Reduction in hypophyseal growth hormone and prolactin expression due to deficiency in ghrelin receptor signaling is associated with Pit-1 suppression: relevance to the immune system.
In mice and in rats, reduced levels of the growth hormone secretagogue receptor (GHS-R1a) results in reduced body weight and lower levels of serum insulin-like growth factor I (IGF-I). However, the mechanism leading to these impairments has not been elucidated. Studies in primary cultures of pituitary cells from very young mice have shown that GHS-R1a agonists, including ghrelin, increase expression of the pituitary-specific transcription factor (Pit-1) that is critical for differentiation of pituitary cells into somatotrophs, lactotrophs, and thyrotrophs. Hence, we hypothesized that ablation of Ghsr would reduce Pit-1 expression and as a consequence reduce growth hormone (GH) production explaining the lower body weight of Ghsr-/- mice. Here, we now show that Pit-1 mRNA levels are significantly lower in the pituitary gland of Ghsr-/- mice compared to wild-type littermates and also with advancing age. This Pit-1 loss is associated with reduced GH mRNA and fewer GH producing cells. To determine whether reduced GH is caused by reduced expression of Pit-1 in Ghsr-/- mice, we also measured prolactin (PRL) expression in the pituitary gland and in the circulation. PRL mRNA was significantly reduced in Ghsr-/- mice compared to wild-type littermates and fewer cells expressed PRL. The reduction in expression of both GH and PRL is consistent with a Pit-1 regulated pathway and demonstrates that the GHS-R has an important role in the pituitary gland as a modulator of Pit-1 expression and provides a possible mechanism to explain the lower plasma IGF-1 and modestly reduced body weight exhibited by Ghsr-/- mice. We also believe that lower systemic and lymphoid hormone expression may also account, in part, for the enhanced thymic involution and reduced thymic output in Ghsr-/- mice.
Yang
Hyunwon
H
Laboratory of Immunology, National Institute on Aging-Intramural Research Program, 5600 Nathan Shock Drive, NIH, Baltimore, MD 21224, USA.
Dixit
Vishwa D
VD
Patel
Kalpesh
K
Vandanmagsar
Bolormaa
B
Collins
Gary
G
Sun
Yuxiang
Y
Smith
Roy G
RG
Taub
Dennis D
DD
D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D013006:Growth Hormone / Q000378:metabolism*; D007150:Immunohistochemistry; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009929:Organ Size; D010902:Pituitary Gland / Q000254:growth & development* / Q000378:metabolism*; D011388:Prolactin / Q000097:blood / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D054440:Receptors, Ghrelin / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050817:Transcription Factor Pit-1 / Q000378:metabolism*
D012333:RNA, Messenger; D054440:Receptors, Ghrelin; D050817:Transcription Factor Pit-1; D007334:Insulin-Like Growth Factor I; D011388:Prolactin; D013006:Growth Hormone