The G‐protein coupled receptor GPR40 mediates long chain fatty acid induced cholecystokinin secretion

INTRODUCTION Long chain fatty acid receptors (LCFARs) have been implicated in the chemosensation of dietary fats, however direct studies on native “I” cells have been difficult due to their rare and isolated distribution. The objective of this study was to determine whether dietary fat‐induced cholecystokinin (CCK) secretion is directly mediated by GPR40 expressed on I cells isolated from duodenal mucosa of CCK‐eGFP BAC transgenic mice by fluorescence activated cell sorting. METHODS Isolated CCK‐eGFP cells were evaluated for LCFAR gene expression by Taqman RT‐PCR. GPR40 −/− mice were crossed with CCK‐eGFP mice to evaluate the functional relevance of GPR40 on linolenic acid‐stimulated CCK secretion, measured by radioimmunoassay, in isolated CCK‐eGFP cells. Also, plasma CCK secretion in response to olive oil gavage was compared between GPR40 +/+ and GPR40 −/− mice. RESULTS Isolated CCK‐eGFP cells display a 100‐fold greater expression of GPR40 compared to non‐eGFP cells. In vitro , linolenic acid increased CCK secretion by 53% in GPR40 +/+ CCK‐eGFP cells compared to no significant secretion in GPR40 −/− CCK‐eGFP cells. In vivo , an olive oil gavage significantly increased plasma CCK levels by 5.7‐fold in GPR40 +/+ mice compared to an increase of 3.1‐fold in GPR40 −/− mice. CONCLUSION This study is the first to demonstrate a direct chemosensory role of GPR40 in dietary fat induced CCK secretion.