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Indian Journal of Pharmacology
Medknow Publications on behalf of Indian Pharmacological Society
ISSN: 0253-7613 EISSN: 1998-3751
Vol. 37, Num. 2, 2005, pp. 133-134

Indian Journal of Pharmacology, Vol. 37, No. 2, March-April, 2005, pp. 133-134

Molecules of the Millennium

Ghrelin: A potential drug target for obesity

Madan A.K.

College of Veterinary and Animals Sciences, GBPUAT, Pantnagar

Correspondence Address:College of Veterinary and Animals Sciences, GBPUAT, Pantnagar

Code Number: ph05028

The suffix "ghre" means "to grow". Ghrelin (pronounced GRELL-in) was discovered in 1999 as a peptide hormone that potently stimulates the 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.

Synthesis and receptor

Ghrelin is synthesized as a pre-prohormone, and then proteolytically processed to yield a 28-amino acid peptide. A modification necessary for biological activity is the binding of n-octanoic acid to one of its amino acids, carried out during its synthesis. Synthesis of ghrelin occurs predominantly in the 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 have a receptor that, when activated, potently stimulates the secretion of the growth hormone. The receptor was named the growth hormone secretagogue receptor (GHS-R). The natural ligand for the GHS-R is ghrelin. The receptors are present on the cells in the pituitary that secrete the growth hormone and also have been identified in the hypothalamus, heart and adipose tissue.[1]

Control and physiological effects of ghrelin

At least two major biological activities have been ascribed to ghrelin

1. Stimulation of growth hormone secretion: Ghrelin, as the ligand for the growth hormone secretagogue receptor, potently stimulates the secretion of the growth hormone. The ghrelin signal is integrated with that of the growth hormone-releasing hormone and somatostatin to control the timing and magnitude of growth hormone secretion.[2]

2. Regulation of energy balance: In rodents and humans, ghrelin functions to increase hunger through its action on the hypothalamic feeding centers. The plasma ghrelin concentrations increase during fasting.[3] Humans injected with ghrelin reported sensations of intense hunger.[4] Ghrelin also appears to suppress fat utilization in the adipose tissue, which is somewhat paradoxical considering that the growth hormone has the opposite effect. Overall, ghrelin seems to be one of several hormonal signals that communicate the state of energy balance in the body to the brain.

Other effects of ghrelin include stimulation of gastric emptying and a variety of positive effects on cardiovascular function (e.g. increased cardiac output). It is not yet clear whether the cardiovascular effects are due to a direct effect of ghrelin or an indirect effect of ghrelin′s ability to stimulate growth hormone secretion.

Disease states and ghrelin

Blood concentrations of ghrelin are lowest shortly after consumption of a meal, and then gradually rise during the fast and reach the peak just prior to the next meal. Ghrelin concentrations in blood are reduced in obese humans compared to lean subjects. However, whether this is the cause or effect is not well defined. Patients with anorexia nervosa have high plasma ghrelin levels whereas obese ones tend to have low levels.

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

Ghrelin as drug target

People who lose weight have higher blood levels of ghrelin, than they did when they were fat. This also supports the concept that the body tends to maintain its ideal weight and when one loses weight, the body should produce more ghrelin to stimulate to regain the lost weight. Therefore ghrelin makes one fatter by causing hunger to eat more and slowing metabolism to burn fewer calories.

A rise or fall in ghrelin is not observed in patients who had gastric bypass surgery, before or after they eat. Their levels of ghrelin remain low all the time. This shows that stomach cells produce ghrelin only when food passes into the stomach. An empty stomach causes stimulation of ghrelin secretion while food in the stomach stops production of ghrelin. However, when no food enters the stomach for a long time, stomach cells stop producing ghrelin and a person stops being hungry. That is why when it is long past normal mealtime a person stops feeling hungry.[5]

So drugs that can block ghrelin will be very effective to overcome obesity without much disturbance in the physiological homeostasis of our body. Intense research is going on in this regard for a breakthrough drug in obesity.

REFERENCES

1.	Hosoda H, Kojima M, Matsuo H, Kangawa K. Ghrelin and des-acyl ghrelin: Two major forms of rat ghrelin peptide in gastrointestinal tissue. Biochem Biophys Res Commun 2000;279:909-13. Back to cited text no. 1
2.	Hosoda H, Kojima M, Matsuo H, Kangawa K. Purification and characterization of rat des-Gln14-Ghrelin, a second endogenous ligand for the growth hormone secretagogue receptor. J Biol Chem 2000;275:21995-2000. Back to cited text no. 2 [PUBMED] [FULLTEXT]
3.	Nakazato M, Murakami N, Date Y, Kojima M, Matsuo H, Kangawa K, et al. A role for ghrelin in the central regulation of feeding. Nature 2001;409:194-8. Back to cited text no. 3
4.	Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 1999;402:656-60. Back to cited text no. 4 [PUBMED] [FULLTEXT]
5.	Weight reduction brought about by caloric restriction caused ghrelin levels to increase, suggesting that ghrelin might contribute to the drive to eat that makes long-term success with dieting so rare. N Engl J Med. 2002 May. Back to cited text no. 5

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