POITOUT LABORATORY
Canada Research Chair in Diabetes and Pancreatic ß-cell Function

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Research Presentation (Français)

Novel G protein-coupled receptors and associated proteins in the beta-cell

Summary

The deorphanization of the G-protein coupled receptor FFA1/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) sparked tremendous interest in this and other fatty acid receptors as potential therapeutic targets to enhance insulin secretion in a glucose-dependent manner in type 2 diabetes (4). Over the last decade we have conducted a series of studies aimed to better understand the role of fatty acid receptors in pancreatic islet function and glucose homeostasis and to identify their mechanisms of action. 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 (5), but is not implicated in their long-term, deleterious effects on beta-cell function (6). 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 (7). We have identified the mechanisms by which glucose regulates the expression of GPR40 (8) and have shown, in collaboration with the group of Patrick MacDonald at the University of Alberta, that activation of GPR40 triggers a signaling cascade that involves protein kinase D and PAK4, and leads to depolymerization of cortical actin and stimulation of second-phase insulin secretion (9; 10) . In collaboration with the group of Michel Bouvier at the University of Montreal, we have demonstrated that GPR40 is subject to biased agonism (11) .

We have recently expanded the scope of this project beyond GPR40 and are now exploring the physiological role of the other long-chain fatty acid receptor, FFA4/GPR120, in glucose homeostasis using a conditional knock-out mouse. Further, we are interrogating the function of the Regulators of G protein Signalling in beta cells. RGS proteins are key regulators of the termination of GPCR signaling yet little is known about their role in beta-cell function. We have recently demonstrated that the RGS protein RGS16 positively regulates insulin secretion and beta-cell proliferation by alleviating the tonic inhibitory action of somatostatin in islets (12).


Funding

This progrma is funded by theCanadian Institutes of Health Research and the Natural Sciences and Engineering Research Council.

References

1. 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

2. 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

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, 200

4. Kebede MA, Alquier T, Latour MG, Poitout V: Lipid receptors and islet function: therapeutic implications? Diabetes Obes Metab 2009;11 Suppl 4:10-20

5. 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

6. 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

7. Alquier T, Peyot ML, Latour MG, Kebede M, Sorensen CM, Gesta S, Ronald Kahn C, Smith RD, Jetton TL, Metz TO, Prentki M, Poitout V: Deletion of GPR40 impairs glucose-induced insulin secretion in vivo in mice without affecting intracellular fuel metabolism in islets. Diabetes 58:2607-2615, 2009

8. Kebede M, Ferdaoussi M, Mancini A, Alquier T, Kulkarni RN, Walker MD, Poitout V: Glucose activates free fatty acid receptor 1 gene transcription via phosphatidylinositol-3-kinase-dependent O-GlcNAcylation of pancreas-duodenum homeobox-1. Proceedings of the National Academy of Sciences of the United States of America 109:2376-2381, 2012

9. Ferdaoussi M, Bergeron V, Zarrouki B, Kolic J, Cantley J, Fielitz J, Olson EN, Prentki M, Biden T, Macdonald PE, Poitout V: G protein-coupled receptor (GPR)40-dependent potentiation of insulin secretion in mouse islets is mediated by protein kinase D1. Diabetologia, 2012;55:2682-2692

10. Bergeron V, Ghislain J, Poitout V: The P21-activated kinase PAK4 is implicated in fatty-acid potentiation of insulin secretion downstream of free fatty acid receptor 1. Islets, 2016 8(6): 157-164

11. Mancini AD, Bertrand G, Vivot K, Carpentier E, Tremblay C, Ghislain J, Bouvier M, Poitout V: beta-Arrestin Recruitment and Biased Agonism at Free Fatty Acid Receptor 1. J Biol Chem 2015;290:21131-21140

12. Vivot K, Moulle VS, Zarrouki B, Tremblay C, Mancini A, Maachi H, Ghislain J, Poitout V: The regulator of G-protein signaling RGS16 promotes insulin secretion and β-cell proliferation in rodent and human islets. Molecular metabolism 2016;5:988-996
 

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