Ghrelin The Peptide Hormone


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

Structure and Its Receptor
The substance is synthesized as a preprohormone, then proteolytically processed to yield a 28-amino acid peptide. An interesting and unique modification is imposed on it 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 occurs predominantly in epithelial cells lining the fundus of the stomach, with smaller amounts produced in the placenta, kidney, pituitary and hypothalamus.

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

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

Control and Physiologic Effects
At least two major biologic activities have been ascribed to ghrelin: 

Stimulation of HGH secretion: Ghrelin, as the ligand for the HGH secretagogue receptor, potently stimulates secretion of HGH. The signal is integrated with that of HGH releasing substances and somatostatin to control the timing and magnitude of HGH 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 concentrations observed during fasting (see below). Additionally, humans injected with it reported sensations of intense hunger. It also appears to suppress fat utilization in adipose tissue, which is somewhat paradoxical considering that HGH has the opposite effect. Overall, it seems to be one of several hormonal signals that communicates the state of energy balance in the body to the brain.

Other effects 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 or represent an indirect effect of it's ability to stimulate HGH secretion.
 
0Blood 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
Concentrations in blood are reduced in obese subjects compared to lean control subjects, but whether this is cause or effect is not defined. Patients with anorexia nervosa have higher than normal plasma levels, which decrease if weight gain occurs.

Prader-Willi syndrome is another disorder relevant to this science. Affected patients develop extreme obesity associated with uncontrollable and voracious appetite. The plasma 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 production contributes to the appetite and obesity components.


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