GPR120 (FFAR4) is preferentially expressed in pancreatic delta cells and regulates somatostatin secretion from murine islets of Langerhans

Abstract

Aims/hypothesisThe NEFA-responsive G-protein coupled receptor 120 (GPR120) has been implicated in the regulation of inflammation, in the control of incretin secretion and as a predisposing factor influencing the development of type 2 diabetes by regulation of islet cell apoptosis. However, there is still considerable controversy about the tissue distribution of GPR120 and, in particular, it remains unclear which islet cell types express this molecule. In the present study, we have addressed this issue by constructing a Gpr120-knockout/β-galactosidase (LacZ) knock-in (KO/KI) mouse to examine the distribution and functional role of GPR120 in the endocrine pancreas.MethodsA KO/KI mouse was generated in which exon 1 of the Gpr120 gene (also known as Ffar4) was replaced in frame by LacZ, thereby allowing for regulated expression of β-galactosidase under the control of the endogenous GPR120 promoter. The distribution of GPR120 was inferred from expression studies detecting β-galactosidase activity and protein production. Islet hormone secretion was measured from isolated mouse islets treated with selective GPR120 agonists.Resultsβ-galactosidase activity was detected as a surrogate for GPR120 expression exclusively in a small population of islet endocrine cells located peripherally within the islet mantle. Immunofluorescence analysis revealed co-localisation with somatostatin suggesting that GPR120 is preferentially produced in islet delta cells. In confirmation of this, glucose-induced somatostatin secretion was inhibited by a range of selective GPR120 agonists. This response was lost in GPR120-knockout mice.Conclusions/interpretationThe results imply that GPR120 is selectively present within the delta cells of murine islets and that it regulates somatostatin secretion.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-014-3213-0) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Functions of omega-3 fatty acids and FFA4 (GPR120) in macrophages

“…Recently, the involvement of G i/o protein in FFA4 signaling was proposed both in the FFA4-mediated inhibition of somatostatin release from murine islets and in ghrelin secretion from primary gastric mucosal cells inhibited by pertussis toxin (a G i/o proteinselective inhibitor) (Engelstoft et al, 2013;Stone et al, 2014).…”

Non-Acidic Free Fatty Acid Receptor 4 Agonists with Antidiabetic Activity

“…12 Moreover, FFA4 is implicated in regulation of glucagon, ghrelin and somatostatin release, representing likely contributing mechanisms of the observed metabolic phenotype. [13][14][15][16] Chart 1. Representative FFA4 agonists…”

Distinct Phosphorylation Clusters Determine the Signaling Outcome of Free Fatty Acid Receptor 4/G Protein–Coupled Receptor 120

“…Indeed, the FFA1 agonist fasiglifam entered phase III clinical trials; although it was clearly able to regulate glycemia and to produce clinically relevant lowering of hemoglobin A1c levels in patients with type 2 diabetes Poitout, 2013, 2015;Kaku et al, 2015), it was withdrawn from further trials because of concerns of possible liver toxicity. Although FFA4 is expressed in the pancreas (Stone et al, 2014;Suckow et al, 2014), where it may play roles in the regulation of glucagon production (Suckow et al, 2014), it is also expressed in various enteroendocrine cells (Parker et al, 2009;Iwasaki et al, 2015;Liu et al, 2015), adipocytes (Oh et al, 2010(Oh et al, , 2014Liu et al, 2015) and macrophages (Oh et al, 2010(Oh et al, , 2014Im, 2015;Liu et al, 2015). Potential combinations of effects on the release of incretins and/or satiety-regulating hormones in the gut, differentiation of and uptake of glucose by adipocytes, and control of the release of inflammatory mediators by macrophages have suggested that FFA4 might also be a useful therapeutic target to modulate insulin resistance and glucose homeostasis Oh et al, 2014;Liu et al, 2015;Milligan et al, 2015).…”