G protein-coupled receptor 120 signaling regulates ghrelin secretion in vivo and in vitro

Abstract

Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor, is produced predominantly 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 GW-9508 (a GPR120 chemical agonist) and ␣-linolenic acid (a natural ligand for GPR120) inhibited the secretion of ghrelin by ϳ50 and 70%, respectively. However, the expression levels of preproghrelin and ghrelin O-acyltransferase (GOAT) mRNAs were not influenced by GW-9508. In contrast, the expression levels of prohormone convertase 1 were decreased significantly by GW-9508 incubation. Moreover, we observed that the inhibitory effect of GW-9508 on ghrelin secretion was blocked by a small interfering RNA (siRNA) targeting the sequence of GPR120. Furthermore, pretreatment with GW-9508 blocked the effect of the norepinephrine (NE)-induced ghrelin elevation in ghrelin cell lines. In addition, we showed that GW-9508 inhibited ghrelin secretion via extracellular signal-regulated kinase activity in ghrelin cell lines. Finally, we found that GW-9508 decreased plasma ghrelin levels in mice. These results suggest that the decrease of ghrelin secretion after feeding is induced partially by long-chain fatty acids that act directly on gastric GPR120-expressing ghrelin cells.

Inhibitory Effect of Oleic Acid on Octanoylated Ghrelin Production

“…GPR120, which functions mainly as a receptor for unsaturated longchain fatty acids 30 , could play a role in the lipid sensing cascade in ghrelin-producing cells 31 . The decrease in octanoylated ghrelin secretion after feeding is partially induced by long-chain fatty acids that act directly on gastric GPR120-expressing ghrelin cells 32 . In addition, it was reported that the G protein α-gustducin is also involved in ghrelin octanoylation 31 and that α-gustducin could couple GPR120 33 .…”

High incorporation of long‐chain fatty acids contributes to the efficient production of acylated ghrelin in ghrelin‐producing cells

“…Recently, it was reported that long-chain fatty acid receptor, GPR120, is expressed in ghrelin-producing cells and that long-chain fatty acids suppress ghrelin secretion via Gi pathway [28][29][30]. It should be noted that GPR120-mediated signaling may have affected the current experiments using palmitate.…”

“…To measure ghrelin concentrations in culture medium, the collected culture media were centrifuged, the resulting supernatants were immediately applied to Sep-Pak C18 cartridges and processed as described above. Two types of ghrelin RIA were performed: C-RIA, in which an anti-COOH-terminal ghrelin (amino acids [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] antiserum was used to detect both ghrelin and des-acyl ghrelin (total ghrelin); and N-RIA, in which an anti-NH 2 -terminal ghrelin (amino acids 1-11) antiserum was used to detect (acylated) ghrelin only, as previously described [2,17].…”

The study of ghrelin secretion and acyl-modification using mice and ghrelinoma cell lines

“…Addition of GPR120 agonists, α-linolenic acid and GW-9508, into the culture medium in ghrelinoma cell lines and primary gastric mucosal cells significantly decreased ghrelin secretion. In contrast, mRNA expression levels of preproghrelin and GOAT were not changed by GPR120 agonists, but prohormone convertase 1 was suppressed by GPR120 agonists [8]. Intracellular signaling mechanisms were investigated and it was found that ERK/MAPK pathway inhibitors recovered GPR120 agonist-induced suppression of ghrelin secretion.…”

“…G-protein coupled receptor 120 (GPR120) mRNA was highly expressed in ghrelin-GFP, SG-1, and PG-1 cells [8]. Addition of GPR120 agonists, α-linolenic acid and GW-9508, into the culture medium in ghrelinoma cell lines and primary gastric mucosal cells significantly decreased ghrelin secretion.…”