Gpr40 is expressed in enteroendocrine cells and mediates free fatty acid stimulation of incretin secretion

Diabetes. 2008 Sep;57(9):2280-7. doi: 10.2337/db08-0307. Epub 2008 Jun 2.

Abstract

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.

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 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Duodenum / cytology
  • Duodenum / physiology
  • Enteroendocrine Cells / metabolism
  • Enteroendocrine Cells / physiology*
  • Fatty Acids, Nonesterified / metabolism*
  • Gastric Inhibitory Polypeptide / metabolism*
  • Gene Expression / physiology
  • Genes, Reporter
  • Glucagon-Like Peptide 1 / metabolism*
  • Homeodomain Proteins / metabolism
  • Insulin / metabolism
  • Insulin Secretion
  • Insulin-Secreting Cells / metabolism
  • Mice
  • Mice, Mutant Strains
  • Pylorus / cytology
  • Pylorus / physiology
  • Receptors, G-Protein-Coupled / genetics*
  • Receptors, G-Protein-Coupled / metabolism*
  • Trans-Activators / metabolism

Substances

  • Fatty Acids, Nonesterified
  • Ffar1 protein, mouse
  • Homeodomain Proteins
  • Insulin
  • Receptors, G-Protein-Coupled
  • Trans-Activators
  • pancreatic and duodenal homeobox 1 protein
  • Gastric Inhibitory Polypeptide
  • Glucagon-Like Peptide 1