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Ghrelin: A Newly Discovered Growth Hormone Secretagogue

E-Newsletter No. 27

A newly discovered natural ligand for the growth hormone secretagogue (GHS) receptor has been identified by a group in Japan (Nature 402; 1999:656-660). The mechanism of the GHS action has been studied since the 1970's, but neither the receptor nor the natural GHS ligand could be identified.

The first GHS peptide, synthetically synthesized in the late 1970's, had weak GH-releasing activity. This was soon followed by more potent substances, some of which were orally active. This stirred up hope that it would soon be possible to obtain growth hormone (GH) benefits without having to resort to the inconvenience of subcutaneous injections. A large pharmaceutical company even cloned a specific GHS receptor (Science 273; 1996:974-977), only to later abandon the entire project.

However, after years of speculation about where a natural GHS hormone could be produced, the peptide Ghrelin was discovered, and it was found to be produced by the oxyntic glands of the stomach. In addition, gene expression has also been found in the placenta, the kidney, and the hypothalamic region of the brain.

This newly discovered gut peptide has a direct action on the pituitary gland to stimulate GH secretion. It also acts on the hypothalamus, the portion of the brain that controls pituitary function. In this regard, GHS activates hypothalamic circuits that have a role in controlling appetite. Body fat in mice treated with another GHS, ipamorelin, is increased, and fat storage is induced, leading to adiposity (meaning they become fat).

This is paradoxically in direct contrast to the beneficial effects of GH which reduce body fat and increase muscle mass. It is speculated that this increased adiposity could result from GHS/Ghrelin effects to alter the body's preference for fuel resources, such as selectively burning up carbohydrates rather than fat, or simply by decreasing energy expenditure. 

Released by the stomach when empty, ghrelin triggers hunger signals in the hypothalamus. Blood levels of the hormone peak before each meal and decrease after. In addition to boosting appetite, ghrelin apparently slows metabolism, sabotaging long-term weight loss efforts. Small studies show that ghrelin levels are higher in obese patients who have recently lost weight compared with obese patients at a steady weight.

Subsequently, drug companies are reportedly searching for drugs that block ghrelin's effects. None have reached clinical trials.

Another new approach seeks to augment levels of ghrelin's hormonal counterpoint, a peptide known as PYY. After eating, the stomach and digestive tract release PYY, signaling,"I'M FULL" to the hypothalamus. In one study, volunteers injected with the hormone ate a third less food from a buffet. [Does that mean they only skipped their third helping?] I say this, because conscious decisions can override the PYY signal.

While drugs inhibiting ghrelin and enhancing PYY appear far off, another appetite-suppressing drug, a modified version of Recombinant human variant ciliary neurotrophic factor, or CTNF[Axokine]. The developer of Axokine, Regeneron Pharmaceuticals Inc., found that the drug suppress neuropeptide Y, a signaling molecule in the hypothalamus triggered by ghrelin. In hungry people, the hypothalamus pumps up neuropeptide Y production, but in ravenous rodents given CNTF, neuropeptide levels stay stable.
Patients who lose weight by restricting caloric intake experience an increase in fasting and postprandial 
serum ghrelin concentrations.

IN contrast, ghrelin concentrations are reduced 70% to 80%, with nearly absent meal-related variations, in patients who have undergone gastric bypass surgery. Low levels of ghrelin are associated with reduced appetite. It is similarly possible that bariatric surgery also may induce changes in the appetite-suppressing gut peptide PYY and other factors that may contribute to weight loss. 

A better understanding of such mechanisms would not only allow improved bariatric surgical procedures, but also may ultimately allow the development of a pharmacological equivalent of bariatic surgery.

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