Gpr40 is expressed in enteroendocrine cells and mediates free fatty acid stimulation of incretin secretion.
OBJECTIVE
The G-protein-coupled receptor Gpr40 is expressed in beta-cells where it contributes to free fatty acid (FFA) enhancement of glucose-stimulated insulin secretion. 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, implying that IPF1/PDX1 might regulate Gpr40 expression. Here, we addressed whether 1) Gpr40 is expressed in the intestine and 2) Ipf1/Pdx1 function is required for Gpr40 expression.


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 beta-cell specific mutants were used to investigate whether Ipf1/Pdx1 controls Gpr40 expression. Plasma insulin, glucose-dependent 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 endocrine 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 Ipf1/Pdx1 is required for expression of Gpr40 in beta-cells and endocrine cells of the anterior gastrointestinal tract.


CONCLUSIONS
Together, our data provide evidence that Gpr40 modulates FFA-stimulated insulin secretion from beta-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.
Umeå Center for Molecular Medicine, University of Umeå, Umeå, Sweden.
Sara
S
Edfalk
Pär
P
Steneberg
Helena
H
Edlund
D000818:Animals; D004386:Duodenum / Q000166:cytology / Q000502:physiology; D019858:Enteroendocrine Cells / Q000378:metabolism / Q000502:physiology*; D005230:Fatty Acids, Nonesterified / Q000378:metabolism*; D005749:Gastric Inhibitory Polypeptide / Q000378:metabolism*; D015870:Gene Expression / Q000502:physiology; D017930:Genes, Reporter; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D011708:Pylorus / Q000166:cytology / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism
D005230:Fatty Acids, Nonesterified; C473036:Ffar1 protein, mouse; D018398:Homeodomain Proteins; D007328:Insulin; D043562:Receptors, G-Protein-Coupled; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D005749:Gastric Inhibitory Polypeptide; D052216:Glucagon-Like Peptide 1