Luminal amino acids have a pivotal role in gut hormone secretion, and thereby modulate food intake and energy metabolism. However, the mechanisms by which amino acids exert this effect remains unknown. The purpose of this research was to investigate the response of L-phenylalanine (L-Phe) to gut hormone secretion and its underlying mechanisms by perfusing the pig duodenum. Eighty mM L-Phe and extracellular Ca2+ stimulated cholecystokinin (CCK) and glucose-dependent insulinotropic peptide (GIP) release, and upregulated the mRNA expression of the calcium-sensing receptor (CaSR), CCK, and GIP. Western blotting results showed that L-Phe also elevated the protein levels of CaSR, the inositol 1,4,5-triphosphate receptor (IP3R), and protein kinase C (PKC). However, the CaSR inhibitor NPS 2143 reduced the mRNA expression of CaSR, CCK, and GIP, and the secretion of CCK and GIP, as well as the protein level of CaSR, IP3R, and PKC. These results indicated that Phe stimulated gut secretion through a CaSR-mediated pathway and its downstream signaling molecules, PKC and IP3R.

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BACKGROUND It is known that cholecystokinin (CCK) plays an essential role in reducing food intake and driving weight loss. Previous studies demonstrated that amino acids were capable of triggering CCK release through G protein‐coupled receptors, but the sensing mechanism remains obscure, especially the intracellular signaling pathway. RESULTS l‐Glu, rather than its d‐isomer, robustly stimulated CCK secretion in a porcine duodenal model, and the secretory response was augmented by incubation with the allosteric ligand of T1R1, while T1R3 antagonist attenuated it. Upon inhibiting phospholipase C (PLC) or transient receptor potential M5 (TRPM5) activity, l‐Glu failed to increase CCK release. Oral administration of monosodium glutamate in rats also suppressed food intake and increased plasma CCK levels, accompanied by elevated expression of T1R1, PLCβ2 and TRPM5 in the duodenum. CONCLUSION These data demonstrated that l‐Glu stimulated CCK secretion through the activation of T1R1/T1R3 in a PLC/TRPM5‐dependent manner. © 2020 Society of Chemical Industry