Study Title:

The Story of Ghrelin and Obesity

Study Abstract

The current epidemic of obesity and diabetes in the face of a surfeit of calories contrasts the natural selection to survive famine that confronted our ancestors. The report in PNAS by Zhao et al. ( 1) shows that ghrelin is an important hormone in this process. By studying mice under severe caloric restriction, they show that knockout (KO) of the enzyme ghrelin O-acyltransferase (GOAT), necessary to convert ghrelin to its active form, manifests the first clear phenotype seen in KO of ghrelin activity; ghrelin is necessary for triggering the growth-hormone (GH) response to nutritional deprivation that prevents hypoglycemia and death.

The road to ghrelin's discovery started with the observation that morphine stimulates GH secretion, isolation of the enkephalins, and development of enkephalin analogs that selectively stimulate secretion of GH [GH-secretagogues (GHSs)] and orally active GHS. One such GHS, MK-0677, was used to expression clone the GHS receptor (GHS-R) ( 2). Using cell lines expressing this receptor, Kojima et al. ( 3) isolated and characterized its endogenous ligand (ghrelin) from rat stomach extracts. They discovered that the third amino acid of ghrelin had an unexpectedly large mass; it was a serine residue modified by the attachment of octanoate, a medium-chain fatty acid. Removing the octanoate blocked ghrelin's ability to bind to or activate its receptor. This acylation of a peptide with a medium-chain fatty acid is unique to ghrelin.

Although ghrelin was named for its GH-releasing activity, its pleiotropic effects, including increased appetite, altered gastrointestinal motility, and regulated lipid and glucose metabolism, cardiac function, blood pressure, immune function, cell proliferation, sleep, anxiety, and even memory, soon became apparent ( 4). However, KO of ghrelin or GHS-R or the combined KO of both receptor and ligand had no distinctive phenotype ( 5).

Study Information

Ralf M. Nass, Bruce D. Gaylinn, Alan D. Rogol, and Michael O. Thorner.
Ghrelin and growth hormone: Story in reverse
2010 May
Department of Medicine, University of Virginia, Charlottesville, VA 22908.

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