Ghrelin is a hunger hormone with gastroprokinetic properties but the factors controlling ghrelin secretion from the stomach are unknown. Bitter taste receptors (T2R) and the gustatory G proteins, α-gustducin (gust) and α-transducin, are expressed in the gut and are involved in the chemosensation of nutrients. This study aimed to investigate whether T2R-agonists affect (i) ghrelin release via α-gustducin and (ii) food intake and gastric emptying via the release of ghrelin. The mouse stomach contains two ghrelin cell populations: cells containing octanoyl and desoctanoyl ghrelin, which were colocalized with α-gustducin and α-transducin, and cells staining for desoctanoyl ghrelin. Gavage of T2R-agonists increased plasma octanoyl ghrelin levels in WT mice but the effect was partially blunted in gust −/− mice. Intragastric administration of T2R-agonists increased food intake during the first 30 min in WT but not in gust −/− and ghrelin receptor knockout mice. This increase was accompanied by an increase in the mRNA expression of agouti-related peptide in the hypothalamus of WT but not of gust −/− mice. The temporary increase in food intake was followed by a prolonged decrease (next 4 h), which correlated with an inhibition of gastric emptying. The delay in emptying, which was partially counteracted by ghrelin, was not mediated by cholecystokinin and GLP-1 but involved a direct inhibitory effect of T2R-agonists on gastric contractility. This study is unique in providing functional evidence that activation of bitter taste receptors stimulates ghrelin secretion. Modulation of endogenous ghrelin levels by tastants may provide novel therapeutic applications for the treatment of weight -and gastrointestinal motility disorders. nutrient sensing | gastrointestinal peptides | appetite

The release of gut hormones involved in the control of food intake is dependent on the acute nutritional status of the body, suggesting that chemosensory mechanisms are involved in the control of their release. G protein-coupled taste receptors similar to those in the lingual system, that respond to sweet, bitter, umami, and fatty acids, are expressed in endocrine cells within the gut mucosa, and coordinate, together with other chemosensory signaling elements, the release of hormones that regulate energy and glucose homeostasis. In health, these nutrient sensors are likely to function as inhibitors to excessive nutrient exposure, and their malfunction may be responsible for a variety of metabolic dysfunctions associated with obesity; they may thus be considered as new therapeutic targets.

BackgroundGhrelin is an important regulator of energy – and glucose homeostasis. The octanoylation at Ser3 is essential for ghrelin’s biological effects but the mechanisms involved in the octanoylation are unknown. We investigated whether the gustatory G-protein, α-gustducin, and the free fatty acid receptors GPR40 and GPR120 are involved in the fatty acid sensing mechanisms of the ghrelin cell.MethodsWild-type (WT) and α-gustducin knockout (gust−/−) mice were fed a glyceryl trioctanoate-enriched diet (OD) during 2 weeks. Ghrelin levels and gastric emptying were determined. Co-localization between GPR40, GPR120 and ghrelin or α-gustducin/α-transducin was investigated by immunofluorescence staining. The role of GPR120 in the effect of medium and long chain fatty acids on the release of ghrelin was studied in the ghrelinoma cell line, MGN3-1. The effect of the GPR40 agonist, MEDICA16, and the GPR120 agonist, grifolic acid, on ghrelin release was studied both in vitro and in vivo. ResultsFeeding an OD specifically increased octanoyl ghrelin levels in the stomach of WT mice but not of gust−/− mice. Gastric emptying was accelerated in WT but not in gust−/− mice. GPR40 was colocalized with desoctanoyl but not with octanoyl ghrelin, α-gustducin or α-transducin positive cells in the stomach. GPR120 only colocalized with ghrelin in the duodenum. Addition of octanoic acid or α-linolenic acid to MGN3-1 cells increased and decreased octanoyl ghrelin levels, respectively. Both effects could not be blocked by GPR120 siRNA. MEDICA16 and grifolic acid did not affect ghrelin secretion in vitro but oral administration of grifolic acid increased plasma ghrelin levels.ConclusionThis study provides the first evidence that α-gustducin is involved in the octanoylation of ghrelin and shows that the ghrelin cell can sense long- and medium-chain fatty acids directly. GPR120 but not GPR40 may play a role in the lipid sensing cascade of the ghrelin cell.

No abstract

No abstract