Growth hormone secretagogues on the somatotropic axis The neurotrophin-inducible gene vgf, was originally identified as a neurotrophin-regulated gene product in PC12 cells (Levi et al., 1985). It was subsequently found to be processed into peptides in a tissue-specific manner in neuronal and neuroendocrine cells and released through the regulated secretory pathway (Possenti et al., 1989; Trani et al., 1995, 2002; Rindi et al 2007).
Vgf encodes for a 68 k Da protein (VGF) that plays a critical role in the regulation of energy homeostasis (Hahm et al 1999). In the rat, VGF is expressed in the central and peripheral nervous system, with high levels in the hypothalamus. Starvation increases the expression of VGF in the arcuate nucleus and, since VGF-knockout (VGF-KO) mice are thin, hypermetabolic, hyperactive and relatively infertile, it is possible to think that VGF is involved in the regulation of energy metabolism (Hahm et al., 1999; Hahm et al., 2002).
Based on the phenotype of VGF_/_ mice (Hahm et al., 1999; Hahm et al., 2002), it can be predicted that VGF-derived peptides possess anabolic properties. However, the native VGF is a large 617 amino acids protein that is cleaved by prohormone convertases into a number of peptides, several of which have been shown to be biologically active (Levi et al., 2004). Recently, one of them, the peptide TLQP-21, which spans from residue 556 to residue 576 of the precursor sequence, was found to be one of the major fragments present in the brain of rats (Bartolomucci et al. 2006). Contrary of the general predictions, it was shown able to increase the energy expenditure and to block the early phase of high-fat diet-induced obesity in mice (Bartolomucci et al. 2006). A result that has been recently confirmed, at least in part, in another species, the Siberian hamster (Jethwa et al, 2007). Altogether, these interesting results suggest that TLQP-21 may be a lead compound to develop new anti-obesity drugs. Up to now, it is not known the nature of the receptors with which TLQP-21 interacts to induce its metabolic changes. However, before developing new analogs it is mandatory to find the receptor/s that bind TLQP-21 and that may become an important target to improve the efficacy of anorexant theraphy.
In order to identify TLQP-21 receptors we will use a photoreactive derivative of TLQP-21, using the photoactivatable amino acid derivative p-benzyl-L-phenylalanine (Bpa) incorporated in the peptide molecule, using a methodology already successfully applied to the identification of a growth hormone-releasing peptidein the anterior pituitary of rat and man (Ong et al. 1998). The TLQP-21 photoactivatable ligand will be used to covalently label receptors present in membranes of cells responding to the TLQP-21 in terms of intracellular calcium release, and will allow the identification of the receptor of TLQP-21.
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