Review
The ghrelin axis in disease: Potential therapeutic indications

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Abstract

Ghrelin, the natural ligand for the growth hormone (GH)-secretagogue receptor (GHS-R), is produced predominantly in the stomach. It is present in the circulation in two major forms, an acylated and an unacylated form, both of which have reported activities. Some of the best understood actions of acylated ghrelin administration are its orexigenic effects, and the stimulation of GH secretion. Ghrelin also seems to play a role in glucose homeostasis, lipid metabolism and immune function. Based on its orexigenic and metabolic effects, ghrelin and ghrelin mimetics have potential benefit in antagonizing protein breakdown and weight loss in catabolic conditions such as cancer cachexia, renal, cardiac and pulmonary disease, and age-related frailty. Ghrelin also has potentially useful positive effects on cardiac function and gastric motility. Ghrelin antagonists may be of benefit to increase insulin sensitivity and potentiate weight loss. The following chapter presents some background on ghrelin and ghrelin assays and discusses some of the potential therapeutic approaches for the use of ghrelin, ghrelin mimetic compounds and ghrelin antagonists in clinical disease.

Section snippets

Physiology

Ghrelin is a 28 amino acid peptide hormone secreted predominantly from the stomach that acts to regulate appetite and metabolism. The ghrelin peptide has an unusual post-translational modification; an 8 or 10 carbon fatty acid is ester linked to serine 3. This acylation is unstable, and the majority of ghrelin seen in the circulation is in an unacylated form (Kojima et al., 1999). Only acylated ghrelin has biological activity at the known ghrelin receptor (Smith, 2005), though the des-acylated

Ghrelin assays

Circulating ghrelin is heterogeneous (see above) and labile to degradation by both proteases and especially by esterases in blood (Hosada et al., 2000, Liu et al., 2008). This results in a mixture of ghrelin forms and degradation products. Assays for ghrelin must first start with a sample preparation method where further degradation has been stabilized, and then must characterize which forms of ghrelin or its fragments will be detected.

Potential use of ghrelin or ghrelin antagonists in disease

A discussion about modulating ghrelin receptor action must consider 2 different therapeutic approaches: (a) enhancing ghrelin receptor action and (b) blocking ghrelin receptor action. The following review will address some of the studies published.

Conclusion

Several conditions such as CHF, ESKD, COPD, cancer and the sarcopenia of aging are associated with significant weight loss and increased protein breakdown, which ultimately lead to increased morbidity and mortality. Based on its orexigenic effects, ghrelin and ghrelin mimetics have been shown to be of potential benefit in antagonizing protein breakdown and weight loss in catabolic conditions. Compared to ghrelin, ghrelin mimetics have the advantage that some can be given once daily and some are

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