title: Ghrelin stimulation of growth hormone release and appetite is mediated through the growth hormone secretagogue receptor.
abstract: Synthetic agonists of the growth hormone secretagogue receptor (GHSR) rejuvenate the pulsatile pattern of GH-release in the elderly, and increase lean but not fat mass in obese subjects. Screening of tissue extracts in a cell line engineered to overexpress the GHSR led to the identification of a natural agonist called ghrelin. Paradoxically, this hormone was linked to obesity. However, it had not been directly shown that the GHSR is a physiologically relevant ghrelin receptor. Furthermore, ghrelin's structure is significantly different from the synthetic agonist (MK-0677) used to expression-clone the GHSR. To address whether the GHSR mediates ghrelin's stimulatory effects on GH release and appetite, we generated Ghsr-null mice. In contrast to wild-type mice, acute treatment of Ghsr-null mice with ghrelin stimulated neither GH release nor food intake, showing that the GHSR is a biologically relevant ghrelin receptor. Nevertheless, Ghsr-null mice are not dwarfs; their appetite and body composition are comparable to that of wild-type littermates. Furthermore, in contrast to suggestions that ghrelin regulates leptin and insulin secretion, fasting-induced changes in serum levels of leptin and insulin are identical in wild-type and null mice. Serum insulin-like growth factor 1 levels and body weights of mature Ghsr-null mice are modestly reduced compared to wild-type littermates, which is consistent with ghrelin's property as an amplifier of GH pulsatility and its speculated role in establishing an insulin-like growth factor 1 set-point for maintaining anabolic metabolism. Our results suggest that chronic treatment with ghrelin antagonists will have little effect on growth or appetite.
authors.affiliation: Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Yuxiang
authors.initials: Y
authors.lastname: Sun
authors.forename: Pei
authors.initials: P
authors.lastname: Wang
authors.forename: Hui
authors.initials: H
authors.lastname: Zheng
authors.forename: Roy G
authors.initials: RG
authors.lastname: Smith
mesh_terms: D000818:Animals; D001066:Appetite / Q000187:drug effects*; D001483:Base Sequence; D001823:Body Composition; D001835:Body Weight; D015519:Bone Density; D017931:DNA Primers; D005215:Fasting; D054439:Ghrelin; D013006:Growth Hormone / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D036361:Peptide Hormones / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D011986:Receptors, Somatotropin / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D015183:Restriction Mapping; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D017931:DNA Primers; D054439:Ghrelin; D036361:Peptide Hormones; D011986:Receptors, Somatotropin; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone