TAK-875, a selective G protein-coupled receptor 40/free fatty acid 1 agonist, on insulin and glucagon secretion in isolated rat and human islets. J Pharmacol Exp Ther 340: 483-489.
154. Yen CH, Tseng YH, Kuo YW, Lee MC, Chen HL, (2011). Long-term supplementation of isomalto-oligosaccharides improved colonic microflora profile, bowel function, and blood cholesterol levels in constipated elderly people-a placebo-controlled, diet-controlled trial. Nutrition 27: 445-450.
155. Yonezawa T, Katoh K, Obara Y, (2004). Existence of GPR40 functioning in a human breast cancer cell line, MCF-7. Biochem Biophys Res Commun 314: 805-809.
156. Zaibi MS, Stocker CJ, O'Dowd J, Davies A, Bellahcene M, Cawthorne MA, et al. (2010). Roles of GPR41 and GPR43 in leptin secretory responses of murine adipocytes to short chain fatty acids. FEBS Lett 584: 2381-2386.
157. Zhang Y, Xu M, Zhang S, Yan L, Yang C, Lu W, et al. (2007). The role of G protein-coupled receptor 40 in lipoapoptosis in mouse beta-cell line NIT-1. J Mol Endocrinol 38: 651-661.