Ghrelin the Peptide Hormone

Ghrelin was discovered as the peptide hormone that potently stimulates release of growth hormone from the anterior pituitary. It was subsequently determined that ghrelin, along with several other hormones, has significant effects on appetite and energy balance. The predominant source of ghrelin is epithelial cells in the stomach.

Structure of Ghrelin and Its Receptor
Ghrelin is synthesized as a preprohormone, then proteolytically processed to yield a 28-amino acid peptide. An interesting and unique modification is imposed on the hormone during synthesis in the form of an n-octanoic acid bound to one of its amino acids; this modification is necessary for biologic activity.

Synthesis of ghrelin occurs predominantly in epithelial cells lining the fundus of the stomach, with smaller amounts produced in the placenta, kidney, pituitary and hypothalamus.

The ghrelin receptor was known well before ghrelin was discovered. Cells within the anterior pituitary bear a receptor that, when activated, potently stimulates secretion of growth hormone - that receptor was named the growth hormone secretagoue receptor (GHS-R). The natural ligand for the GHS-R was announced in 1999 as ghrelin, and ghrelin was named for its ability to provoke growth hormone secretion (the suffix ghre means "grow").

Ghrelin receptors are present on the cells in the pituitary that secrete growth hormone, and also have been identified in the hypothalamus, heart and adipose tissue.

Control and Physiologic Effects of Ghrelin
At least two major biologic activites have been ascribed to ghrelin: 

Stimulation of growth hormone secretion: Ghrelin, as the ligand for the growth hormone secretagogue receptor, potently stimulates secretion of growth hormone. The ghrelin signal is integrated with that of growth hormone releasing hormone and somatostatin to control the timing and magnitude of growth hormone secretion.

Regulation of energy balance: In both rodents and humans, ghrelin functions to increase hunger though its action on hypothalamic feeding centers. This makes sense relative to increasing plasma ghrelin concentrations observed during fasting (see below). Additionally, humans injected with ghrelin reported sensations of intense hunger. Ghrelin also appears to suppress fat utilization in adipose tissue, which is somewhat paradoxical considering that growth hormone has the opposite effect. Overall, ghrelin seems to be one of several hormonal signals that communicates the state of energy balance in the body to the brain.

Other effects of ghrelin include stimulating gastric emptying and having a variety of positive effects on cardiovascular function (e.g. increased cardiac output). It is not totally clear whether the cardiovascular effects are a direct effect of ghrelin or represent an indirect effect of ghrelin's ability to stimulate growth hormone secretion.
 
Blood concentrations of ghrelin are lowest shortly after consumption of a meal, then rise during the fast just prior to the next meal. The figure to the right shows this pattern based on assays of plasma ghrelin in 10 humans during the course of a day.

Disease States
Ghrelin concentrations in blood are reduced in obese humans compared to lean control subjects, but whether this is cause or effect is not defined. Patients with anorexia nervosa have higher than normal plasma ghrelin levels, which decrease if weight gain occurs.

Prader-Willi syndrome is another disorder relevant to ghrelin science. Affected patients develop extreme obesity associated with uncontrollable and voracious appetite. The plasma ghrelin levels are exceptionally high in comparison to patients similarly obese due to other causes. Prader-Willi syndrome is clearly a complex disease with many defects; it may be that excessive ghrelin production contributes to the appetite and obesity components.

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