New Experimental Approaches To Study Gh Effects In The

An insight into many aspects of normal physiology has been obtained from the study of mutations in animals. Originally, such animal models were generated by recognizing spontaneous mutations, but the ability to manipulate the genome makes it possible to introduce specific genetic mutations to advance our understanding of the underlying mechanisms involving GH feedback in the CNS.

There are various animal models of GH deficiency in rodents that can be used as an alternative to hypophysectomy to avoid the loss of all the other pituitary hormones. In particular, a number of spontaneous mutations in mice have proved extremely useful in studying the GH axis, and the mutations responsible for some of these defects have been characterized. The Snell (dw/dw) and Jackson (dwj/dwj) dwarf mice have mutations of the transcription factor Pit-1 (112), which causes profound deficiency in GH as well as in PRL and TSH. Most recently, the mutation in the Ames dwarf has also been identified, as a transcription factor Propl (113), acting earlier than Pit-1 in pituitary differentiation, but still affecting the same cell types. In addition, the defect in GH production in the little (lit/lit) mouse has now been shown to be caused by a defective GHRH receptor (114). There are also rat models that have arisen spontaneously, such as the spontaneous dwarf rat (dr/dr), which has a mutation in the GH gene itself causing premature termination of the protein sequence (115). Another dwarf rat (dw/dw) is homozygous recessive for a specific GH-deficient dwarf phenotype (116) associated with a defect in signal transduction although the mutation has not yet been identified (117,118). Where examined, all these rodent mutations causing GH deficiency are associated with increases in GHRH expression, and to a lesser extent, decreases in PeN SRIF expression as a secondary consequence of GH deficiency, some of which may be reversed with GH excess (119,120).

On the other hand, there are conditions in humans in which GH secretion is intact or even increased, but the GH is ineffective because of mutations in the GHR resulting in Laron-type dwarfism. The high spontaneous GH secretion in this condition is probably caused by a combination of lack of GH and IGF-1 feedback. IGF-1 replacement in these individuals suppresses GH secretion (121) just as it does in normal individuals subjected to fasting-induced increases in GH secretion (122). A mouse model with the GHR gene

Fig. 7. GH secretory patterns obtained during an 8-h sampling period from a normal rat (A) or a rat infused intracerebroventricularly with antisense oligonucleotides against the rat GHR at 2 nmol/h (B). Antisense GHR treatment increased basal, peak height and peak area of GH secretion and reduced the interval between GH secretory peaks compared with control animals. Redrawn from ref. 3.

Fig. 7. GH secretory patterns obtained during an 8-h sampling period from a normal rat (A) or a rat infused intracerebroventricularly with antisense oligonucleotides against the rat GHR at 2 nmol/h (B). Antisense GHR treatment increased basal, peak height and peak area of GH secretion and reduced the interval between GH secretory peaks compared with control animals. Redrawn from ref. 3.

knockout has only recently been announced (123). Although not yet characterized, it will be extremely interesting to study the hypothalamic changes in this animal and their reversibility with IGF-1 treatment so that the effects of IGF feedback on GHRH and SRIF may be evaluated separately from effects of GH.

Another approach to GH insensitivity that has recently been exploited is to use antisense oligonucleotides against the GHR to reduce the effectiveness of direct feedback at the hypothalamus (3). The effects of central administration of antisense GHR oligonucleotides were readily evident in the profile of GH secretion (Fig. 7). The antisense oligo-nucleotides reduced GHR expression, presumably reducing GH feedback, thereby inducing a secondary increase in release of GHRH and/or reduction in SRIF. The effect was specific for GHRs with no effect on GH when antisense against PRL receptors was used. The resultant increased GH peak amplitude through levels, and the number of GH peaks compared to controls provide further direct evidence implicating a role of CNS GHRs in GH autofeedback control (3).

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