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    • Main Text FFAR GPR is a long

    2021-11-26

    Main Text FFAR1 (GPR40) is a long-chain fatty USA (LCFA) receptor highly expressed and enriched in enteroendocrine cells, where it senses LCFAs generated from dietary triglycerides, and in pancreatic islet cells, where it acts as a powerful stimulator of insulin secretion. However, the physiological role of FFAR1 in the islets remained unclear until now, as the Offermanns group surprisingly places FFAR1 and the omega-hydroxylated fatty acid 20-hydroxyeicosatetraenoic acid (20-HETE) at center stage in β cell function (Figure 1A) (Tunaru et al., 2018). FFAR1-selective agonists and β cell-specific overexpression of FFAR1 increase glucose-dependent insulin secretion (GDIS) in rodents. TAK-875 or fasiglifam, a first-generation FFAR1 agonist, showed meaningful efficacy in decreasing basal glucose and improving glucose tolerance in diabetic patients up to phase III clinical trials but was eventually stopped due to non-mechanism-based liver toxicity (Kaku et al., 2016). However, this promising pharmacological development occurred without a clear understanding of the physiology of FFAR1. Most strikingly, it has been unclear what the physiological ligand was for FFAR1 in the β cells, as it was obviously not circulating free fatty acids. The problem is that, as opposed to insulin, circulating LCFAs are low after a meal and high during fasting, as they mainly are derived from adipose tissue lipolysis. Instead, it has been proposed that dietary LCFAs released from postprandial chylomicrons through lipoprotein lipase activity locally in islet capillaries could be a physiological stimulus for FFAR1 on β cells (Husted et al., 2017) (Figure 1A). For almost a decade it has been known, but not really appreciated, that FFAR1 is required not only for LCFA-induced insulin secretion, but also for a major part of glucose- and arginine-induced insulin secretion (Alquier et al., 2009, Kebede et al., 2008). Under hyperglycemic clamp conditions, insulin secretion is reduced to less than 50% in Ffar1-deficient DIO mice as compared to littermate controls (Alquier et al., 2009). Similarly, arginine-induced insulin secretion is reduced to less than one-third in Ffar1-deficient animals—importantly, in both cases, without altered fuel metabolism in the islets but via a mechanism involving classical FFAR1 receptor signaling pathways (Alquier et al., 2009). These puzzling observations can now be explained, as Tunaru and coworkers find 20-HETE to be a more potent, efficacious, and selective agonist for FFAR1 than any previously reported LCFA and show that 20-HETE functions as an autocrine feed-forward stimulator of insulin secretion through FFAR1 (Tunaru et al., 2018). Circulating concentrations of 20-HETE are in the low-nanomolar range, which is too low for it to act as an endocrine ligand for FFAR1. Importantly, Tunaru and coworkers demonstrate that islets generate and release 20-HETE in a glucose-dependent manner and that 20-HETE acting through FFAR1 is responsible for a major part of glucose-induced insulin secretion. Thus, inhibition of CYP4- and CYP2-dependent formation of 20-HETE from arachidonic acid or pharmacological blockade of FFAR1 reduces GDIS in murine and human islets. Interestingly, the 20-HETE-mediated positive autocrine regulatory loop is impaired in islets from diabetic animals and patients. Although basal production of 20-HETE in islets from DIO and ob/ob mice and islets from type 2 diabetic patients was slightly increased, the glucose-induced 20-HETE production was significantly decreased (Tunaru et al., 2018). FFAR1 is highly expressed not only in β cells but also in α cells (Segerstolpe et al., 2016), which gives the interesting perspective that 20-HETE may function both as an autocrine and as a paracrine regulator of islet cell function (Figure 1A), i.e., acting in symphony with the many other intra-islet cross-talk mechanisms. It is, however, likely that a potential 20-HETE-induced stimulation of glucagon secretion through FFAR1 will be overruled by paracrine inhibition of α cells mediated by classical β cell secretory products (Figure 1A). In relation to glucagon secretion, it is more likely that free LCFAs derived from adipose tissue lipolysis function as a physiological stimulus of α cells as circulating LCFAs increase during fasting and consequently are associated with relatively low glucose as opposed to 20-HETE, which will be generated during hyperglycemia (Figure 1A). Whether α cells and endocrine cells other than β cells produce 20-HETE remains to be determined. However, in relation to the already highly complex intra-islet communication, it may be a relief that FFAR1 at least is not expressed in somatostatin-producing δ cells (Segerstolpe et al., 2016).