The cytoprotective effects of oleoylethanolamide in insulin-secreting cells do not require activation of GPR119
Article first published online: 23 MAR 2012
© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society
British Journal of Pharmacology
Special Issue: Themed Section: Cannabinoids in Biology and Medicine, Part II. Guest Editors: Itai Bab and Steve Alexander
Volume 165, Issue 8, pages 2758–2770, April 2012
How to Cite
Stone, V. M., Dhayal, S., Smith, D. M., Lenaghan, C., Brocklehurst, K. J. and Morgan, N. G. (2012), The cytoprotective effects of oleoylethanolamide in insulin-secreting cells do not require activation of GPR119. British Journal of Pharmacology, 165: 2758–2770. doi: 10.1111/j.1476-5381.2011.01755.x
- Issue published online: 23 MAR 2012
- Article first published online: 23 MAR 2012
- Accepted manuscript online: 26 OCT 2011 06:29AM EST
- Received; 22 July 2011; Revised; 12 September 2011; Accepted; 1 October 2011
- fatty acid amide hydrolase;
BACKGROUND AND PURPOSE β-cells express a range of fatty acid-responsive G protein-coupled receptors, including GPR119, which regulates insulin secretion and is seen as a potential therapeutic target in type 2 diabetes. The long-chain unsaturated fatty acid derivative oleoylethanolamide (OEA) is an endogenous agonist of GPR119 and, under certain conditions, some long-chain unsaturated fatty acids can promote β-cell cytoprotection. It is not known, however, if OEA is cytoprotective in β-cells. The present study has examined this and determined whether GPR119 is involved.
METHODS Clonal rat insulin-secreting cell lines, BRIN-BD11 or INS-1E, were exposed to fatty acids complexed with BSA. cAMP levels, insulin release and cell viability were measured. Protein expression was studied by Western blotting and receptor expression by RT-PCR.
KEY RESULTS GPR119 was expressed in both BRIN-BD11 and INS-1E cells and OEA was cytoprotective in these cells. However, cytoprotection was not reproduced by any of a range of selective, synthetic ligands of GPR119. The cytoprotective response to OEA was lost during exposure to inhibitors of fatty acid amide hydrolase (FAAH) suggesting that OEA per se is not the cytoprotective species but that release of free oleate is required. Similar data were obtained with anandamide, which was cytoprotective only under conditions favouring release of free arachidonate.
CONCLUSIONS AND IMPLICATIONS Activation of GPR119 is not required to mediate the cytoprotective actions of OEA in BRIN-BD11 or INS-1E cells. Rather, OEA is internalised and subjected to hydrolysis by FAAH to release free oleate, which then mediates the cytoprotection.