Ghrelin stimulation of growth hormone release and appetite is mediated through the growth hormone secretagogue receptor.
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.
Sun
Yuxiang
Y
Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA.
Wang
Pei
P
Zheng
Hui
H
Smith
Roy G
RG
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
D017931:DNA Primers; D054439:Ghrelin; D036361:Peptide Hormones; D011986:Receptors, Somatotropin; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone