The growth hormone (GH)-axis of GH receptor/binding protein gene-disruptedand metallothionein-human GH-releasing hormone transgenic mice: Hypothalamic neuropeptide and pituitary receptor expression in the absence and presence of GH feedback

Elevation of circulating GH acts to feed back at the level of the hypothala mus to decrease GH-releasing hormone (GHRH) and increase somatostatin (SRIF ) production. In the rat, GH-induced changes in GHRH and SRIF expression ar e associated with changes in pituitary GHRH receptor (GHRH-R), GH secretago gue receptor (GHS-R), and SRIF receptor subtype messenger RNA (mRNA) levels . These observations suggest that GH regulates its own synthesis and releas e not only by altering expression of key hypothalamic neuropeptides but als o by modulating the sensitivity of the pituitary to hypothalamic input, by regulating pituitary receptor synthesis. To further explore this possibilit y, we examined the relationship between the expression of hypothalamic neur opeptides [GHRH, SRIF, and neuropeptide Y (NPY)] and pituitary receptors [G HRH-R, GHS-R, and SRIF receptor subtypes (sst2 and sst5)] in two mouse stra ins with alterations in the GH-axis; the GH receptor/binding protein gene-d isrupted mouse (GHR/BP -/- ) and the metallothionein promoter driven human GHRH (MT-hGHRH) transgenic mouse. In GHR/BP-/- mice, serum insulin-like gro wth factor I levels are low, and circulating GH is elevated because of the lack of GH negative feedback. Hypothalamic GHRH mRNA levels in GHR/BP-/- mi ce were 232 +/- 20% of GHR/BP+/+ littermates (P < 0.01), whereas SRIF and N PY mRNA levels were reduced to 86 +/- 28 and 52 +/- 3% of controls, respect ively (P < 0.05; ribonuclease protection assay). Pituitary GHRH-R and CHS-R mRNA levels of GHR/BP-/- mice were elevated to 275 +/- 55% and 319 +/- 68% of GHR/BP+/+ values (P < 0.05, respectively), whereas the sst2 and sst5 mR NA levels did not differ from GHR/BP intact controls as determined by multi plex RT-PCR. Therefore, in the absence of GH negative feedback, both hypoth alamic and pituitary expression is altered to favor stimulation of GH synth esis and release. In MT-hGHRH mice, ectopic hGHRH transgene expression elev ates circulating GH and insulin-like growth factor I. In this model of GH e xcess, endogenous (mouse) hypothalamic GHRH mRNA levels were reduced to 69 +/- 60% of nontransgenic controls, whereas SRIF mRNA levels were increased to 128 +/- 6% (P < 0.01). NPY mRNA levels were not significantly affected b y hGHRH transgene expression. Also, MT-hGHRH pituitary GHRH-R and GHS-R mRN A levels did not differ from controls. However, sst2 and sst5 mRNA levels i n MT-hGHRH mice were increased to 147 +/- 18% and 143 +/- 168 of normal val ues, respectively (P < 0.05). Therefore, in the presence of GH negative fee dback, both hypothalamic and pituitary expression is altered to favor suppr ession of GH synthesis and release.