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.
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.
Department of Physics,Chemistry and Pharmacy, University of Southern Denmark,Campusvej 55,DK-5230Odense M,Denmark.
Elisabeth
E
Christiansen
Molecular Pharmacology Group, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow,Glasgow G12 8QQ, Scotland,UK.
Kenneth R
KR
Watterson
Buckingham Institute of Translational Medicine, University of Buckingham,Hunter Street,BuckinghamMK18 1EG,UK.
Claire J
CJ
Stocker
Department of Biochemistry and Molecular Biology,Villum Center for Bioanalytical Sciences, University of Southern Denmark,Campusvej 55,DK-5230Odense M,Denmark.
Elena
E
Sokol
Molecular Pharmacology Group, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow,Glasgow G12 8QQ, Scotland,UK.
Laura
L
Jenkins
Institute of Pharmaceutical Biology, University of Bonn,Nussallee 6,D-53115Bonn,Germany.
Katharina
K
Simon
Institute of Pharmaceutical Biology, University of Bonn,Nussallee 6,D-53115Bonn,Germany.
Manuel
M
Grundmann
Department of Biology,University of Copenhagen,Ole Maaløes Vej 5,DK-2200,Copenhagen N,Denmark.
Rasmus K
RK
Petersen
Buckingham Institute of Translational Medicine, University of Buckingham,Hunter Street,BuckinghamMK18 1EG,UK.
Edward T
ET
Wargent
Molecular Pharmacology Group, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow,Glasgow G12 8QQ, Scotland,UK.
Brian D
BD
Hudson
Institute of Pharmaceutical Biology, University of Bonn,Nussallee 6,D-53115Bonn,Germany.
Evi
E
Kostenis
Department of Biochemistry and Molecular Biology,Villum Center for Bioanalytical Sciences, University of Southern Denmark,Campusvej 55,DK-5230Odense M,Denmark.
Christer S
CS
Ejsing
Buckingham Institute of Translational Medicine, University of Buckingham,Hunter Street,BuckinghamMK18 1EG,UK.
Michael A
MA
Cawthorne
Molecular Pharmacology Group, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow,Glasgow G12 8QQ, Scotland,UK.
Graeme
G
Milligan
Department of Physics,Chemistry and Pharmacy, University of Southern Denmark,Campusvej 55,DK-5230Odense M,Denmark.
Trond
T
Ulven
D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000517:prevention & control; D004041:Dietary Fats / Q000494:pharmacology*; D004195:Disease Models, Animal; D005951:Glucose Tolerance Test; D057809:HEK293 Cells; D006801:Humans; D007328:Insulin / Q000097:blood / Q000378:metabolism; D007333:Insulin Resistance; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008042:Linolenic Acids / Q000494:pharmacology*; D008297:Male; D024821:Metabolic Syndrome / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D009754:Nuts / Q000737:chemistry; D028223:Pinus; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000235:genetics* / Q000378:metabolism
D004041:Dietary Fats; C498007:FFAR4 protein, mouse; C473036:Ffar1 protein, mouse; D007328:Insulin; D008042:Linolenic Acids; D043562:Receptors, G-Protein-Coupled; C034302:5,9,12-octadecatrienoic acid
FFAR1; FFAR4; G protein-coupled receptor 120; G protein-coupled receptor 40; NEFA; Pinolenic acid; Type 2 diabetes