Novel Mechanism of Fatty Acid Sensing in Enteroendocrine Cells: Specific Structures in Oxo‐Fatty Acids Produced by Gut Bacteria Are Responsible for CCK Secretion in STC‐1 Cells via GPR40

Scope The secretion of gut hormones, such as cholecystokinin (CCK) is stimulated by fatty acids. Although a chain length–dependent mechanism has been proposed, other structural relationships to releasing activity remain unclear. We aimed to elucidate specific structures in fatty acids that are responsible for their CCK‐releasing activity, and related sensing mechanisms in enteroendocrine cells. Methods and results CCK secretory activities were examined in a murine CCK‐producing cell line STC‐1 by exposing the cells to various modified fatty acids produced by gut lactic acid bacteria. The effects of fatty acids on gastric emptying rate as a CCK‐mediated function were examined using acetaminophen and phenol red methods in rats. Out of more than 30 octadecanoic‐derived fatty acids tested, 5 oxo‐fatty acids potently stimulated CCK secretion without cytotoxic effects in STC‐1 cells. Three fatty acids had a distinct specific structure containing one double bond, whereas the other two had two double bonds, nearby an oxo residue. CCK secretion induced by representative fatty acids (10‐oxo‐trans‐11‐18:1 and 13‐oxo‐cis‐9,cis‐15‐18:2) was attenuated by a fatty acid receptor G‐protein coupled receptor 40 antagonist. Oral administration of 13‐oxo‐cis‐9,cis‐15‐18:2 lowered the gastric emptying rate in rats in a dose‐ and structure‐dependent manner. Conclusion These results reveal a novel fatty acid‐sensing mechanism in enteroendocrine cells. Two specific structures (containing oxo‐groups) in fatty acids are identified that are responsible for potent CCK releasing activity in a CCK‐producing enteroendocrine cell line, STC‐1, by exploring 35 different hydroxy‐ and oxo‐octadecanoic fatty acids produced as metabolites of gut lactic acid bacteria. The stimulatory effects of these fatty acids are mediated by a fatty acid receptor, GPR40. Our findings provide a novel insight into the chemical sensing mechanisms of enteroendocrine cells.