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| Research Presentation |
The role of the fatty-acid receptor GPR40 in pancreatic beta-cell function
Summary
The deorphanization of the G-protein coupled receptor GPR40 in 2003 and the demonstration that it was activated by medium-to-long-chain fatty acids and selectively expressed in pancreatic beta-cells (1-3) led us to examine its role in pancreatic beta-cell function and glucose homeostasis. Using GPR40 knock-out mice, we have shown that GPR40 mediates approximately 50% of the stimulatory effect of fatty acids on insulin secretion in vitro and in vivo (4), but is not implicated in their long-term, deleterious effects on beta-cell function (5). Recently, we have shown that GPR40 plays a role in the maintenance of glucose homeostasis in vivo via a mechanism of action that does not involve changes in intracellular fuel metabolism in islets. We are currently investigating the mode of regulation of GPR40 expression as well as the intracellular signaling pathways activated downstream of the receptor.
Collaborations
This work is performed in collaboration with Amgen, which provided the GPR40 KO mice; Dr Michael Walker (Weizman Institute of Science, Israel); Dr Rohit Kulkarni (Joslin Diabetes Center, Boston); Dr Tom Jetton (University of Vermont); Dr Thomas Metz (Pacific Northwest National Laboratories, Richland, WA); Dr Marc Prentki (University of Montréal); and Dr Eric Marsault (Université Sherbrooke).
Funding
This project is funded by theCanadian Institutes of Health Research.
References
1. Briscoe CP, Tadayyon M, Andrews JL, Benson WG, Chambers JK, Eilert MM, Ellis C, Elshourbagy NA, Goetz AS, Minnick DT, Murdock PR, Sauls HR, Jr., Shabon U, Spinage LD, Strum JC, Szekeres PG, Tan KB, Way JM, Ignar DM, Wilson S, Muir AI: The orphan G protein-coupled receptor GPR40 is activated by medium and long chain fatty acids. J Biol Chem 278:11303-11311, 2003
2. Itoh Y, Kawamata Y, Harada M, Kobayashi M, Fujii R, Fukusumi S, Ogi K, Hosoya M, Tanaka Y, Uejima H, Tanaka H, Maruyama M, Satoh R, Okubo S, Kizawa H, Komatsu H, Matsumura F, Noguchi Y, Shinohara T, Hinuma S, Fujisawa Y, Fujino M: Free fatty acids regulate insulin secretion from pancreatic beta cells through GPR40. Nature 422:173-176, 2003
3. Kotarsky K, Nilsson NE, Flodgren E, Owman C, Olde B: A human cell surface receptor activated by free fatty acids and thiazolidinedione drugs. Biochem Biophys Res Commun 301:406-410, 2003
4. Latour MG, Alquier T, Oseid E, Tremblay C, Jetton TL, Luo J, Lin DC, Poitout V: GPR40 is necessary but not sufficient for fatty acid stimulation of insulin secretion in vivo. Diabetes 56:1087-1094, 2007
5. Kebede M, Alquier T, Latour MG, Semache M, Tremblay C, Poitout V: The fatty acid receptor GPR40 plays a role in insulin secretion in vivo after high-fat feeding. Diabetes 57:2432-2437, 2008
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