Ghghr Autoregulation

In peripheral tissues, particularly liver, GH appears to regulate the abundance of its own receptors. Acutely, GH downregulates GH binding sites in the liver (33). Chronic treatment increases hepatic GH binding (34), although this requires continuous rather than intermittent GH replacement (35). It is not clear whether GHRs in the CNS are sensitive to different patterns of GH quite separately from their effects on growth. Differential sensitivity to different aspects of the GH secretory pattern has been clearly shown for hepatic receptors in GH-deficient rats (36), but it is doubtful whether such pattern sensitivities can be maintained to targets that lie behind a blood-brain barrier, which would certainly dampen, if not prevent, CNS exposure to rapid fluctuations in plasma GH. However, conversely, it may be that only the high plasma concentrations attained by secretory pulses of GH will enable sufficient GH to traverse these barriers to stimulate GHRs in some regions of the CNS.

Following hypophysectomy, GHR expression varies in a tissue-specific manner. For example, GHR transcripts have been shown to increase in muscle (37), increase or remain unchanged in liver (13,37), and decrease in the ovary (38) and adipose tissue (37). Central GHR expression is also sensitive to regulation by GH. Hypothalamic GHR expression decreases in hypophysectomy or in dwarf rats with specific Gh deficiency, and is restored by treating them with exogenous GH (Fig. 3) (39,40).

Most recent measurements have focused on hypothalamic abundance of GHR RNA. The aspect of these studies that always needs to be kept in mind is the mechanism of changing mRNA abundance. The authors and others assume they relate mostly to changes in GHR gene transcription, but particularly in the case of steroid regulation (41) they could also reflect changes in stabilization of mRNAs with no change in transcription rate. Although both mechanisms could reasonably be expected to lead to more translation product, this is by no means certain. Even if GH treatment can be shown to be associated with changes in transcription of GHR gene expression, these effects could also be secondary to changes in the activity of SRIF cells in PeN or NPY cells in ARC since the peptide products of these cells are also profoundly regulated by GH feedback. Nevertheless, the authors' working hypothesis is that the autoregulation of GHRs is part of the

Fig. 4. In situ hybridization histochemistry for GH receptor mRNA in brain and liver of normal rats (A,B), rats given estradiol for 14 d, (C,D), or given dexamethasone 14 d (E,F). Note the reduction in signal intensity with estradiol in brain, but not liver, and the reduction in GH receptor with dexamethasone in liver, but not brain. In situ hybridization with a probe specific for transcripts containing the GHRj 5'UTR shows prominent expression in liver (G), but no expression in brain (H). Redrawn from ref. 47.

Fig. 4. In situ hybridization histochemistry for GH receptor mRNA in brain and liver of normal rats (A,B), rats given estradiol for 14 d, (C,D), or given dexamethasone 14 d (E,F). Note the reduction in signal intensity with estradiol in brain, but not liver, and the reduction in GH receptor with dexamethasone in liver, but not brain. In situ hybridization with a probe specific for transcripts containing the GHRj 5'UTR shows prominent expression in liver (G), but no expression in brain (H). Redrawn from ref. 47.

autofeedback loop by which GH regulates its own secretion and action, both peripherally and in the CNS (40,42).

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