We recently showed that a-gustducin also plays a role in the effect of bitter agonists on ghrelin secretion. Both a-gustducin and atransducin are colocalized with octanoyl containing ghrelin cells in the mouse stomach. In addition a-gustducin but not atransducin is also present in the brush cells in close contact with some ghrelin cells. These brush cells may Fulvestrant function as input cells to convey signals from the lumen via PGP9.5-innervating fibers to neighboring cells. a-gustducin is also present in the mouse small intestine where it is colocalized with 5-HT and GLP-1. Also in humans expression of a-gustducin has been demonstrated in stomach and small intestine. Recent data stress the role of lipid sensing mechanisms in the regulation of energy balance. Also the ghrelin cell must sense lipids since the secretion of ghrelin is inhibited by lipids and ghrelin octanoylation is modified by dietary lipids, in particularly by the availability of MCFA. The function of ghrelin may therefore not exclusively be that of a hunger signal reflecting an empty stomach, but the ghrelin-GOAT system may act as an energy-sensor to alert the central nervous system about the presence of a calorie-rich environment to optimize lipid storage and permit growth. However, the signaling pathways involved in sensing of lipids by the ghrelin cell are not known. In the current paper we described for the first time a role for the gustatory G-protein, a-gustducin, in the octanoylation of ghrelin. Feeding mice a diet enriched with glyceryl trioctanoate for two weeks increased octanoyl ghrelin levels in stomach extracts from WT but not from gust2/2 mice. We have previously shown that agustducin is present in the brush cells of the stomach in close contact with octanoyl containing ghrelin cells but also in endocrine cells immunoreactive for octanoyl ghrelin. Since orally ingested medium chain triglycerides can passively diffuse from the GI tract to the portal system, it is therefore questionable if the a-gustducin-containing brush cells, which are in direct contact with the lumen, are involved in the sensing of these lipids. Our data also show that the octanoylation of ghrelin can be increased in vitro by addition of octanoic acid to the culture medium of the ghrelinoma cell line, MGN3-1. However, in contrast to the in vivo situation, the increased octanoyl ghrelin was also effectively secreted in the cell culture medium. This reinforces the hypothesis that the a-gustducin containing endocrine ghrelin cells contain the machinery to sense the octanoic acid directly, probably from signals coming via the blood stream and thus independent from luminal stimuli transmitted via the brush cells. In contrast to octanoyl ghrelin levels, total ghrelin levels in the stomach were not affected by the diet, insinuating that only the octanoylation process was influenced by an excessive availability of octanoic acid in the diet. Similar findings were obtained by addition of octanoic acid to the cell culture medium of the ghrelinoma cell line.