Gpr40 is expressed in enteroendocrine cells and mediates free fatty acid 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). However, other sites of Gpr40 expression, including the intestine, have 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 1) Gpr40 is expressed in the intestine and 2) Ipfl/Pdxl 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. Ipfl/Pdxl-null and(β-cell specific mutants were used to investigate whether Ipfl/ Pdχl controls Gpr40 expression. Plasma insulin, glucose-depen dent insulinotropic polypeptide(GIP), glucagon-like peptide-1(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 endo crine cells of the gastrointestinal tract, including cells expressing the incretin hormones GLP-1 and GIP, and that Gpr40 mediates FFA-stimulated incretin secretion. We also show that Ipfl/Pdχl is required for expression of Gpr40 in(β-cells and endocrine cells of the anterior gastrointestinal tract. CONCLUSIONS-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 Ipfl/Pdχl and Gpr40 in FFA-mediated secretion of hormones that regulate glucose and overall energy homeostasis. © 2008 by the American Diabetes Association.