Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor (GHS-R), is predominantly produced in the stomach. It has been reported that endogenous ghrelin levels are increased by fasting and decreased immediately after feeding, and that fasting-induced ghrelin release is controlled by the sympathetic nervous system. However, the mechanisms of plasma ghrelin decrement after feeding are poorly understood. Here, we studied the control of ghrelin secretion using ghrelin-producing cell lines, and found that these cells express high levels of mRNA encoding G-protein coupled receptor 120 (GPR120). Addition of GW9508 (a GPR120 chemical agonist) and α-linolenic acid (a natural ligand for GPR120) inhibited the secretion of ghrelin by approximately 50 % and 70 %, respectively. However, the expression levels of preproghrelin and ghrelin O-acyltransferase (GOAT) mRNAs were not influenced by GW9508. In contrast, the expression levels of prohormone convertase 1 (PC1) were significantly decreased by GW9508 incubation. Moreover, we observed that the inhibitory effect of GW9508 on ghrelin secretion was blocked by a small interfering RNA (siRNA) targeting the sequence of GPR120. Further, pretreatment with GW9508 blocked the effect of the norepinephrine (NE)-induced ghrelin elevation in ghrelin cell lines. In addition, we showed that GW9508 inhibited ghrelin secretion via extracellular signal-regulated kinase (ERK) activity in ghrelin cell lines. Finally, we found that GW9508 decreased plasma ghrelin levels in mice. These results suggest that the decrease of ghrelin secretion after feeding is partially induced by long chain fatty acids that act directly on gastric GPR120-expressing ghrelin cells.