Mechanism Of Feedback

Although expression of GHRs can be detected in the pituitary gland (82), there is little evidence in favor of a direct effect of GH to inhibit its own release at the pituitary (83,84), but rather that it acts in the hypothalamus to target the peptidergic systems controlling GH release (76,85,86). This may also have implication for the time-scale of GH feedback. Although acute effects on GH release may be easy to demonstrate, the more physiologi

Fig. 5. Effects of iv infusions of human GH on spontaneous GH secretion in a conscious male rat. (Left): saline infusion. (Right): hGH infusion at 60 ^g/h for 6 h (dark bar). Serial blood samples were withdrawn automatically and assayed for rGH. From ref. 135.

Fig. 5. Effects of iv infusions of human GH on spontaneous GH secretion in a conscious male rat. (Left): saline infusion. (Right): hGH infusion at 60 ^g/h for 6 h (dark bar). Serial blood samples were withdrawn automatically and assayed for rGH. From ref. 135.

cally relevant timescale may be much more prolonged since the GH feedback on pulsatile GH release is maintained with time (86). In the case of GH deficiency, whether partial or total, specific or nonspecific, hypothalamic GHRH expression is increased (87), whereas GH treatment reverses these changes (40). Conversely, hypophysectomy reduces SRIF expression in the hypothalamus, whereas excess GH stimulates hypothalamic SRIF synthesis and release (76,88). Changes in GHRH activity may be responsible for altering the hypothalamic drive to maintain the somatotroph proliferation so that the main physiological role of GH feedback on GHRH is to regulate the GH secretory reserve over a much longer timescale. Since these changes in GHRH and SRIF can be readily observed with GH, but not with IGF-1 alone (52), and both these cells either express GHRs themselves or are in close proximity to cells that do so, it is likely that these provides sites of direct feedback for GH and not secondary to peripheral IGF-1 generation (86), although local generation of IGF-1 in response to GH action in the CNS cannot be ruled out.

Other evidence for an effect of GH is provided by studies showing that c-Fos expression in some specific brain regions is also stimulated by exogenous GH (89-91). Although GHRH expression is markedly increased in GH deficiency, this may be mediated indirectly via lack of GH feedback on NPY cells. Chronic administration of NPY icv markedly reduces pituitary and plasma GH, whereas intraventricular injection of NPY antiserum causes a significant increase in plasma GH (92,93). Chan et al. showed that NPY expression is GH sensitive and may be the primary target for GH feedback in the ARC (94). The authors have also found that ARC NPY mRNA is reduced in GH-deficient dw/dw dwarf rats, and this deficit is corrected by GH administration (95). Therefore, it is easy to construct a hypothesis whereby GHRs exert negative feedback on GHRH-induced GH release via ARC NPY cells, whereas the effects on SRIF could most simply be explained via direct stimulatory effects on PeN SRIF-positive and GHR-positive cells. However, ARC NPY expression of GHR may not be confined to the control of GH. For

Fig. 6. Distribution of GHS-R, GHRH, and NPY transcripts in dw/dw rats. Sections were hybridized for (A) GHS-R, (B) GHRH, and (C) NPY expression and are shown in dark-field. Note the ventral expression of GHS-R in ARC compared to the more lateral expression in GHRH, and the lack of NPY expression in VMN, which shows prominent GHS-R expression. Scale bar is 1 mm. From ref. 99.

Fig. 6. Distribution of GHS-R, GHRH, and NPY transcripts in dw/dw rats. Sections were hybridized for (A) GHS-R, (B) GHRH, and (C) NPY expression and are shown in dark-field. Note the ventral expression of GHS-R in ARC compared to the more lateral expression in GHRH, and the lack of NPY expression in VMN, which shows prominent GHS-R expression. Scale bar is 1 mm. From ref. 99.

example, NPY is implicated in regulation of food intake, so GH action on these cells might be involved in coordinating food intake drive with activity in the GH/IGF-1 axis affecting food utilization, rather than being primarily involved in growth regulation.

GHR expression is also found in extrahypothalamic areas and in other hypothalamic nuclei associated with peptides, which may or may not be directly involved in GH control. For example, CRF inhibits GH secretion whereas a CRF antagonist increases it (96). It is not clear whether CRF normally participates in the regulation of GH, but if so it could be regulated by GH feedback, which might then explain the GHR expression in PVN (Fig. 1), the primary site of synthesis of hypothalamic CRF. GH secretagogues may also have a role in central GH control. The recently identified GH secretogogue receptor (GHS-R) is expressed in the hypothalamus (97,98), and the authors have recently demonstrated that the GHS-R gene is expressed within the ARC in areas that overlap with the expression of NPY and GHRH (Fig. 6). It has been suggested that this receptor and its putative ligand may have a role in regulating central GH actions, because the expression of this receptor is positively correlated with GHRH, inversely correlated with NPY, and negatively regulated by GH (99). GH secretagogues activate neuronal firing and c-Fos expression in the hypothalamus (100) in a cell population that also includes GHR-expressing cell (101), but the more widespread central physiology of this new receptor and its relationship to GH feedback remains to be explored.

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