Background The gastrointestinal peptide hormone ghrelin was discovered in 1999 as the endogenous ligand of the growth hormone secretagogue receptor. memory gut motility and gastric acid secretion sleep/wake rhythm reward seeking behavior taste sensation and glucose metabolism. gene codes for the full-length G-protein coupled seven transmembrane protein GHSR1a but a truncated isoform (GHSR1b) which has a wide tissue distribution is also transcribed [51]. GHSR1a has been shown to homodimerize but the possibility has been raised that GHSR1a and GHSR1b also heterodimerize [52 53 and that the heterodimer inhibits the activation of GHSR1a [53]. GHSR1a is usually expressed predominantly in the anterior pituitary gland pancreatic islets adrenal gland thyroid myocardium ARC hippocampus the substantia nigra pars compacta (SNpc) ventral tegmental area (VTA) and raphe nuclei [40 51 In the ARC in addition to being expressed in GHRH neurons is usually colocalized in neurons that express neuropeptide Y (synthesized fatty acids in comparison to those directly derived from the diet as substrate of GOAT for ghrelin acylation remains unknown. Mutation studies in the region of the acylated serine 3 have revealed that glycine 1 serine 3 and phenylalanine 4 are crucial components of the recognition sequence for GOAT whereas serine 2 leucine 5 serine 6 and proline 7 seem to be less important [62]. Biochemically GOAT appears to have two crucial substrates des-acyl ghrelin and short-to mid-chain fatty acids thioesterified with Coenzyme A. Cells expressing both ghrelin and GOAT synthesize serine 3 acyl-ghrelin with the acyl moiety precursors derived from fatty acids ranging from acetate (C2) to tetradecanoic acid (C14) [56]. The length of the fatty acid used for ghrelin acylation seems to be of importance for ghrelin’s metabolic effects as alterations in the fatty sodium 4-pentynoate acid length result in differential activation of GHSR1a and alter ghrelin’s effect on food intake and adiposity studies recreating the acyl-modification of ghrelin with des-acyl ghrelin peptides fatty acid CoA esters and GOAT made up of microsomes define the substrate specificity for GOAT. These studies support the idea that GOAT requires fatty acid substrates as high energy fatty acid CoA thioesters and that the amino acid sequence GXSFX where G X S and F correspond to unblocked amino terminal glycine Rabbit Polyclonal to ROCK2. (G) any amino acid (X) serine (S) and phenylalanine (F) respectively is sufficient as a substrate for GOAT acylation [67]. The structural constraints defined by this amino acid motif appear specific only for ghrelin and suggest that ghrelin may be the principal peptide substrate for GOAT. Most recent studies comparing the selectivity of hexanoyl- and octanoyl-CoA substrates suggest that GOAT may actually prefer hexanoyl CoA over octanoyl CoA substrates highlighting the importance of the specific fatty acid metabolism in acyl ghrelin producing cells responsible for producing circulating levels of octanoyl and decanoyl ghrelin [67]. 3.3 Evidence suggesting a role of the GOAT-ghrelin system as a nutrient sensor Most recent studies with genetically modified mice which are either lacking GOAT or overexpressing both ghrelin and GOAT establish that this GOAT-ghrelin system acts as a nutrient sensor informing the body of the presence of nutrients rather than the absence as commonly proposed [61]. Several observations support this statement. First prolonged fasting of mice led to well-established increased levels of total ghrelin which were caused by increased des-acyl ghrelin rather than acyl ghrelin. This increase in des-acyl ghrelin occurred as GOAT transcript levels decreased in response to the prolonged fasting treatments [61]. Consistent with these observations GOAT-null mice showed significantly increased total ghrelin levels being driven only by des-acyl ghrelin as these mice are unable to produce acyl altered ghrelin [56 61 Second several studies showed that dietary medium-chain fatty acids (MCFAs) can be a direct source of substrates for ghrelin acylation in sodium 4-pentynoate rodents and that sensing of MCFAs involves the gustatory G-protein α-gustducin [61 63 68 Third studies also show that mice lacking have lower body weight and excess fat mass on a MCFA-containing diet compared to wt mice whereas transgenic sodium 4-pentynoate mice overexpressing ghrelin and show.