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Abstract
The role of the free fatty acid (FFA) receptor and the intracellular metabolites of linoleic acid (LA) in LA-stimulated increase in cytosolic free calcium concentration ([Ca2+]i) was investigated. [Ca2+]i was measured using Fura-2 as indicator in rat pancreatic β-cells in primary culture. LA (20 µM for 2 min) stimulated a transient peak increase followed by a minor plateau increase in [Ca2+]i. Elongation of LA stimulation up to 10 min induced a strong and long-lasting elevation in [Ca2+]i. Activation of FFA receptors by the non-metabolic agonist GW9508 (40 µM for 10 min) resulted in an increase in [Ca2+]i similar to that of 2-min LA treatment. Inhibition of acyl-CoA synthetases by Triacsin C suppressed the strong and long-lasting increase in [Ca2+]i. The increase in [Ca2+]i induced by 2 min LA or GW9508 were fully eliminated by exhaustion of endoplasmic reticulum (ER) Ca2+ stores or by inhibition of phospholipase C (PLC). Removal of extracellular Ca2+ did not influence the transient peak increase in [Ca2+]i stimulated by 2 min LA or GW9508. The strong and long-lasting increase in [Ca2+]i induced by 10 min LA was only partially suppressed by extracellular Ca2+ removal or thapsigargin pretreatment, whereas remaining elevation in [Ca2+]i was eliminated after exhaustion of mitochondrial Ca2+ using triphenyltin. In conclusion, LA stimulates Ca2+ release from ER through activation of the FFA receptor coupled to PLC and mobilizes mitochondrial Ca2+ by intracellular metabolites in β-cells.
Highlights
Long-chain free fatty acids (FFAs) diversely regulate pancreatic b-cell function under different conditions
GW9508 (40 measurements was composed of (mM), for 10 min) stimulated the transient peak increase in [Ca2+]i followed by a minor plateau increase in [Ca2+]i (Fig. 2A and C, n = 7), highly identical to that of 2 min linoleic acid (LA) stimulation (Fig. 1B)
We demonstrate that linoleic acid stimulated increase in [Ca2+]i in rat b-cells via both FFA receptor mediated pathway and intracellular metabolite mediated pathway
Summary
Long-chain free fatty acids (FFAs) diversely regulate pancreatic b-cell function under different conditions. FFAs acutely potentiate glucose-stimulated insulin secretion from both b-cell lines and bcells in primary culture. Long chain acyl-CoA activates or modulates various processes, such as diacylglycerol generation, triglyceride generation, PKC activation and protein acylation, in b-cells to influence insulin secretion [7,8,9]. Acyl-CoA is transported into mitochondria for b-oxidation, which links fuel metabolism of b-cells to insulin secretion. It was reported that FFAs activate GPR40 to stimulate insulin secretion from an insulinoma b-cell line, MIN6 cells, and from rodent pancreatic islets [11,12,13]. FFAs regulate b-cell function via both intracellular metabolites- and membrane receptor GPR40-mediated pathways. Insulin secretion is controlled by the levels of cytosolic Ca2+
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