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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E. M. Kreps, Cell Membrane Lipids, Nauka, Leningrad (1981).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
A. O. Shpakov, The Adenylate Cyclase System in Health and Diabetic Pathology, Polytechnic University Press, St. Petersburg (2016).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
A. P. Liou, X. Lu, Y. Sei, et al., Gastroenterology, 140, No. 3, 903–912 (2011).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
M. Y. Donath and S. E. Shoelson, “Type 2 diabetes as an inflammatory disease,” Nat. Rev. Immunol., 11, No. 2, 98–107 (2011).
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).
L. A. Velloso and M. W. Schwartz, “Altered hypothalamic function in diet-induced obesity,” Int. J. Obes. (Lond.), 35, 1455–1465 (2011).
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).
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).
J. C. Moraes, A. Coope, J. Morari, et al., “High-fat diet induces apoptosis of hypothalamic neurons,” PLoS One, 4, e5045 (2009).
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).
M. D. Dorfman and J. P. Thaler, “Hypothalamic inflammation and gliosis in obesity,” Curr. Opin. Endocrinol. Diabetes Obes., 22, 325–330 (2015).
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).
F. Panza, V. Frisardi, D. Seripa, et al., “Metabolic syndrome, mild cognitive impairment, and dementia,” Curr. Alzheimer Res., 8, No. 5, 492–509 (2011).
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).
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).
E. Schwartz and C. V. Mobbs, “Hypothalamic BDNF and obesity: found in translation,” Nat. Med., 18, No. 4, 496–497 (2012).
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).
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).
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).
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).
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).
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).
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).
K. Nakamoto, F. Aizawa, K. Miyagi, et al., “Dysfunctional GPR40/FFAR1 signaling exacerbates pain behavior in mice,” PLoS One, 12, No. 7, e0180610 (2017).
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).
T. Yamashima, “Dual effects of the non-esterified fatty acid receptor ‘GPR40’ for human health,” Prog. Lipid Res., 58, 40–50 (2015).
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).
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).
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).
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).
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).
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).
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).
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).
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).
G. V. Richieri and A. M. Kleinfeld, “Unbound free fatty acid levels in human serum,” J. Lipid Res., 36, No. 2, 229–240 (1995).
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
- free fatty acids
- GPR40/FFA1 receptors
- insulin secretion
- allosteric regulation