Free fatty acid receptor 1 (FFA(1)R/GPR40) and its involvement in fatty-acid-stimulated insulin secretion

• Published in: Cell and tissue research Vol. 322; no. 2; pp. 207 - 215
• Main Authors: Salehi, A, Flodgren, E, Nilsson, N E, Jimenez-Feltstrom, J, Miyazaki, J, Owman, C, Olde, B
• Format: Journal Article
• Language: English
• Published: Germany 01.11.2005
• Subjects: 2-bromo palmitate; Animals; Biologi; Biological Sciences; Cell Biology; Cell Line; Cellbiologi; Fatty Acids - metabolism; Female; free fatty acid; GPR40; Humans; Hypoglycemic Agents - metabolism; insulin; Insulin - metabolism; Insulin Secretion; Islets of Langerhans - cytology; Islets of Langerhans - metabolism; Linoleic Acid - metabolism; Mice; mouse (NMRI); Natural Sciences; Naturvetenskap; Oligonucleotides, Antisense - metabolism; Palmitates - metabolism; pancreatic islet; Phosphatidylinositols - metabolism; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism
• ISSN: 0302-766X; 1432-0878
• DOI: 10.1007/s00441-005-0017-z

Free fatty acids (FFA) have generally been proposed to regulate pancreatic insulin release by an intracellular mechanism involving inhibition of CPT-1. The recently de-orphanized G-protein coupled receptor, FFA(1)R/GPR40, has been shown to be essential for fatty-acid-stimulated insulin release in MIN6 mouse insulinoma cells. The CPT-1 inhibitor, 2-bromo palmitate (2BrP), was investigated for its ability to interact with mouse FFA(1)R/GPR40. It was found to inhibit phosphatidyl inositol hydrolysis induced by linoleic acid (LA) (100 muM in all experiments) in HEK293 cells transfected with FFA(1)R/GPR40 and in the MIN6 subclone, MIN6c4. 2BrP also inhibited LA-stimulated insulin release from mouse pancreatic islets. Mouse islets were subjected to antisense intervention by treatment with a FFA(1)R/GPR40-specific morpholino oligonucleotide for 48 h. Antisense treatment of islets suppressed LA-stimulated insulin release by 50% and by almost 100% when islets were pretreated with LA for 30 min before applying the antisense. Antisense treatment had no effect on tolbutamide-stimulated insulin release. Confocal microscopy using an FFA(1)R/GPR40-specific antibody revealed receptor expression largely localized to the plasma membrane of insulin-producing cells. Pretreating the islets with LA for 30 min followed by antisense oligonucleotide treatment for 48 h reduced the FFA(1)R/GPR40 immunoreactivity to background levels. The results demonstrate that FFA(1)R/GPR40 is inhibited by the CPT-1 inhibitor, 2BrP, and confirm that FFA(1)R/GPR40 is indeed necessary, at least in part, for fatty-acid-stimulated insulin release.