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.
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.
Ariyasu
Hiroyuki
H
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
Iwakura
Hiroshi
H
Yamada
Go
G
Kanamoto
Naotetsu
N
Bando
Mika
M
Kohno
Kenji
K
Sato
Takahiro
T
Kojima
Masayasu
M
Nakao
Kazuwa
K
Kangawa
Kenji
K
Akamizu
Takashi
T
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
D054439:Ghrelin; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D013007:Growth Hormone-Releasing Hormone