Gpr40 is expressed in enteroendocrine cells and mediates FFA stimulation of incretin secretion

Abstract

Objective: The G-protein coupled receptor Gpr40 is expressed in β-cells where it contributes to free fatty acid (FFA) enhancement of glucose stimulated insulin secretion (1-4). Other sites of Gpr40 expression, including the intestine, have however been suggested. The transcription factor IPF1/PDX1 was recently shown to bind to an enhancer element within the 5′ flanking region of Gpr40 (5), implying that IPF1/PDX1 might regulate Gpr40 expression. Here we addressed whether i) Gpr40 is expressed in the intestine and ii) Ipf1/Pdx1 function is required for Gpr40 expression.

Research Design and Methods: In the present study Gpr40 expression was monitored by X-gal staining using Gpr40 reporter mice and by in situ hybridization. Ipf1/Pdx1 null and β-cell specific mutants were used to investigate whether Ipf1/Pdx1 controls Gpr40 expression. Plasma insulin, GIP, GLP-1 and glucose levels in response to acute oral fat diet were determined in Gpr40 mutant and control mice.

Results: Here we show that Gpr40 is expressed in endocrine cells of the gastrointestinal (GI) tract, including cells expressing the incretin hormones GLP-1 and GIP, and that Gpr40 mediates FFA stimulated incretin secretion. We also show that Ipf1/Pdx1 is required for expression of Gpr40 in β-cells and endocrine cells of the anterior GI tract.

Conclusion: Together our data provide evidence that Gpr40 modulates FFA stimulated insulin secretion from β-cells not only directly but also indirectly via regulation of incretin secretion. Moreover, our data suggest a conserved role for Ipf1/Pdx1 and Gpr40 in FFA-mediated secretion of hormones that regulate glucose and overall energy homeostasis.