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

Virginia M Stone,Carol Lenaghan,Noel G Morgan,Mårten Hammar,Xiufeng Xu,David M Smith,Shalinee Dhayal,Maria Sörhede Winzell,Katy J Brocklehurst

doi:10.1007/s00125-014-3213-0

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.

Highlights

MethodsThe G-protein coupled receptor 120 (GPR120, classified as free fatty acid receptor 4 [FFAR4]; www.iuphar-db.org, accessed 31 January 2014) was identified by Fredriksson et al [1] and is encoded within four exons located on chromosome 10q23.33 in humans [2, 3]
GPR120 is expressed in a subset of endocrine cells located peripherally in mouse islets GPR120 is reportedly expressed in the gastrointestinal tract of mice [6, 23,24,25] and, in confirmation of this, sections of colon from KO/KI animals treated to reveal β-galactosidase activity, and by inference GPR120, demonstrated a distinct staining pattern within specific luminal epithelial cells (Fig. 1c)
The expression pattern of GPR120 within the endocrine pancreas remains controversial with initial reports suggesting its absence from human islets of Langerhans as well as from clonal mouse pancreatic beta cells [6, 19]

Summary

Introduction

MethodsThe G-protein coupled receptor 120 (GPR120, classified as free fatty acid receptor 4 [FFAR4]; www.iuphar-db.org, accessed 31 January 2014) was identified by Fredriksson et al [1] and is encoded within four exons located on chromosome 10q23.33 in humans [2, 3]. Conclusions/interpretation The results imply that GPR120 is selectively present within the delta cells of murine islets and that it regulates somatostatin secretion. Initial studies suggested that Gpr120 ( known as Ffar4) mRNA is not detectable in whole pancreas, isolated islets of Langerhans or in certain pancreatic beta cell lines [6, 14, 19].

Results

Conclusion