title: A postweaning reduction in circulating ghrelin temporarily alters growth hormone (GH) responsiveness to GH-releasing hormone in male mice but does not affect somatic growth.
abstract: Ghrelin was initially identified as an endogenous ligand for the GH secretagogue receptor. When administrated exogenously, ghrelin stimulates GH release and food intake. Previous reports in ghrelin-null mice, which do not exhibit impaired growth nor appetite, question the physiologic role of ghrelin in the regulation of the GH/IGF-I axis. In this study, we generated a transgenic mouse that expresses human diphtheria toxin (DT) receptor (DTR) cDNA in ghrelin-secretion cells [ghrelin-promoter DTR-transgenic (GPDTR-Tg) mice]. Administration of DT to this mouse ablates ghrelin-secretion cells in a controlled manner. After injection of DT into GPDTR-Tg mice, ghrelin-secreting cells were ablated, and plasma levels of ghrelin were markedly decreased [nontransgenic littermates, 70.6 +/- 10.2 fmol/ml vs. GPDTR-Tg, 5.3 +/- 2.3 fmol/ml]. To elucidate the physiological roles of circulating ghrelin on GH secretion and somatic growth, 3-wk-old GPDTR-Tg mice were treated with DT twice a week for 5 wk. The GH responses to GHRH in male GPDTR-Tg mice were significantly lower than those in wild-type mice at 5 wk of age. However, those were normalized at 8 wk of age. In contrast, in female mice, there was no difference in GH response to GHRH between GPDTR-Tg mice and controls at 5 or 8 wk of age. The gender-dependent differences in response to GHRH were observed in ghrelin-ablated mice. However, GPDTR-Tg mice did not display any decreases in IGF-I levels or any growth retardation. Our results strongly suggest that circulating ghrelin does not play a crucial role in somatic growth.
authors.affiliation: Ghrelin Research Project, Translational Research Center, Kyoto University Hospital, 54 Shogin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan. ariyasu@kuhp.kyoto-u.ac.jp
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ariyasu
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Iwakura
authors.forename: Go
authors.initials: G
authors.lastname: Yamada
authors.forename: Naotetsu
authors.initials: N
authors.lastname: Kanamoto
authors.forename: Mika
authors.initials: M
authors.lastname: Bando
authors.forename: Kenji
authors.initials: K
authors.lastname: Kohno
authors.forename: Takahiro
authors.initials: T
authors.lastname: Sato
authors.forename: Masayasu
authors.initials: M
authors.lastname: Kojima
authors.forename: Kazuwa
authors.initials: K
authors.lastname: Nakao
authors.forename: Kenji
authors.initials: K
authors.lastname: Kangawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Akamizu
mesh_terms: D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D015519:Bone Density / Q000502:physiology; D004435:Eating / Q000235:genetics; D005260:Female; D054439:Ghrelin / Q000097:blood* / Q000235:genetics; D006128:Growth / Q000502:physiology*; D013006:Growth Hormone / Q000235:genetics / Q000378:metabolism*; D013007:Growth Hormone-Releasing Hormone / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D007031:Hypothalamus / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010902:Pituitary Gland / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012737:Sex Factors
chemical_list: D054439:Ghrelin; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D013007:Growth Hormone-Releasing Hormone