GPR40/FFA1 Free Fatty Acid Receptors and Their Functional Role

The endogenous ligands of GPR40/FFA1 receptors, which are members of the G protein-coupled receptor class, are saturated and unsaturated free fatty acids (C6–C12) and long-chain (>C12) structures. The highest levels of expression of these receptors are seen in pancreatic β cells and neurons in various parts of the CNS. An enormous amount of experimental data on the functional roles of these receptors in the central and peripheral regulation of the body’s metabolic status has been published since the “deorphanization” of these receptors in 2003. This review summarizes current understanding of the mechanisms regulating GPR40/FFA1 receptors by endogenous and synthetic ligands and the intracellular signal transduction systems activated on exposure to free fatty acids. The mechanisms of GPR40/FFA1-mediated effects of free fatty acids on glucose-stimulated insulin secretion by pancreatic β cells are addressed, along with the production of incretins by enteroendocrine cells; the mechanisms of actions on the support of neurogenesis and neurodifferentiation are also considered. Advances and potentials in the use of synthetic ligands of GPR40/FFA1 receptors in the treatment of metabolic disorders are assessed.

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References

  1. 1.

    E. M. Kreps, Cell Membrane Lipids, Nauka, Leningrad (1981).

    Google Scholar 

  2. 2.

    A. Wise, S. C. Jupe, and S. Rees, “The identification of ligands at orphan G-protein coupled receptors,” Annu. Rev. Pharmacol. Toxicol., 44, 43–66 (2004).

    CAS  PubMed  Google Scholar 

  3. 3.

    L. A. Stoddart, N. J. Smith, and G. Milligan, “International Union of Pharmacology. LXXI. Free fatty acid receptors FFA1, -2, and -3: pharmacology and pathophysiological functions,” Pharmacol. Rev., 60, No. 4, 405–417 (2008).

    CAS  PubMed  Google Scholar 

  4. 4.

    M. Sawzdargo, S. R. George, T. Nguyen, et al., “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, No. 2, 543–547 (1997).

    CAS  PubMed  Google Scholar 

  5. 5.

    Y. Itoh, Y. Kawamata, M. Harada, et al., “Free fatty acids regulate insulin secretion from pancreatic beta cells πhrough GPR40,” Nature, 422, No. 6928, 173–176 (2003).

    CAS  PubMed  Google Scholar 

  6. 6.

    C. P. Briscoe, M. Tadayyon, J. L. Andrews, et al., “The orphan G protein-coupled receptor GPR40 is activated by medium and long chain fatty acids,” J. Biol. Chem., 278, No. 13, 11,303–11,311 (2003).

    CAS  Google Scholar 

  7. 7.

    K. Kotarsky, N. E. Nilsson, B. Olde, and C. Owman, “Progress in methodology Improved reporter gene assays used to identify ligands acting on orphan seven-transmembrane receptors,” Pharmacol. Toxicol., 93, 249–258 (2003).

    CAS  PubMed  Google Scholar 

  8. 8.

    T. Tomita, H. Masuzaki, H. Iwakura, et al., “Expression of the gene for a membrane-bound fatty acid receptor in the pancreas and islet cell tumours in humans: evidence for GPR40 expression in pancreatic beta cells and implications for insulin secretion,” Diabetologia, 49, No. 5, 962–968 (2006).

    CAS  PubMed  Google Scholar 

  9. 9.

    A. Salehi, E. Flodgren, N. E. Nilsson, et al., “Free fatty acid receptor 1 (FFA(1)R/GPR40) and its involvement in fatty-acid-stimulated insulin secretion,” Cell Tissue Res., 322, No. 2, 207–215 (2005).

    CAS  PubMed  Google Scholar 

  10. 10.

    H. Shapiro, S. Shachar, I. Sekler, et al., “Role of GPR40 in fatty acid action on the beta cell line INS-1E,” Biochem. Biophys. Res. Commun, 335, 97–104 (2005).

    CAS  PubMed  Google Scholar 

  11. 11.

    M. Kebede, T. Alquier, M. G. Latour, et al., “The fatty acid receptor GPR40 plays a role in insulin secretion in vivo after high-fat feeding,” Diabetes, 57, No. 9, 2432–2437 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    K. Nagasumi, R. Esaki, K. Iwachidow, et al., “Overexpression of GPR40 in pancreatic beta-cells augments glucose-stimulated insulin secretion and improves glucose tolerance in normal and diabetic mice,” Diabetes, 58, No. 5, 1067–1076 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    M. Prentki, B. E. Corkey, and S. R. M. Madiraju, “Lipid-associated metabolic signalling networks in pancreatic beta cell function,” Diabetologia, 63, No. 1, 10–20 (2020).

    CAS  PubMed  Google Scholar 

  14. 14.

    A. D. Mancini and V. Poitout, “GPR40 agonists for the treatment of type 2 diabetes: life after ‘TAKing’ a hit,” Diabetes Obes. Metab., 17, No. 7, 622–629 (2015).

    CAS  PubMed  Google Scholar 

  15. 15.

    M. G. Latour, T. Alquier, E. Oseid, et al., “GPR40 is necessary but not sufficient for fatty acid stimulation of insulin secretion in vivo,” Diabetes, 56, No. 4, 1087–1094 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    K. Fujiwara, F. Maekawa, and T. Yada, “Oleic acid interacts with GPR40 to induce Ca2+ signaling in rat islet beta-cells: mediation by PLC and L-type Ca2+ channel and link to insulin release,” Am. J. Physiol. Endocrinol. Metab., 289, No. 4, E670–677 (2005).

    CAS  PubMed  Google Scholar 

  17. 17.

    S. Schnell, M. Schaefer, and C. Schöfl , “Free fatty acids increase cytosolic free calcium and stimulate insulin secretion from beta-cells through activation of GPR40,” Mol. Cell. Endocrinol., 263, No. 1–2, 173–80 (2007).

    CAS  PubMed  Google Scholar 

  18. 18.

    K. Sakuma, C. Yabuki, M. Maruyama, et al., “Fasiglifam (TAK-875) has dual potentiating mechanisms via Gαq-GPR40/FFAR1 signaling branches on glucose-dependent insulin secretion,” Pharmacol. Res. Perspect., 4, No. 3, e00237 (2016).

    PubMed  PubMed Central  Google Scholar 

  19. 19.

    Z. Wang and D. C. Thurmond, “Mechanisms of biphasic insulin-granule exocytosis – roles of the cytoskeleton, small GTPases and SNARE proteins,” J. Cell Sci., 122, No. 7, 893–903 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    A. O. Shpakov, The Adenylate Cyclase System in Health and Diabetic Pathology, Polytechnic University Press, St. Petersburg (2016).

    Google Scholar 

  21. 21.

    K. S. Gwiazda, T. L. Yang, Y. Lin, and J. D. Johnson, “Effects of palmitate on ER and cytosolic Ca2+ homeostasis in beta-cells,” Am. J. Physiol. Endocrinol. Metab., 296, No. 4, E690–E701 (2009).

    CAS  PubMed  Google Scholar 

  22. 22.

    M. Ferdaoussi, V. Bergeron, B. Zarrouki, et al., “G protein-coupled receptor (GPR) 40-dependent potentiation of insulin secretion in mouse islets is mediated by protein kinase D1,” Diabetologia, 55, No. 10, 2682–2692 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    R. Usui, D. Yabe, M. Fauzi, et al., “GPR40 activation initiates store-operated Ca2+ entry and potentiates insulin secretion via the IP3R1/STIM1/Orai1 pathway in pancreatic β-cells,” Sci. Rep., 9, No. 1, 15562 (2019).

    PubMed  PubMed Central  Google Scholar 

  24. 24.

    M. Muik, I. Frischauf, I. Derler, et al., “Dynamic coupling of the putative coiled-coil domain of ORAI1 with STIM1 mediates ORAI1 channel activation,” J. Biol. Chem., 283, No. 12, 8014–8022 (2008).

    CAS  PubMed  Google Scholar 

  25. 25.

    N. A. Tamarina, A. Kuznetsov, and L. H. Philipson, “Reversible translocation of EYFP-tagged STIM1 is coupled to calcium influx in insulin secreting beta-cells,” Cell Calcium, 44, No. 6, 533–44 (2008).

    CAS  PubMed  Google Scholar 

  26. 26.

    G. Tian, A. V. Tepikin, A. Tengholm, and E. Gylfe, “cAMP induces stromal interaction molecule 1 (STIM1) puncta but neither Orai1 protein clustering nor store-operated Ca2+ entry (SOCE) in islet cells,” J. Biol. Chem., 287, No. 13, 9862–9872 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Y. Tsujihata, R. Ito, M. Suzuki, et al., “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, No. 1, 228–237 (2011).

    CAS  PubMed  Google Scholar 

  28. 28.

    Y. Urano, S. Oda, K. Tsuneyama, and T. Yokoi, “Comparative hepatic transcriptome analyses revealed possible pathogenic mechanisms of fasiglifam (TAK-875)-induced acute liver injury in mice,” Chem. Biol. Interact., 296, 185–197 (2018).

    CAS  PubMed  Google Scholar 

  29. 29.

    A. O. Shpakov, K. V. Derkach, A. A. Bakhtyukov, and E. A. Shpakova, G-Protein-Coupled Receptors and their Allosteric Regulators, Polytech-Press, St. Petersburg (2019).

    Google Scholar 

  30. 30.

    C. S. Sum, I. G. Tikhonova, S. Neumann, et al., “Identification of residues important for agonist recognition and activation in GPR40,” J. Biol. Chem., 282, No. 40, 29248–29255 (2007).

    CAS  PubMed  Google Scholar 

  31. 31.

    D. C. Lin, Q. Guo, Luo J, et al., “Identification and pharmacological characterization of multiple allosteric binding sites on the free fatty acid 1 receptor,” Mol. Pharmacol., 82, No. 5, 843–859 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    A. Srivastava, J. Yano, Y. Hirozane, et al., “High-resolution structure of the human GPR40 receptor bound to allosteric agonist TAK-875,” Nature, 513, 124–127 (2014).

    CAS  PubMed  Google Scholar 

  33. 33.

    M. Krasavin, A. Lukin, D. Bagnyukova, et al., “Polar aromatic periphery increases agonist potency of spirocyclic free fatty acid receptor (GPR40) agonists inspired by LY2881835,” Eur. J. Med. Chem., 127, 357–368 (2017).

    CAS  PubMed  Google Scholar 

  34. 34.

    A. D. Mancini, G. Bertrand, K. Vivot, et al., “beta-Arrestin recruitment and biased agonism at free fatty acid receptor 1,” J. Biol. Chem., 290, 21,131–21,140 (2015).

    CAS  Google Scholar 

  35. 35.

    M. Hauge, M. A. Vestmar, A. S. Husted, 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, No. 1, 3–14 (2014).

    PubMed  PubMed Central  Google Scholar 

  36. 36.

    J. R. Lane, P. M. Sexton, and A. Christopoulos, “Bridging the gap: bitopic ligands of G-protein-coupled receptors,” Trends Pharmacol. Sci., 34, No. 1, 59–66 (2013).

    CAS  PubMed  Google Scholar 

  37. 37.

    C. Yabuki, H. Komatsu, Y. Tsujihata, et al., “A novel antidiabetic drug, fasiglifam/TAK-875, acts as an ago-allosteric modulator of FFAR1,” PLoS One, 8, No. 10, e76280 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    S. Edfalk, P. Steneberg, and H. Edlund, “Gpr40 is expressed in enteroendocrine cells and mediates free fatty acid stimulation of incretin secretion,” Diabetes, 57, No. 9, 2280–2287 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    A. P. Liou, X. Lu, Y. Sei, et al., Gastroenterology, 140, No. 3, 903–912 (2011).

    CAS  PubMed  Google Scholar 

  40. 40.

    J. H. Ekberg, M. Hauge, L. V. Kristensen, et al., “GPR119, a major enteroendocrine sensor of dietary triglyceride metabolites coacting in synergy with FFA1 (GPR40),” Endocrinology, 157, No. 12, 4561–4569 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Y. Xiong, G. Swaminath, Q. Cao, et al., “Activation of FFA1 mediates GLP-1 secretion in mice. Evidence for allosterism at FFA1,” Mol. Cell. Endocrinol., 369, No. 1–2, 119–129 (2013).

    CAS  PubMed  Google Scholar 

  42. 42.

    E. Leifke, H. Naik, J. Wu, 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, No. 1, 29–39 (2012).

    CAS  PubMed  Google Scholar 

  43. 43.

    J. Luo, G. Swaminath, S. P. Brown, et al., “A potent class of GPR40 full agonists engages the enteroinsular axis to promote glucose control in rodents,” PLoS One, 7, No. 10, e46300 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    D. Ma, L. Lu, N. B. Boneva, et al., “Expression of free fatty acid receptor GPR40 in the neurogenic niche of adult monkey hippocampus,” Hippocampus, 18, No. 3, 326–333 (2008).

    CAS  PubMed  Google Scholar 

  45. 45.

    K. Nakamoto, T. Nishinaka, K. Matsumoto, et al., “Involvement of the long-chain fatty acid receptor GPR40 as a novel pain regulatory system,” Brain Res., 1432, 74–83 (2012).

    CAS  PubMed  Google Scholar 

  46. 46.

    M. Zamarbide, I. Etayo-Labiano, A. Ricobaraza, et al., “GPR40 activation leads to CREB and ERK phosphorylation in primary cultures of neurons from the mouse CNS and in human neuroblastoma cells,” Hippocampus, 24, 733–739 (2014).

    CAS  PubMed  Google Scholar 

  47. 47.

    M. Z. Khan, X. Zhuang, and L. He, “GPR40 receptor activation leads to CREB phosphorylation and improves cognitive performance in an Alzheimer’s disease mouse model,” Neurobiol. Learn. Mem., 131, 46–55 (2016).

    CAS  PubMed  Google Scholar 

  48. 48.

    C. Sona, A. Kumar, S. Dogra, et al., “Docosa-hexaenoic acid modulates brain-derived neurotrophic factor via GPR40 in the brain and alleviates diabesity-associated learning and memory deficits in mice,” Neurobiol. Dis., 118, 94–107 (2018).

    CAS  PubMed  Google Scholar 

  49. 49.

    S. Obici, Z. Feng, A. Arduini, et al., “Inhibition of hypothalamic carnitine palmitoyltransferase-1 decreases food intake and glucose production,” Nat. Med., 9, 756–761 (2003).

    CAS  PubMed  Google Scholar 

  50. 50.

    I. Miller, G. V. Ronnett, T. H. Moran, and S. Aja, “Anorexigenic C75 alters c-Fos in mouse hypothalamic and hindbrain subnuclei,” Neuroreport, 15, 925–929 (2004).

    CAS  PubMed  Google Scholar 

  51. 51.

    S. Obici, Z. Feng, K. Morgan, et al., “Central administration of oleic acid inhibits glucose production and food intake,” Diabetes, 51, No. 2, 271–275 (2002).

    CAS  PubMed  Google Scholar 

  52. 52.

    R. Wang, C. Cruciani-Guglielmacci, S. Migrenne, et al., “Effects of oleic acid on distinct populations of neurons in the hypothalamic arcuate nucleus are dependent on extracellular glucose levels,” J. Neurophysiol, 95, No. 3, 1491–1498 (2006).

    CAS  PubMed  Google Scholar 

  53. 53.

    L. F. Nascimento, G. F. Souza, J. Morari, et al., “n-3 fatty acids induce neurogenesis of predominantly POMC-expressing cells in the hypothalamus,” Diabetes, 65, No. 3, 673–686 (2016).

    CAS  PubMed  Google Scholar 

  54. 54.

    N. R. V. Dragano, C. Solon, A. F. Ramalho, et al., “Polyunsaturated fatty acid receptors, GPR40 and GPR120, are expressed in the hypothalamus and control energy homeostasis and inflammation,” J. Neuroinflammation, 14, No. 1, 91 (2017).

    PubMed  PubMed Central  Google Scholar 

  55. 55.

    M. Y. Donath and S. E. Shoelson, “Type 2 diabetes as an inflammatory disease,” Nat. Rev. Immunol., 11, No. 2, 98–107 (2011).

    CAS  PubMed  Google Scholar 

  56. 56.

    S. Dutheil, K. T. Ota, E. S. Wohleb, et al., “High-fat diet induced anxiety and anhedonia: impact on brain homeostasis and inflammation,” Neuropsychopharmacology, 41, 1874–1887 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57.

    L. A. Velloso and M. W. Schwartz, “Altered hypothalamic function in diet-induced obesity,” Int. J. Obes. (Lond.), 35, 1455–1465 (2011).

    CAS  Google Scholar 

  58. 58.

    R. S. Carraro, G. F. Souza, C. Solon, et al., “Hypothalamic mitochondrial abnormalities occur downstream of inflammation in diet-induced obesity,” Mol. Cell. Endocrinol., 460, 238–245 (2018).

    CAS  PubMed  Google Scholar 

  59. 59.

    U. Ozcan, E. Yilmaz, L. Ozcan, et al., “Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes,” Science, 313, 1137–1140 (2006).

    PubMed  PubMed Central  Google Scholar 

  60. 60.

    J. C. Moraes, A. Coope, J. Morari, et al., “High-fat diet induces apoptosis of hypothalamic neurons,” PLoS One, 4, e5045 (2009).

    Google Scholar 

  61. 61.

    Z. Wang, D. Liu, F. Wan, et al., “Saturated fatty acids activate microglia via Toll-like receptor 4/NF-κB signalling,” Br. J. Nutr., 107, 229–241 (2012).

    CAS  PubMed  Google Scholar 

  62. 62.

    M. D. Dorfman and J. P. Thaler, “Hypothalamic inflammation and gliosis in obesity,” Curr. Opin. Endocrinol. Diabetes Obes., 22, 325–330 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    D. E. Cintra, E. R. Ropelle, J. C. Moraes, et al., “Unsaturated fatty acids revert diet-induced hypothalamic inflammation in obesity,” PLoS One, 7, No. 1, e30571 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64.

    F. Panza, V. Frisardi, D. Seripa, et al., “Metabolic syndrome, mild cognitive impairment, and dementia,” Curr. Alzheimer Res., 8, No. 5, 492–509 (2011).

    CAS  PubMed  Google Scholar 

  65. 65.

    K. Pal, N. Mukadam, I. Petersen, and C. Cooper, “Mild cognitive impairment and progression to dementia in people with diabetes, prediabetes and metabolic syndrome: a systematic review and meta-analysis,” Soc. Psychiatry Psychiatr. Epidemiol., 53, No. 11, 1149–1160 (2018).

    PubMed  PubMed Central  Google Scholar 

  66. 66.

    A. Passaro, E. Dalla Nora, M. L. Morieri, et al., “Brain-derived neurotrophic factor plasma levels: relationship with dementia and diabetes in the elderly population,” J. Gerontol. A. Biol. Sci. Med. Sci., 70, No. 3, 294–302 (2015).

    CAS  PubMed  Google Scholar 

  67. 67.

    E. Schwartz and C. V. Mobbs, “Hypothalamic BDNF and obesity: found in translation,” Nat. Med., 18, No. 4, 496–497 (2012).

    CAS  PubMed  Google Scholar 

  68. 68.

    R. Molteni, R. J. Barnard, Z. Ying, et al., “A high-fat, refined sugar diet reduces hippocampal brain-derived neurotrophic factor, neuronal plasticity, and learning,” Neuroscience, 112, No. 4, 803–814 (2002).

    CAS  PubMed  Google Scholar 

  69. 69.

    E. A. Fox, J. E. Biddinger, K. R. Jones, et al., “Mechanism of hyperphagia contributing to obesity in brain-derived neurotrophic factor knockout mice,” Neuroscience, 229, 176–199 (2013).

    CAS  PubMed  Google Scholar 

  70. 70.

    V. F. Labrousse, A. Nadjar, C. Joffre, et al., “Short-term long chain omega3 diet protects from neuroinfl ammatory processes and memory impairment in aged mice,” PLoS One, 7, No. 5, e36861 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71.

    C. I. Janssen and A. J. Kiliaan, “Long-chain polyunsaturated fatty acids (LCPUFA) from genesis to senescence: the influence of LCPUFA on neural development, aging, and neurodegeneration,” Prog. Lipid Res., 53, 1–17 (2014).

    CAS  PubMed  Google Scholar 

  72. 72.

    M. Healy-Stoffel and B. Levant, “n-3 (Omega-3) fatty acids: effects on brain dopamine systems and potential role in the etiology and treatment of neuropsychiatric disorders,” CNS Neurol. Disord. Drug Targets, 17, No. 3, 216–232 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73.

    F. Aizawa, Y. Ogaki, N. Kyoya, et al., “The deletion of GPR40/FFAR1 signaling damages maternal care and emotional function in female mice,” Biol. Pharm. Bull., 40, No. 8, 1255–1259 (2017).

    PubMed  Google Scholar 

  74. 74.

    D. Ma, M. Zhang, C. Larsen, et al., “DHA promotes the neuronal differentiation of rat neural stem cells transfected with GPR40 gene,” Brain Res., 1330, 1–8 (2010).

    CAS  PubMed  Google Scholar 

  75. 75.

    K. Nakamoto, F. Aizawa, K. Miyagi, et al., “Dysfunctional GPR40/FFAR1 signaling exacerbates pain behavior in mice,” PLoS One, 12, No. 7, e0180610 (2017).

    PubMed  PubMed Central  Google Scholar 

  76. 76.

    Y. P. Zhou and V. E. Grill, “Long-term exposure of rat pancreatic islets to fatty acids inhibits glucose-induced insulin secretion and biosynthesis through a glucose fatty acid cycle,” J. Clin. Invest., 93, No. 2, 870–876 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77.

    T. Yamashima, “Dual effects of the non-esterified fatty acid receptor ‘GPR40’ for human health,” Prog. Lipid Res., 58, 40–50 (2015).

    CAS  PubMed  Google Scholar 

  78. 78.

    Y. Sako and V. E. Grill, “A 48-hour lipid infusion in the rat time-dependently inhibits glucose-induced insulin secretion and B cell oxidation through a process likely coupled to fatty acid oxidation,” Endocrinology, 127, No. 4, 1580–1589 (1990).

    CAS  PubMed  Google Scholar 

  79. 79.

    A. Carpentier, S. D. Mittelman, B. Lamarche, et al., “Acute enhancement of insulin secretion by FFA in humans is lost with prolonged FFA elevation,” Am. J. Physiol., 276, No. 6, E1055–1066 (1999).

    CAS  PubMed  Google Scholar 

  80. 80.

    W. Gehrmann, M. Elsner, and S. Lenzen, “Role of metabolically generated reactive oxygen species for lipotoxicity in pancreatic β-cells,” Diabetes Obes. Metab., 12, Supplement 2, 149–158 (2010).

  81. 81.

    J. Wu, P. Sun, X. Zhang, et al., “Inhibition of GPR40 protects MIN6 β cells from palmitate-induced ER stress and apoptosis,” J. Cell. Biochem., 113, No. 4, 1152–1158 (2012).

    CAS  PubMed  Google Scholar 

  82. 82.

    P. Steneberg, N. Rubins, R. Bartoov-Shifman, et al., “The FFA receptor GPR40 links hyperinsulinemia, hepatic steatosis, and impaired glucose homeostasis in mouse,” Cell Metab., 1, No. 4, 245–258 (2005).

    CAS  PubMed  Google Scholar 

  83. 83.

    C. P. Tan, Y. Feng, Y. P. Zhou, et al., “Selective small-molecule agonists of G protein-coupled receptor 40 promote glucose-dependent insulin secretion and reduce blood glucose in mice,” Diabetes, 57, No. 8, 2211–2219 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84.

    F. G. Almaguel, J. W. Liu, F. J. Pacheco, et al., “Lipotoxicitymediated cell dysfunction and death involve lysosomal membrane permeabilization and cathepsin L activity,” Brain Res., 1318, 133–143 (2010).

    CAS  PubMed  Google Scholar 

  85. 85.

    J. Schmidt, K. Liebscher, N. Merten, et al., “Conjugated linoleic acids mediate insulin release through islet G protein-coupled receptor FFA1/GPR40,” J. Biol. Chem., 286, No. 14, 11890–11894 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86.

    J. C. Honoré, A. Kooli, D. Hamel, et al., “Fatty acid receptor Gpr40 mediates neuromicrovascular degeneration induced by transarachidonic acids in rodents,” Arterioscler. Thromb. Vasc. Biol., 33, No. 5, 954–961 (2013).

    PubMed  Google Scholar 

  87. 87.

    G. V. Richieri and A. M. Kleinfeld, “Unbound free fatty acid levels in human serum,” J. Lipid Res., 36, No. 2, 229–240 (1995).

    CAS  PubMed  Google Scholar 

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Correspondence to R. G. Parnova.

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Translated from Rossiiskii Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 106, No. 5, pp. 584–600, May, 2020.

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Parnova, R.G. GPR40/FFA1 Free Fatty Acid Receptors and Their Functional Role. Neurosci Behav Physi 51, 256–264 (2021). https://doi.org/10.1007/s11055-021-01064-8

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Keywords

  • free fatty acids
  • GPR40/FFA1 receptors
  • insulin secretion
  • incretins
  • neurons
  • neurogenesis
  • allosteric regulation