As the hormone ghrelin is linked to appetite and weight gain, as well as impaired glucose-induced insulin secretion, there is considerable interest in this peptide as a potential drug target. Although the overall lack of success in this field has been disappointing, research inhibiting the ghrelin-modifying enzyme GOAT (MBOAT4) has produced promising results.
Ghrelin is a peptide hormone secreted by the stomach. Though first described as the ligand of the growth hormone secretagogue receptor, ghrelin has gained notoriety since it was found that circulating ghrelin levels rise then fall before and after a meal respectively, and that it stimulates appetite and weight gain. Targeting the ghrelin system could therefore be a way to treat or prevent obesity. Obese people actually have low circulating ghrelin, but it has been shown that in these individuals the suppression of ghrelin after eating is much less, suggesting that inhibiting the ghrelin system could still be an effective way to lessen appetite in the obese. Additionally, ghrelin is expressed in the pancreas, and studies have associated ghrelin with reduced glucose tolerance; thus, antagonism of the ghrelin system is a potential strategy for diabetes therapy.
Ghrelin is very unusual in two ways: its orexigenic effect, and its O-acylation with the eight-carbon fatty acid octanoate. This posttranslational modification at serine-3 of ghrelin is vital for it to bind to and activate its receptor. The ghrelin O-acyltransferase, abbreviated GOAT, was first identified and characterized by Yang et al. After utilizing western blotting (immunoblotting) with a ghrelin antibody to find cell lines capable of cleaving the ghrelin peptide from its precursor prepro-ghrelin, they carried out a number of experiments employing reverse-phase chromatography (to separate octanoylated and desacyl-ghrelin by their differing hydrophobicities) followed by probing with the ghrelin antibody in western blots. In this way they showed, for example, that in cells transfected with GOAT cDNA (but not other similar enzymes), ghrelin is acylated; that the conserved hydroxyl group at position 3 (serine or threonine) of ghrelin is vital for this modification; and that the GOAT catalytic residues are the conserved asparagine and histidine.
Blocking GOAT from acylating ghrelin could be a way to prevent its effects. Barnett et al. have obtained some encouraging results with the novel compound GO-CoA-Tat. This bisubstrate analog comprises a (partial) octanoylated ghrelin, CoA (the acyl donor), and a Tat peptide to aid cell penetration. They demonstrated in cell lines that GO-CoA-Tat inhibits ghrelin acylation by GOAT, is a selective antagonist for this enzyme and is nontoxic. They then administered GO-CoA-Tat to mice and found that again the drug was nontoxic and acyl ghrelin levels decreased; furthermore, when fed a high-fat diet, mice treated with GO-CoA-Tat were protected from the weight gain seen in untreated controls, and exhibited lower fat mass. Moreover, following a glucose challenge, the mice treated with GO-CoA-Tat were shown to have a significantly increased insulin response and decreased blood glucose levels. Double immunohistochemical staining (IHC) of pancreatic islets from the mice with insulin and ghrelin antibodies revealed ghrelin-producing cells (ghrelin-positive and insulin-negative) in addition to the beta cells. Together, these findings indicate that GOAT inhibition may be a useful treatment strategy for both obesity and type 2 diabetes. This is particularly significant because of the lack of success achieved by groups using other approaches (neutralizing ghrelin in circulation, or antagonising ghrelin’s receptor GHS-R1a).
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Written by Carly Hammond
