Skip to main content Accessibility help
×
Home

Activity of dietary fatty acids on FFA1 and FFA4 and characterisation of pinolenic acid as a dual FFA1/FFA4 agonist with potential effect against metabolic diseases

  • Elisabeth Christiansen (a1), Kenneth R. Watterson (a2), Claire J. Stocker (a3), Elena Sokol (a4), Laura Jenkins (a2), Katharina Simon (a5), Manuel Grundmann (a5), Rasmus K. Petersen (a6), Edward T. Wargent (a3), Brian D. Hudson (a2), Evi Kostenis (a5), Christer S. Ejsing (a4), Michael A. Cawthorne (a3), Graeme Milligan (a2) and Trond Ulven (a1)...

Abstract

Various foods are associated with effects against metabolic diseases such as insulin resistance and type 2 diabetes; however, their mechanisms of action are mostly unclear. Fatty acids may contribute by acting as precursors of signalling molecules or by direct activity on receptors. The medium- and long-chain NEFA receptor FFA1 (free fatty acid receptor 1, previously known as GPR40) has been linked to enhancement of glucose-stimulated insulin secretion, whereas FFA4 (free fatty acid receptor 4, previously known as GPR120) has been associated with insulin-sensitising and anti-inflammatory effects, and both receptors are reported to protect pancreatic islets and promote secretion of appetite and glucose-regulating hormones. Hypothesising that FFA1 and FFA4 mediate therapeutic effects of dietary components, we screened a broad selection of NEFA on FFA1 and FFA4 and characterised active compounds in concentration–response curves. Of the screened compounds, pinolenic acid, a constituent of pine nut oil, was identified as a relatively potent and efficacious dual FFA1/FFA4 agonist, and its suitability for further studies was confirmed by additional in vitro characterisation. Pine nut oil and free and esterified pure pinolenic acid were tested in an acute glucose tolerance test in mice. Pine nut oil showed a moderately but significantly improved glucose tolerance compared with maize oil. Pure pinolenic acid or ethyl ester gave robust and highly significant improvements of glucose tolerance. In conclusion, the present results indicate that pinolenic acid is a comparatively potent and efficacious dual FFA1/FFA4 agonist that exerts antidiabetic effects in an acute mouse model. The compound thus deserves attention as a potential active dietary ingredient to prevent or counteract metabolic diseases.

  • View HTML
    • Send article to Kindle

      To send this article to your Kindle, first ensure no-reply@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

      Note you can select to send to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

      Find out more about the Kindle Personal Document Service.

      Activity of dietary fatty acids on FFA1 and FFA4 and characterisation of pinolenic acid as a dual FFA1/FFA4 agonist with potential effect against metabolic diseases
      Available formats
      ×

      Send article to Dropbox

      To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

      Activity of dietary fatty acids on FFA1 and FFA4 and characterisation of pinolenic acid as a dual FFA1/FFA4 agonist with potential effect against metabolic diseases
      Available formats
      ×

      Send article to Google Drive

      To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

      Activity of dietary fatty acids on FFA1 and FFA4 and characterisation of pinolenic acid as a dual FFA1/FFA4 agonist with potential effect against metabolic diseases
      Available formats
      ×

Copyright

Corresponding author

* Corresponding author: T. Ulven, email ulven@sdu.dk

References

Hide All
1 International Diabetes Federation (2013) IDF Diabetes Atlas, 2014 Update, 6th ed. Brussels: International Diabetes Federation. http://www.idf.org/diabetesatlas.
2 Perez-Martinez, P, Garcia-Rios, A, Delgado-Lista, J, et al. (2011) Mediterranean diet rich in olive oil and obesity, metabolic syndrome and diabetes mellitus. Curr Pharm Des 17, 769777.
3 Heikkila, HM, Krachler, B, Rauramaa, R, et al. (2014) Diet, insulin secretion and insulin sensitivity – the Dose–Responses to Exercise Training (DR's EXTRA) Study (ISRCTN45977199). Br J Nutr 112, 15301541.
4 Hirahatake, KM, Slavin, JL, Maki, KC, et al. (2014) Associations between dairy foods, diabetes, and metabolic health: potential mechanisms and future directions. Metabolism 63, 618627.
5 Jiang, X, Zhang, D & Jiang, W (2014) Coffee and caffeine intake and incidence of type 2 diabetes mellitus: a meta-analysis of prospective studies. Eur J Nutr 53, 2538.
6 Wu, JH, Micha, R, Imamura, F, et al. (2012) Omega-3 fatty acids and incident type 2 diabetes: a systematic review and meta-analysis. Br J Nutr 107, Suppl. 2, S214S227.
7 Yanai, H, Hamasaki, H, Katsuyama, H, et al. (2015) Effects of intake of fish or fish oils on the development of diabetes. J Clin Med Res 7, 812.
8 Ran-Ressler, RR, Bae, S, Lawrence, P, et al. (2014) Branched-chain fatty acid content of foods and estimated intake in the USA. Br J Nutr 112, 565572.
9 Kotarsky, K, Nilsson, NE, Flodgren, E, et al. (2003) A human cell surface receptor activated by free fatty acids and thiazolidinedione drugs. Biochem Biophys Res Commun 301, 406410.
10 Itoh, Y, Kawamata, Y, Harada, M, et al. (2003) Free fatty acids regulate insulin secretion from pancreatic β cells through GPR40. Nature 422, 173176.
11 Briscoe, CP, Tadayyon, M, Andrews, JL, et al. (2003) The orphan G protein-coupled receptor GPR40 is activated by medium and long chain fatty acids. J Biol Chem 278, 1130311311.
12 Hirasawa, A, Tsumaya, K, Awaji, T, et al. (2005) Free fatty acids regulate gut incretin glucagon-like peptide-1 secretion through GPR120. Nat Med 11, 9094.
13 Le Poul, E, Loison, C, Struyf, S, et al. (2003) Functional characterization of human receptors for short chain fatty acids and their role in polymorphonuclear cell activation. J Biol Chem 278, 2548125489.
14 Brown, AJ, Goldsworthy, SM, Barnes, AA, 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, 1131211319.
15 Nilsson, NE, Kotarsky, K, Owman, C, et al. (2003) Identification of a free fatty acid receptor, FFA2R, expressed on leukocytes and activated by short-chain fatty acids. Biochem Biophys Res Commun 303, 10471052.
16 Natarajan, N & Pluznick, JL (2014) From microbe to man: the role of microbial short chain fatty acid metabolites in host cell biology. Am J Physiol Cell Physiol 307, C979C985.
17 Cani, PD, Everard, A & Duparc, T (2013) Gut microbiota, enteroendocrine functions and metabolism. Curr Opin Pharmacol 13, 935940.
18 Ulven, T (2012) Short-chain free fatty acid receptors FFA2/GPR43 and FFA3/GPR41 as new potential therapeutic targets. Front Endocrinol 3, 111.
19 Offermanns, S (2014) Free fatty acid (FFA) and hydroxy carboxylic acid (HCA) receptors. Annu Rev Pharmacol Toxicol 54, 407434.
20 Briscoe, CP, Peat, AJ, McKeown, SC, 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, 619628.
21 Del Guerra, S, Bugliani, M, D'Aleo, V, 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, 2225.
22 Burant, CF, Viswanathan, P, Marcinak, J, 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, 14031411.
23 Luo, J, Swaminath, G, Brown, SP, et al. (2012) A potent class of GPR40 full agonists engages the enteroinsular axis to promote glucose control in rodents. PLOS ONE 7, e46300.
24 Liou, AP, Lu, X, Sei, Y, et al. (2011) The G-protein-coupled receptor GPR40 directly mediates long-chain fatty acid-induced secretion of cholecystokinin. Gastroenterology 140, 903912.
25 Edfalk, S, Steneberg, P & Edlund, H (2008) Gpr40 is expressed in enteroendocrine cells and mediates free fatty acid stimulation of incretin secretion. Diabetes 57, 22802287.
26 Engelstoft, MS, Park, WM, Sakata, I, et al. (2013) Seven transmembrane G protein-coupled receptor repertoire of gastric ghrelin cells. Mol Metab 2, 376392.
27 Gong, Z, Yoshimura, M, Aizawa, S, et al. (2014) G protein-coupled receptor 120 signaling regulates ghrelin secretion in vivo and in vitro . Am J Physiol Endocrinol Metab 306, E28E35.
28 Paulsen, SJ, Larsen, LK, Hansen, G, et al. (2014) Expression of the fatty acid receptor GPR120 in the gut of diet-induced-obese rats and its role in GLP-1 secretion. PLOS ONE 9, e88227.
29 Oh, DY, Talukdar, S, Bae, EJ, et al. (2010) GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell 142, 687698.
30 Stone, VM, Dhayal, S, Brocklehurst, KJ, et al. (2014) GPR120 (FFAR4) is preferentially expressed in pancreatic delta cells and regulates somatostatin secretion from murine islets of Langerhans. Diabetologia 57, 11821191.
31 Li, X, Yu, Y & Funk, CD (2013) Cyclooxygenase-2 induction in macrophages is modulated by docosahexaenoic acid via interactions with free fatty acid receptor 4 (FFA4). FASEB J 27, 49874997.
32 Cintra, DE, Ropelle, ER, Moraes, JC, et al. (2012) Unsaturated fatty acids revert diet-induced hypothalamic inflammation in obesity. PLOS ONE 7, e30571.
33 Wellhauser, L & Belsham, DD (2014) Activation of the omega-3 fatty acid receptor GPR120 mediates anti-inflammatory actions in immortalized hypothalamic neurons. J Neuroinflammation 11, 60.
34 Ichimura, A, Hirasawa, A, Poulain-Godefroy, O, et al. (2012) Dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human. Nature 483, 350354.
35 Tyagi, R, Shimpukade, B, Blattermann, S, et al. (2012) A concise synthesis of the potent inflammatory mediator 5-oxo-ETE. MedChemComm 3, 195198.
36 Hudson, BD, Shimpukade, B, Mackenzie, AE, et al. (2013) The pharmacology of TUG-891, a potent and selective agonist of the free fatty acid receptor 4 (FFA4/GPR120), demonstrates both potential opportunity and possible challenges to therapeutic agonism. Mol Pharmacol 84, 710725.
37 Hudson, BD, Christiansen, E, Tikhonova, IG, et al. (2012) Chemically engineering ligand selectivity at the free fatty acid receptor 2 based on pharmacological variation between species orthologs. FASEB J 26, 49514965.
38 Shimpukade, B, Hudson, BD, Hovgaard, CK, et al. (2012) Discovery of a potent and selective GPR120 agonist. J Med Chem 55, 45114515.
39 Schroder, R, Janssen, N, Schmidt, J, et al. (2010) Deconvolution of complex G protein-coupled receptor signaling in live cells using dynamic mass redistribution measurements. Nat Biotechnol 28, 943949.
40 Schroder, R, Schmidt, J, Blattermann, S, et al. (2011) Applying label-free dynamic mass redistribution technology to frame signaling of G protein-coupled receptors noninvasively in living cells. Nat Protoc 6, 17481760.
41 Christie, WW (1993) Advances in Lipid Methodology – Two. Dundee: P.J. Barnes & Associates (The Oily Press).
42 Serth, J, Lautwein, A, Frech, M, et al. (1991) The inhibition of the GTPase activating protein–Ha-ras interaction by acidic lipids is due to physical association of the C-terminal domain of the GTPase activating protein with micellar structures. EMBO J 10, 13251330.
43 Kumar, A, Bullard, RL, Patel, P, et al. (2011) Non-esterified fatty acids generate distinct low-molecular weight amyloid-β (Aβ42) oligomers along pathway different from fibril formation. PLoS ONE 6, e18759.
44 Mukerjee, P & Mysels, KJ (1971) Critical Micelle Concentrations of Aqueous Surfactant Systems (NSRDS-NBS 36). Washington, DC: US Government Printing Office.
45 Powell, WS & Rokach, J (2013) The eosinophil chemoattractant 5-oxo-ETE and the OXE receptor. Prog Lipid Res 52, 651665.
46 Vestergren, R, Berger, U, Glynn, A, et al. (2012) Dietary exposure to perfluoroalkyl acids for the Swedish population in 1999, 2005 and 2010. Environ Int 49, 120127.
47 Le, NH, Shin, S, Tu, TH, et al. (2012) Diet enriched with Korean pine nut oil improves mitochondrial oxidative metabolism in skeletal muscle and brown adipose tissue in diet-induced obesity. J Agric Food Chem 60, 1193511941.
48 Christiansen, E, Urban, C, Merten, N, et al. (2008) Discovery of potent and selective agonists for the free fatty acid receptor 1 (FFA(1)/GPR40), a potential target for the treatment of type II diabetes. J Med Chem 51, 70617064.
49 Wolff, RL, Pedrono, F, Pasquier, E, et al. (2000) General characteristics of Pinus spp. seed fatty acid compositions, and importance of Δ5-olefinic acids in the taxonomy and phylogeny of the genus. Lipids 35, 122.
50 Danish Food Composition Database. http://www.foodcomp.dk/v7/fcdb_details.asp?FoodId = 0153.
51 Christiansen, E, Due-Hansen, ME, Urban, C, et al. (2012) Free fatty acid receptor 1 (FFA1/GPR40) agonists: mesylpropoxy appendage lowers lipophilicity and improves ADME properties. J Med Chem 55, 66246628.
52 Watterson, KR, Hudson, BD, Ulven, T, et al. (2014) Treatment of type 2 diabetes by free fatty acid receptor agonists. Front Endocrinol (Lausanne) 5, 137.
53 Milligan, G, Ulven, T, Murdoch, H, et al. (2014) G-protein-coupled receptors for free fatty acids: nutritional and therapeutic targets. Br J Nutr 111, Suppl. 1, S3S7.
54 Dranse, HJ, Kelly, ME & Hudson, BD (2013) Drugs or diet? – developing novel therapeutic strategies targeting the free fatty acid family of GPCRs. Br J Pharmacol 170, 696711.
55 Fujiwara, K, Maekawa, F & Yada, T (2005) Oleic acid interacts with GPR40 to induce Ca2+ signaling in rat islet β-cells: mediation by PLC and L-type Ca2+ channel and link to insulin release. Am J Physiol Endocrinol Metab 289, E670E677.
56 Cao, H, Gerhold, K, Mayers, JR, et al. (2008) Identification of a lipokine, a lipid hormone linking adipose tissue to systemic metabolism. Cell 134, 933944.
57 Micha, R & Mozaffarian, D (2009) Trans fatty acids: effects on metabolic syndrome, heart disease and diabetes. Nat Rev Endocrinol 5, 335344.
58 Kennedy, A, Martinez, K, Schmidt, S, et al. (2010) Antiobesity mechanisms of action of conjugated linoleic acid. J Nutr Biochem 21, 171179.
59 Schmidt, J, Liebscher, K, Merten, N, et al. (2011) Conjugated linoleic acids mediate insulin release through islet G protein-coupled receptor FFA1/GPR40. J Biol Chem 286, 1189011894.
60 Miyamoto, J, Mizukure, T, Park, SB, et al. (2014) A gut microbial metabolite of linoleic acid, 10-hydroxy-cis-12-octadecenoic acid, ameliorates intestinal epithelial barrier impairment partially via GPR40/MEK-ERK pathway. J Biol Chem 290, 29022918.
61 Walker, CG, Jebb, SA & Calder, PC (2013) Stearidonic acid as a supplemental source of omega-3 polyunsaturated fatty acids to enhance status for improved human health. Nutrition 29, 363369.
62 Sugano, M, Ikeda, I, Wakamatsu, K, et al. (1994) Influence of Korean pine (Pinus koraiensis)-seed oil containing cis-5, cis-9, cis-12-octadecatrienoic acid on polyunsaturated fatty acid metabolism, eicosanoid production and blood pressure of rats. Br J Nutr 72, 775783.
63 Tanaka, T, Takimoto, T, Morishige, J, et al. (1999) Non-methylene-interrupted polyunsaturated fatty acids: effective substitute for arachidonate of phosphatidylinositol. Biochem Biophys Res Commun 264, 683688.
64 Tanaka, T, Uozumi, S, Morito, K, et al. (2014) Metabolic conversion of C20 polymethylene-interrupted polyunsaturated fatty acids to essential fatty acids. Lipids 49, 423429.
65 Chuang, LT, Tsai, PJ, Lee, CL, et al. (2009) Uptake and incorporation of pinolenic acid reduces n-6 polyunsaturated fatty acid and downstream prostaglandin formation in murine macrophage. Lipids 44, 217224.
66 Huang, WC, Tsai, PJ, Huang, YL, et al. (2014) PGE2 production is suppressed by chemically-synthesized Δ7-eicosatrienoic acid in macrophages through the competitive inhibition of COX-2. Food Chem Toxicol 66, 122133.
67 Nakamura, MT, Yudell, BE & Loor, JJ (2014) Regulation of energy metabolism by long-chain fatty acids. Prog Lipid Res 53, 124144.
68 Lee, JW, Lee, KW, Lee, SW, et al. (2004) Selective increase in pinolenic acid (all-cis-5,9,12-18 : 3) in Korean pine nut oil by crystallization and its effect on LDL-receptor activity. Lipids 39, 383387.
69 Pasman, WJ, Heimerikx, J, Rubingh, CM, et al. (2008) The effect of Korean pine nut oil on in vitro CCK release, on appetite sensations and on gut hormones in post-menopausal overweight women. Lipids Health Dis 7, 10.
70 Mancini, AD & Poitout, V (2013) The fatty acid receptor FFA1/GPR40 a decade later: how much do we know? Trends Endocrinol Metab 24, 398407.

Keywords

Related content

Powered by UNSILO
Type Description Title
PDF
Supplementary materials

Christiansen supplementary material
Figures S1-S4

 PDF (1.5 MB)
1.5 MB

Activity of dietary fatty acids on FFA1 and FFA4 and characterisation of pinolenic acid as a dual FFA1/FFA4 agonist with potential effect against metabolic diseases

  • Elisabeth Christiansen (a1), Kenneth R. Watterson (a2), Claire J. Stocker (a3), Elena Sokol (a4), Laura Jenkins (a2), Katharina Simon (a5), Manuel Grundmann (a5), Rasmus K. Petersen (a6), Edward T. Wargent (a3), Brian D. Hudson (a2), Evi Kostenis (a5), Christer S. Ejsing (a4), Michael A. Cawthorne (a3), Graeme Milligan (a2) and Trond Ulven (a1)...

Metrics

Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed.