Gastric O-acyl transferase activates hunger signal to the brain
- Departments of Psychiatry and Medicine, Obesity Research Centre and Genome Research Institute, University of Cincinnati College of Medicine, Cincinnati, OH 45237
Some of us may remember from school biology lessons that goats are classified as ruminants because they have four stomachs. However, recent findings now demonstrate that most mammals have GOAT in their stomach. In this issue of PNAS, Gutierrez et al. identified and characterized the enzyme ghrelin O-acyl transferase (GOAT) that adds a fatty acid moiety to the gastric hormone ghrelin (1). This important discovery marks a major step forward in understanding the ghrelin signaling system and could have significant implications both for body weight regulation and nutrient–gene interactions.
About Ghrelin
Ghrelin is an orexigenic peptide hormone secreted mainly from the stomach and proximal small bowel (2, 3). It is cleaved from a larger precursor, preproghrelin, which bears a signal sequence dictating secretion into the circulation (2). Uniquely, ghrelin requires posttranslational modification in which the serine-3 hydroxy-containing residue is covalently linked to a medium-chain fatty acid, typically octanoate, through an ester bond. This is required for the peptide to bind to its receptor, GHSR1a. Most biological actions ascribed to ghrelin require this acylation (4), whereas desacyl ghrelin has as yet no defined biological action (2, 5, 6). Thus, GOAT may play a key role in the molecular regulation of energy metabolism, and also represent a prime drug target for the treatment of obesity and diabetes.
Discovery of GOAT
The discovery of GOAT can be traced back to the identification of a family of acyl transferases named MBOATs for membrane-bound O-acyl transferases that catalyze O-acylation reactions related to Wnt signaling (7). Wnt-secreting cells are known to require the action of a gene product called porcupine, which exhibits structural similarities to MBOATs and transfers acyl groups, such as palmitic acid, to a conserved cysteine residue (8, 9). Knowledge on …
*To whom correspondence should be addressed. E-mail: tschoemh{at}ucmail.uc.edu
