- RESEARCH
Fatty-acid receptors and regulatory proteins in islets
Following our previous work on RGS16, we are now interrogating the role of RGS9 in the control of insulin secretion and beta-cell proliferation.
Summary
The deorphanization of the G-protein coupled receptor (GPCR) FFA1/GPR40 in 2003 and the demonstration that it is 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 T2D (4). Over the last 15 years we have conducted a series of studies aimed to 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) (in collaboration with Dan Lin, Amgen), but is not implicated in their long-term, deleterious effects on beta-cell function (6). We observed 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) (in collaboration with Tom Metz, Pacific Northwest National Laboratories; and Marc Prentki, U Montréeal). We identified the mechanisms by which glucose regulates the expression of GPR40 (8) (in collaboration with Rohit Kulkarni, U Harvard and Michael Walker, Weizmann Institute) and showed that activation of GPR40 triggers a signaling cascade that involves protein kinase D1 (PKD1) and p21-activated kinase 4, and leads to depolymerization of cortical actin and stimulation of second-phase insulin secretion (9; 10) (in collaboration with Patrick MacDonald, U Alberta). In vivo, beta-cell PKD1 controls adaptive insulin secretion in response to high-fat feeding and hence contributes to the maintenance of glucose homeostasis during metabolic stress (11). In collaboration with the group of Michel Bouvier (U Montréal), we have demonstrated that GPR40 is subject to biased agonism (12).
Downstream of GPCRs, G proteins are inactivated by GTPase-activating proteins (GAP), most of which belong to the Regulators of G-protein Signalling (RGS) protein family (13). RGS proteins are key regulators of the termination of GPCR signaling yet little is known about their role in beta-cell function. We have demonstrated that the RGS protein RGS16 positively regulates insulin secretion and beta-cell proliferation by alleviating the tonic inhibitory action of somatostatin in islets (14).
We have expanded the scope of this project beyond GPR40 to explore the physiological role of the other long-chain fatty acid receptor, FFA4/GPR120, in glucose homeostasis and beta-cell function using a conditional knockout mouse and investigating possible interactions between GPR40 and GPR120 in double knockouts. We have recently completed a study (15) demonstrating that GPR120 is predominantly active in islet delta cells and that its activation lowers cAMP levels, inhibits somatostatin secretion, and thereby alleviates tonic inhibition of insulin and glucagon secretion by beta and alpha cells, respectively (in collaboration with Mark Huising, UC Davis). We are also examining the additive effects of GPR40 and GPR120 on glucose homeostasis and insulin secretion in male mice.
Following our previous work on RGS16, we are now interrogating the role of RGS9 in the control of insulin secretion and beta-cell proliferation.
Funding
These projects are funded by Canadian Institutes of Health Research (CIHR) and the Natural Sciences and Engineering Research Council (NSERC).
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