Basic—Alimentary TractThe G-Protein−Coupled Receptor GPR40 Directly Mediates Long-Chain Fatty Acid−Induced Secretion of Cholecystokinin
Section snippets
Experimental Animals
Transgenic mice with CCK promoter-driven enhanced green fluorescent protein (eGFP) were developed by the GenSat Bacterial Artificial Chromosomes (BAC) Transgenic project14 and obtained from the Mutant Mouse Regional Resource Center (Davis, CA).
A GPR40-targeted knockout mouse was developed by replacing the GPR40 coding region with a 21-nucleotide DNA fragment encoding genes for 9 amino acids of influenza hemagglutinin antigen, eGFP, and neomycin (Supplementary Figure 1A). eGFP was inserted with
Validation of Purity of CCK-eGFP Cells From the CCK-eGFP BAC Transgenic Mouse
Rare eGFP-expressing cells from CCK-eGFP BAC transgenic mice were sparsely distributed along the epithelium of the duodenal mucosa, displaying typical teardrop enteroendocrine cell morphology and co-immunoreactivity with CCK (Figure 1A). Roughly 0.1%−0.2% of the preparation of singly dispersed duodenal mucosal cells were eGFP+ cells, as determined by flow cytometric analysis (data not shown). Enzymatically dispersed eGFP+ cells continued to be immunoreactive with CCK antiserum (Figure 1B and E
Discussion
In the present study, we utilized BAC transgenic mice expressing CCK-promoter driven eGFP to isolate a pure population of intestinal I cells and identify the expression of GPR40 on a gene and protein level. Furthermore, to show that GPR40 is a LCFA receptor directly mediating fatty acid−induced CCK secretion, we obtained in vitro functional data from these isolated cells and demonstrated that targeted deletion of GPR40 markedly reduces [Ca2+]i signaling and CCK secretion in response to LCFAs.
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Conflicts of interest The authors disclose no conflicts.
Funding Supported by the Veterinary Scientists Training Program, University of California, Davis School of Veterinary Medicine (APL), National Institutes of Health DK41004 (HER), and National Institute of Diabetes, Digestive, and Kidney Diseases Intramural funding.