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Hypothalamic Growth Hormone Secretagogue-Receptor (GHS-R) Expression Is Regulated by Growth Hormone in the Rat

Division of Neurophysiology, National Institute for Medical Research, The Ridgeway, Mill Hill, London, NW7 IAA, United Kingdom; and Merck Research Laboratories, Rahway, New Jersey 07065

Address all correspondence and requests for reprints to: I. C. A. F. Robinson, Division of Neurophysiology, National Institute for Medical Research, The Ridgeway, Mill Hill, London, NW7 IAA, United Kingdom. E-mail: irobins{at}nimr.mrc.ac.uk

	Abstract

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Synthetic GH secretagogues (GHSs) act via a receptor (GHS-R) distinct from that for GH-releasing hormone (GHRH). We have studied the hypothalamic expression and regulation of this receptor by in situ hybridization using a homologous riboprobe for rat GHS-R. GHS-R mRNA is prominently expressed in arcuate (ARC) and ventromedial nuclei (VMN) and in hippocampus, but not in the periventricular nucleus. Little or no specific hybridization could be observed in the pituitary under the conditions that gave strong signals in the hypothalamus. No sex difference in GHS-R expression was found in ARC or hippocampus, though expression in VMN was lower in males than in females. Compared with GHRH and neuropeptide Y (NPY), GHS-R was expressed in a distinct region of ventral ARC, and in regions of VMN not expressing GHRH or NPY. GHS-R expression was highly sensitive to GH, being markedly increased in GH-deficient dw/dw dwarf rats, and decreased in dw/dw rats treated with bovine GH (200 µg/day) for 6 days. Similar changes were observed in GHRH expression, whereas NPY expression was reduced in dw/dw rats and increased by bGH treatment. Continuous sc infusion of GHRP-6 in normal female rats did not alter ARC or VMN GHS-R expression. Our data implicate ARC and VMN cells as major hypothalamic targets for direct GHS action. The sensitivity of ARC GHS-R expression to modulation by GH suggests that GHS-Rs may be involved in feedback regulation of GH.

	Introduction

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IN RECENT YEARS, a variety of peptide and nonpeptide GH secretagogues (GHSs) have been developed from the prototype GHRP-6 hexapeptide described by Bowers and his colleagues (1, 2, 3). Initial studies in vitro concentrated on the direct GH-releasing effects of GHSs from pituitary cells (4), activating GH release via G-protein coupled receptors and intracellular signaling pathways different (5, 6) from those for GH-releasing hormone (GHRH). Later in vivo studies suggested that GHSs also act in the hypothalamus to activate a subpopulation of arcuate (ARC) neurones to alter their electrical activity and activate expression of the immediate early gene c-Fos (7, 8, 9). Attenuation of GHS-induced GH release by GHRH antisera (10) and release of GHRH in hypophysial portal blood following GHS administration (11) implicated ARC GHRH cells as targets for GHSs. However, the action of GHSs is not restricted to GHRH neurons, as Fos responses to GHSs were also seen in the ventromedial portion of the ARC, where few GHRH cells are localized, and a higher proportion of these Fos-responsive cells express NPY than express GHRH (12). GHSs also elicit these hypothalamic effects in animals with nonfunctional GHRH receptors (13).

Studies with radiolabeled peptide and nonpeptide GHSs identified binding sites in both pituitary and hypothalamic membranes (14, 15, 16), leading to the identification, cloning, and sequencing of the first specific GHS receptor (GHS-R) in swine and human (17). This work established the existence of an endogenous receptor mediating GHS-induced GH release and confirmed its expression in both pituitary and hypothalamus (17). The rat GHS-R homolog has recently been cloned (18) and an initial mapping study of GHS-R identified its expression in both hypothalamic and extrahypothalamic sites in the rat brain (19). However, nothing is yet known about the regulation of this receptor in brain. Semiquantitative in situ hybridization has proved useful in studying the distribution and expression of the hypothalamic factors regulating GH secretion and their sensitivity to GH feedback (20, 21). Accordingly, we have used this method to study the expression of GHS-R in the rat hypothalamus and its regulation by GH, using a homologous riboprobe corresponding to the full length rat GHS-R cDNA.

	Materials and Methods

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Animals and treatments
All experiments were carried out under the appropriate Institutional and National ethical guidelines. Normal and dwarf (dw/dw) rats (22) of the NIMR:AS strain (8 weeks of age), were bred at the National Institute for Medical Research, Mill Hill, and housed under controlled conditions (22 C: 12-h light, 12-h dark cycle) with free access to food and water. For GH replacement, a group of five female dwarf animals were briefly anesthetized with halothane for sc insertion of osmotic minipumps (Alza Corporation, Palo Alto, CA) delivering recombinant bovine GH (bGH, courtesy of Dr. W. Baumbach, Cyanamid, NJ) at 200 µg/day for 6 days. GH treated dwarf rats were compared with age-matched normal and dwarf female rats. GHRP-6 was given by sc implantation of osmotic minipumps (Alza Corporation), delivering 100 µg/day to a group of eight adult normal female rats, while a control group of eight animals received saline infusions. All animals were killed at the same time of day by ip overdose of Sagatal (May & Baker, Dagenham, Essex, UK) and the brains removed, frozen on dry ice and stored at -70 C. Coronal brain sections (12 µm) through the ARC, periventricular nucleus (PeN) or paraventricular nucleus (PVN) were cut at -16 C, thaw-mounted onto gelatin and chrome alum-coated slides, and stored at -70 C until use for in situ hybridization.

Probe preparation
Full-length antisense and sense transcripts incorporating ³⁵S-UTP (NEN Research Products, Stevenage, Herts, UK) were generated from appropriate plasmid probes using an Sp6/T7 transcription kit according to the manufacturer’s instructions (Boehringer Mannheim, Lewes, East Sussex, UK). Transcripts were stored at -70 C until use. The GHS-R probe was generated from the full-length rat GHS-R cDNA (18). Riboprobes for GHRH were generated from a 500 bp HindIII fragment of exon 5, subcloned from a GHRH cDNA (23) (kindly provided by Dr. K. E. Mayo, Northwestern University, Evanston, IL) into pGEM 7Z. The NPY riboprobe used was a 370bp PCR fragment of a rat NPY cDNA corresponding to nucleotides 79–449 cloned into pGEM 5Zf (courtesy of Dr. D. M. Flavell, NIMR).

In situ hybridization
This was carried out essentially as previously described (21, 24). Briefly, sections were fixed in 4% paraformaldehyde, acetylated, dehydrated, and delipidated in chloroform. Sections were hybridized overnight at 50 C, in buffer containing 1 x 10⁶ cpm/slide of denatured riboprobe in 50% formamide, 0.025 M Tris, pH 7.5, 0.001 M EDTA, pH 8.0, 0.4 M NaCl, 1 x Denhardt’s solution (0.02% Ficoll, 0.02% polyvinylpyrrolidone, and 0.02% BSA), and 10% dextran sulfate (mol wt 500,000), under Nescofilm coverslips (Bando Chemical Industries, Ltd., Kobe, Japan). Following hybridization, the slides were washed and then incubated in 20 µg/ml RNase A for 30 min at 37 C. Sections were then washed in 2 x SSC/50% formamide at 50 C, rinsed in water, then air dried.

Image analysis
Slides were apposed to autoradiographic film (Biomax MR, Kodak, Rochester, NY) for up to 7 days and the resulting images analyzed densitometrically, running the program called Image (W. Rasband, NIMH, Bethesda, MD). The values represent integrated optical density expressed in arbitrary units. For each transcript, comparisons were made with the same batch of labeled probe on sections from all animals exposed concurrently in Fig. 2. However, the relative abundance of the different peptide transcripts measured in Fig. 3 differed substantially, so different exposures were necessary to quantify these. Therefore, the optical density values should not be compared between the different panels in Fig. 3. For higher resolution images, some slides were then dipped in photographic emulsion NB2 (Kodak, Rochester, NY), made up according to the manufacturer’s instructions. Slides were exposed for 10–21 days then developed in D-18 developer (Kodak, Rochester, NY). The slides were counter stained in cresyl-fast violet, dehydrated, cleared in histoclear, and mounted in DPX.

View larger version (26K): [in this window] [in a new window]   Figure 2. Comparison of GHS-R transcript levels in male and female normal and dw/dw rats as measured by in situ hybridization histochemistry. A, Arcuate nucleus; B, ventromedial nucleus. Data are mean ± SEM, n = 6 in each group. *, P < 0.05; **, P < 0.01; ***, P < 0.001; a compared with normal male control; b compared with normal female control, using (A)Dunn’s or (B) Student Newman Kuels tests.

View larger version (30K): [in this window] [in a new window]   Figure 3. Effect of bovine GH (bGH) treatment on GHS-R, NPY, and GHRH expression in dw/dw rats. Sections from normal female rats (open bars), dw/dw female rats (hatched bars), and dw/dw female rats treated with bGH (200 µg/day) for 6 days (solid bars) were subjected to in situ hybridization using probes against (A, B and C) GHS-R; (D) GHRH or (E) NPY, and the signal quantified by image analysis. *, P < 0.05; ***, P < 0.001, compared with the control group. In this figure, the optical density values should not be compared between probes because different exposures were necessary to adjust for the large differences in relative abundance of these transcripts. Data are mean ± SEM, n = 5–6 in each group.

	Results

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Distribution of GHS receptor mRNA in normal rat brain
In normal animals, prominent expression of GHS-R transcripts was found in ARC and ventromedial nucleus (VMN), significant expression was also noted in CA1, CA3, and particularly dentate gyrus of the hippocampus, which was most abundant in the ventral region (Fig. 1A). In other sections, a weak signal was seen in the PVN but there no discernable hybridization in the PeN (data not shown). No signal was evident in consecutive sections hybridized with a sense probe (Fig. 1B). GHS-R expression in sections of pituitary gland was also examined under the same conditions, but no specific regional expression was detected (Fig. 1, E and F).

View larger version (142K): [in this window] [in a new window]   Figure 1. In situ hybridization of rat GHS-R mRNA in (A) normal female rat brain hybridized with an antisense GHS-R probe and a consecutive section from the same animal (B) hybridized with sense control probe. Note the prominent signal in the arcuate nucleus (ARC), ventromedial nucleus (VMN), hippocampus, and dentate gyrus (DG). C, GHS-R expression in a section of female dw/dw rat brain exposed for the same time as (A) and (B). D, Higher resolution image of a female dw/dw ARC nucleus section dipped in emulsion at x25 magnification. Individual cells in ARC (arrows) are decorated with clusters of silver grains. E and F, GHS-R expression in normal female rat pituitary gland hybridized under the same conditions, with antisense (E) or sense (F) probes. No specific signal could be detected. The scale bars represent 1 mm.

To examine whether these changes in dwarf rats could be reversed by GH treatment, sections were also analyzed from a group of five dw/dw rats given bGH (200 µg/day sc for 6 days) by osmotic minipump. Administration of bGH completely reversed these changes in ARC and VMN with GHS-R expression falling in ARC and VMN to levels significantly below those in normal rats (P < 0.05 in both cases) (Fig. 3, A and B). The raised levels of GHS-R expression in dwarf hippocampus were also reduced by bGH but not significantly below normal (Fig. 3C). GHRH and NPY transcripts were also measured in consecutive sections from the same animals. As expected, GHRH levels were significantly raised (P < 0.05) in dwarf rats and normalized by GH administration (Fig. 3D), whereas NPY levels in the ARC were reduced in dwarf rats (P < 0.001), and increased by GH treatment (P < 0.05) (Fig. 3E).

Distribution of GHS-R, GHRH, and NPY transcripts
Serial sections from some animals were also hybridized to GHRH or NPY riboprobes and their distributions compared with that of GHS-R. Although these signals overlapped in ARC, particularly with the more abundant NPY-positive cells, the overall patterns were quite distinct (Fig. 4). GHS-R was also expressed in regions of VMN, not showing NPY or GHRH expression.

View larger version (58K): [in this window] [in a new window]   Figure 4. Distribution patterns of GHS-R, GHRH, and NPY transcripts in ARC and VMN in dw/dw rats. Consecutive sections were hybridized with riboprobes against (A) GHS-R (B) GHRH and (C) NPY and are shown in dark field. Although there was some overlap, all three transcripts shows distinct patterns of distribution. Note the ventral expression of GHS-R in ARC compared with the more lateral expression in GHRH in ARC, and the lack of NPY expression in ventral areas of VMN showing prominent GHS-R expression. Scale bar, 1 mm.

	Discussion

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Following the cloning of the rat GHS-R (18), in situ hybridization using pairs of ³³P-labeled oligonucleotide probes has been used to identify numerous sites of GHS-R expression in both hypothalamic and extrahypothalamic areas of the normal rat brain (19). In the present study, we used ³⁵S-labeled riboprobes generated from the full length rat GHS-R (18) and compared the distribution of GHS-R expression with that of GHRH and NPY and their responses to varying GH status. The GHS-R riboprobe provided a strong and specific signal in the major hypothalamic structures with moderate exposure times, and the distribution of GHS-R expression was broadly similar to that reported earlier (19), except that we were unable to visualize GHS-R expression in the pituitary gland in this study.

This may simply be a matter of sensitivity because GHS-R transcripts can be demonstrated in rat pituitary RNA extracts by RNAse protection but with relatively large amounts of poly A+ RNA (18). However, GHS-R transcripts were readily detectable in the hypothalamus by in situ hybridization under the same conditions, so their abundance may be much greater, consistent with the idea that the hypothalamus is the major physiological target for GHS-induced GH release in vivo (10, 25, 26). Another explanation might be heterogeneity of pituitary GHS-R mRNAs. The existence of subtypes of pituitary GHS-Rs has been inferred from analog studies (27). If these exist, their transcripts might be recognized differentially by the short oligonucleotides used earlier (19) vs. the full length riboprobes corresponding to GHS-R type 1a, used here. A truncated form of the GHS-R transcript (type 1b) arises by alternative splicing (17, 18), but this would also be recognized by the riboprobe used in the present study. Furthermore, we found no evidence for differential expression of type 1b GHS-Rs in the rat brain (19).

The demonstration of significant GHS-R gene expression in ARC confirms earlier work suggesting that this is a major target for GHS action. Following peripheral GHS administration, increases in GHRH release or pulsatility in portal blood have been demonstrated (11, 28), and increased GHRH mRNA levels in the posterior region of the ARC have also been reported in dwarf rats treated with GHRP-6 (29). The distribution of cells showing a Fos response to GHS-R (7, 9) parallels the GHS-R positive cells in ARC and includes the narrow ventrolateral tract of GHRH neurones extending toward the VMN. Although some of the cells that respond to GHSs with Fos expression contain GHRH, a larger proportion appear to be NPY cells (12). However, comparison of the overall distribution of GHS-R cells with that of NPY and GHRH in consecutive sections shows that, while they overlap in ARC, their distributions are distinct. Quantification of the extent of their co-expression will require double labeling studies.

In addition to GHRH, the other endogenous peptide controlling GH release is SRIF (30); there is indirect evidence to suggest that GHSs may also interact with SRIF (29, 31). However, specific GHS-R mRNA signal was not seen in PeN, (the location of the major hypophysiotropic SRIF-containing cell bodies), so our results suggest that PeN SRIF cells are not major direct targets for GHS action. However, in situ hybridization only detects mRNA, so it is possible that the GHS-R protein could be transported to terminals projecting to PeN (32). GHS-Rs could also be expressed on SRIF neurons within the ventral ARC (33), which may regulate GHRH via SRIF receptors on GHRH cells (34).

GH deficiency could also alter the production of the unidentified ligand for GHS-R, which might itself alter GHS-R expression. Desensitization to the effects of GHSs has been documented (3, 6) and could occur at the level of GHS-R gene transcription. We observed no significant changes in ARC or VMN GHS-R gene expression following continuous sc GHRP-6 infusions but cannot exclude the possibility that a different duration, route, or pattern of GHS administration might affect GHS-R gene expression, because GH release and growth stimulation is sensitive to these parameters of GHS administration (3, 8, 31, 35).

GHS-R is also strongly expressed in regions of the VMN that are neither GHRH-positive nor show Fos responses to GHSs. Indeed, expression in VMN was more intense than in ARC, delineated in at least two distinct subregions. The cell type involved is unknown and does not correspond to NPY (present study) or SRIF distribution (P. A. Bennett, unpublished data) in this nucleus. The immediate role for GHS-R in VMN is unclear. As VMN GHS-R expression was also sensitive to GH status, it could be involved in GH control, conceivably via projections to ARC or PeN. However, GHSs have other hypothalamic effects, for example to release ACTH probably by releasing, or synergizing with, CRF or AVP (26, 36). These effects could be mediated by GHS action in the PVN itself, or via projections from GHS-R-positive cells in VMN or ARC (32). VMN is also involved in the regulation of food intake, and this is known to be stimulated by GHSs independently from their effects on GH in rats (37). As no Fos expression is seen in VMN following GHS administration (7), other cellular responses to GHSs will need to be identified to confirm that GHS-R transcripts in sites other than ARC are indeed translated to functional GHS receptors.

GH regulates its own release through negative feedback loops acting in the hypothalamus via GH receptors in ARC and PeN (20, 21). In GH deficiency, PeN SRIF expression is reduced, whereas ARC GHRH expression is increased, and these changes are reversed in GH excess, implicating GH feedback as an important long-term regulator of these systems (38). GH receptors in ARC are expressed on NPY cells and on some GHRH-positive cells (39, 40) and are also sensitive to GH feedback (21). If GHS-R expression in the ARC is involved in the endogenous control of GH release, we reasoned that GHS-R expression might also be sensitive to GH feedback. This proved to be the case. Brains from dw/dw rats with chronic severe isolated GH deficiency (22) showed an obvious increase in GHS-R signal compared with normal controls, not only in ARC, but also in other brain areas. Furthermore, treatment of dw/dw rats with bGH reduced GHS-R transcript abundance to normal levels in the VMN and significantly lower than normal levels in ARC. These changes parallel the changes in GHRH expression in dw/dw rats with or without GH treatment, and were diametrically opposite to the changes seen in NPY or GH receptor expression (21, 41).

The simplest explanation for our results is that GH feedback regulation of GHRH (39, 40) also regulates GHS receptor expression in a parallel fashion. If so, both GHS-R and the endogenous GHS ligand(s) may be part of the GH feedback system. The GHS system may fulfill a slightly different role than GHRH because the latter is also important for somatotroph proliferation via activation of adenylate cyclase (42), whereas the effects of GHSs seem to be primarily on GH release, via a different intracellular mechanism (43, 44) and only indirectly affect cAMP via synergism with GHRH (5, 45).

It is possible that the changes in GHS-R expression induced by GH are indirect. Expression of GHS-R could be inhibited by IGF-1, which is also reduced in GH deficiency and increased in GH excess, and there is some evidence that effects of GHSs on GH release may be reduced by sustained increases in IGF-1 (46). However, this issue will need to be addressed in other studies in which IGF-I is administered and/or endogenous plasma IGF-1 levels measured.

What might be the functional significance of changing GHS-R expression with GH status? The pituitary GH response to GHRP-6 is low in dw/dw rats (47) but this probably reflects the reduced amount of pituitary GH available, rather than reduced sensitivity to GHSs. This is not reflected in the hypothalamic responses to GHSs, because dw/dw rats show a robust ARC Fos response to GHSs (13). This difference is even more pronounced in the lit/lit mouse that exhibits a marked hypothalamic Fos response to GHSs (13), with no detectable pituitary GH response to GHSs (48).

Increased hypothalamic GHS-R expression in GH deficiency could lead to enhanced sensitivity to the central actions of GHSs. Both GH release (35) and Fos responses (8) are sensitive to lower doses of GHSs when administered centrally rather than peripherally, but it is not clear whether this sensitivity is increased in GH-deficient animals. It is also important to recall that some ARC cells are inhibited by GHS administration (8) and that larger doses of GHSs administered via the icv route can inhibit GH release in the conscious rat (49). Thus, the effects of changing GHS-R expression in several hypothalamic areas may be difficult to predict. GHS responses are greater in females than in males (50), but the only sex difference in hypothalamic GHS-R expression we observed was in the VMN; no sex difference in ARC GHS-R expression was found.

Although not the primary focus of this study, we confirmed the conspicuous expression of GHS-R in the hippocampus (19). Although not an obvious site of GH control, we have previously shown that hippocampal GH receptors are also regulated by GH and gonadal steroids (21, 24). We report here that hippocampal GHS-R expression was also sensitive to GH regulation, being increased in GH-deficient dwarves and normalized by GH treatment. GHS-Rs are also expressed in many other regions of the rat brain (19), which do not express GH receptors in adulthood. As GHSs are now known to have activities that appear unrelated to GH release (37, 51), further studies on the regulation of GHS-R expression in these extrahypothalamic CNS sites are clearly warranted.

	Acknowledgments

 
We are grateful to Drs. Kelly Mayo, Dave Flavell, and Sara Wells for the GHRH and NPY clones, and to Dr. Bill Baumbach for providing bovine GH.

Received May 1, 1997.

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