in size and number, also suggesting that reduced GH mRNA
is accompanied by hypoplasia of somatotropes in this model.
Taken together with the results from bGH mice, diminished
GHRH receptor signaling seems to be responsible for both
reduced murine GH mRNA expression and hypoplasia of
We showed that the expression of IGF-I in pituitary of
GHA was comparable to those of control littermates despite
low GH action and low concentrations of circulating IGF-I.
It should be noted that murine GH mRNA levels were in-
creased (Fig. 4) and locally produced MT-bGH (G119K) was
negligible in pituitary gland (Table 3). Unexpectedly, pitu-
itaries of lit/lit mice and lit/⫹ mice also showed comparable
levels of IGF-I mRNA in pituitary gland despite reduced
expression of local GH as well as circulating GH in lit/lit mice.
One possible explanation is that GH-independent factors
may maintain local production of IGF-I in chronic state of
reduced GH action such as lit/lit or GHA mice. It is inter-
esting that pituitaries of other animal models with low cir-
culating IGF-I levels induced by streptozotocin (31) or food-
deprived (32) also demonstrated no changes of IGF-I mRNA
in pituitary gland. In contrast, we showed that IGF-I mRNA
levels in pituitary of bGH mice were increased significantly,
suggesting that excessive GH played an additive role to
stimulate IGF-I expression in pituitary gland. Our results
also confirmed the previous report demonstrating that GH
stimulates the IGF-I expression in pituitary gland in an en-
docrine rather than autocrine/paracrine fashion (11). Fagin
et al. (11) evaluated pituitary IGF-I gene expression in rats
harboring sc implanted somatomammotropic tumors. The
pituitary IGF-I gene expression was stimulated in these an-
imals despite reduced pituitary GH mRNA expression.
Therefore, they concluded that stimulated pituitary IGF-I
mRNA appeared to be dependent on endocrine, and not
paracrine, pituitary GH concentrations. Our results using
bGH mice also demonstrated that pituitary IGF-I mRNA
levels in bGH mice were approximately twice as high as
those in control mice, whereas pituitary GH mRNA levels in
bGH mice were 14% of those in control mice.
In contrast to the results from liver, GHR mRNA levels in
pituitary were not statistically different in all three animal
models we used. In addition, we confirmed that GHR mRNA
levels in pituitary were extremely low compared with 18S
rRNA (Fig. 6). Low levels of GHR mRNA may be responsible
for reduced GH responsiveness, and for unaltered IGF-I
mRNA levels in pituitary of all mice we used except of bGH
mice. Moreover, our results showed that there was no cor-
relation between IGF-I and GHR mRNA levels in pituitary
gland in any mice group (Fig. 8), in contrast with the results
from liver (Fig. 7). The physiological significance of GHR in
pituitary is still unclear. The pituitary cells of GHR-disrupted
mice exhibited normal ultrastructural morphology except for
hyperplasia of somatotropes (33). However, Honda et al. (34)
detected the GHR mRNA using in situ hybridization tech-
nique on somatotropes, lactotropes, and some gonadotropes,
but not corticotropes or thyrotropes in mice. Moreover, they
demonstrated that GH stimulated IGF-I mRNA expression
directly in cultured mouse anterior pituitary cells, suggesting
that GHR mRNA detected in pituitary cells was translated
into the functional protein. The localizations of GHR in pi-
tuitary gland suggest that GHR might play a role in the cell
biology of somatotropes, lactotropes, and/or gonadotropes
although disrupted GHR signaling causes no morphological
changes on these cells (33).
There are several distinct 5⬘ untranslated region variants
in mouse GHR (35, 36). Expression of each transcript is reg-
ulated in a tissue- and developmental stage-specific manner.
The difference of regulation of GHR expression between liver
and pituitary may be explained by use of different tran-
scripts. Further investigation is required to clarify the reg-
ulation of GHR in pituitary gland.
In conclusion, our results showed that regulation of GHR
as well as IGF-I mRNA levels are tissue specific. There was
a significant correlation in the mRNA levels between hepatic
GHR and IGF-I. The local expression of GHR may play a role
to regulate GHR signaling in a tissue-specific manner to
maintain the local homeostasis.
We are grateful to Dr. Bruce Gaylinn, Amy Holland, and Pattie
Hellmann for their excellent technical assistance.
Received November 3, 2003. Accepted January 7, 2004.
Address all correspondence and requests for reprints to: M. O. Thor-
ner, Box 800466, Department of Internal Medicine, University of Vir-
ginia, Charlottesville, Virginia 22908. E-mail: email@example.com.
This work was supported in part by a grant from Foundation for
Growth Science in Japan (to K.I.) and by a grant from Pharmacia Corp
(to M.O.T.) and a gift to the laboratory by Mr. and Mrs. Sal Ranieri. J.J.K.
is supported, in part, by the state of Ohio’s Eminent Scholar Program that
includes a gift by Milton and Lawrence Goll and by DiAthegen, LLC.
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