In the last decade the discovery of ghrelin, a gut peptide discovered in 1999 by Kojima and colleagues (1), has led to the identification of a complex system that introduced new perspectives in neuroendocrine and metabolic research. Ghrelin is a peptide-hormone of 28 amino acids, predominantly produced by the stomach and detected in a lower amount in other central and peripheral tissues (1-11). The ghrelin peptide has a biological peculiarity, which is the esterification of a fatty (mostly n-octanoic) acid at its third serine residue (1). This modification is necessary for binding and activation of the growth hormone secretagogue receptor type 1a (GHS-R1a), the only cloned ghrelin receptor so far (1, 12, 13). Before the discovery of ghrelin, the GHS-R1a was an orphan G-protein coupled receptor specific for a family of synthetic molecules exerting a strong GH-releasing activity and therefore named Growth Hormone Secretagogues (GHS). The acyl-modified forms of ghrelin (AG), as well as some of the synthetic GHSs, have pleiotropic activities, including modulation of insulin secretion and glucose homeostasis. Besides the acylated form of ghrelin (AG), an unacylated ghrelin molecule (unacylated ghrelin, UAG) is also present in circulation. The absence of the acyl modification makes UAG unable to bind or activate the GHS-R1a (1). Moreover, although a specific UAG receptor has not been isolated to date, its existence has been strongly suggested. UAG shares with AG a variety of biological actions, but it also exerts AG-independent activities (11). Recently, a third molecule has been identified as a ghrelin-associated peptide and named obestatin (14). Obestatin is encoded by the same ghrelin gene and is a 23-amino acid product of the pro-ghrelin peptide. However, it does not bind the GHS-R1a (14). The growing body of literature over the last few years profiled the complex identities and interactions of these newly discovered molecules and their known and unknown receptor(s), which constitute the ghrelin system. The line of research and the studies included in this thesis focus on the involvement of the ghrelin system in the regulation of glucose metabolism, with particular emphasis on AG, UAG and their receptor(s).

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Lelij, Prof. Dr. A.J. van der (promotor), Netherlands Organization for Health Research and Development (ZONMW-NWO grant 912-03-022)
A.J. van der Lelij (Aart Jan)
Erasmus MC: University Medical Center Rotterdam

Gauna, C. (2007, September 26). Metabolic aspects of the ghrelin system: Role of acylated and unacylated ghrelin in glucose homeostasis. Retrieved from