Ipamorelin and the Ghrelin/GHSR System: What the Published Literature Covers

Ipamorelin is discussed in the literature in the context of the growth hormone secretagogue receptor (GHSR), the receptor at which the endogenous peptide ghrelin acts. Published work states that ghrelin stimulates growth hormone release from the pituitary via GHSR [1]. The study set retrieved here is limited to a single comparative endocrinology paper in the black seabream (Acanthopagrus schlegeli), in which two GHSR subtypes had previously been isolated from the pituitary of the same species [1]. In that work, the ghrelin cDNA and gene were cloned and characterised in seabream. The full-length cDNA, isolated from seabream stomach, was reported to encode a prepropeptide of 107 amino acids, with a predicted mature ghrelin peptide of 20 amino acids (GSSFLSPSQKPQNRGKSSRV), and the authors noted a putative fish orthologue of the mammalian obestatin peptide embedded within the same transcript [1]. The seabream ghrelin gene, obtained by genomic PCR, was described as comprising four exons and three introns, matching the structural organisation reported in tilapia and goldfish but differing from that in rainbow trout [1]. Promoter analysis was carried out in vitro. A 2230-bp 5'-flanking region recovered by genome walking was reported to contain neither a GC box nor a CAAT box, as is also the case for the human ghrelin gene, while a number of putative transcription-factor-binding sites differing from the human counterpart were identified [1]. When this region was cloned upstream of a luciferase reporter and transfected into several cell lines, positive promoter activity was recorded only in colon-derived Caco-2 cells, which the authors interpreted as tissue-specific promoter activity [1]. The ipamorelin-relevant observation in this paper is an in vivo animal finding. By reverse transcriptase PCR, ghrelin expression was detected only in seabream stomach and not in the other tissues examined, including brain, gill, intestine, kidney, liver and spleen [1]. The authors reported that this stomach-specific expression is subject to regulation, and that administration of growth hormone or ipamorelin to the fish in vivo enhanced ghrelin expression [1]. They noted that this resembles the homologous upregulation previously described for transcriptional control of the seabream GHSR gene, and suggested that a similar homologous regulatory mechanism might operate for ghrelin itself [1]. Researchers should note the scope limits of this evidence. The ipamorelin result is a fish in vivo observation of transcript abundance, not a mammalian or human finding, and the retrieved set contains no human or rodent pharmacology for ipamorelin at GHSR. The authors framed the co-identification of GHSR and ghrelin in a single fish species as a basis for subsequent work on the physiological functions of the ghrelin/GHSR system in teleosts, and raised the possible existence of obestatin in teleosts as a further research avenue on the somatotropic axis in fish [1].