Neuroregulation of growth hormone secretion in domestic animals

Domestic Animal Endocrinology 20 (2001) 65– 87

Neuroregulation of growth hormone secretion in domestic animals C.D. McMahona,*, R.P. Radcliffa, K.J. Lookinglandb, H.A. Tuckera a

Department of Animal Science, Michigan State University, East Lansing, MI 48824, USA Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, USA

b

Received 27 October 2000; accepted 15 December 2000

Abstract Growth hormone (GH) is essential for postnatal somatic growth, maintenance of lean tissue at maturity in domestic animals and milk production in cows. This review focuses on neuroregulation of GH secretion in domestic animals. Two hormones principally regulate the secretion of GH: growth hormone-releasing hormone (GHRH) stimulates, while somatostatin (SS) inhibits the secretion of GH. A long-standing hypothesis proposes that alternate secretion of GHRH and SS regulate episodic secretion of GH. However, measurement of GHRH and SS in hypophysial-portal blood of unanesthetized sheep and swine shows that episodic secretion of GHRH and SS do not account for all episodes of GH secreted. Furthermore, the activity of GHRH and SS neurons decreases after steers have eaten a meal offered for a 2-h period each day (meal-feeding) and this corresponds with reduced secretion of GH. Together, these data suggest that other factors also regulate the secretion of GH. Several neurotransmitters have been implicated in this regard. Thyrotropin-releasing hormone, serotonin and ␥-aminobutyric acid stimulate the secretion of GH at somatotropes. Growth hormone releasing peptide-6 overcomes feeding-induced refractoriness of somatotropes to GHRH and stimulates the secretion of GHRH. Norepinephrine reduces the activity of SS neurons and stimulates the secretion of GHRH via ␣2-adrenergic receptors. N-methyl-d, l-aspartate and leptin stimulate the secretion of GHRH, while neuropeptide Y stimulates the secretion of GHRH and SS. Activation of muscarinic receptors decreases the secretion of SS. Dopamine stimulates the secretion of SS via D1 receptors and inhibits the secretion of GH from somatotropes via D2 receptors. Thus, many neuroendocrine factors regulate the secretion of GH in livestock via altering secretion of GHRH and/or SS, communicating between GHRH and SS neurons, or acting independently at somatotropes to coordinate the secretion of GH. © 2001 Elsevier Science Inc. All rights reserved.

* Corresponding author. Dairy Science Building, AgResearch, Ruakura Agricultural Center, P.B. 3123, Hamilton 2001, New Zealand. Tel.: ⫹064-07-838-5099; fax: ⫹064-07-838-5628. E-mail address: [email protected] (C.D. McMahon). 0739-7240/01/$ – see front matter © 2001 Elsevier Science Inc. All rights reserved. PII: S 0 7 3 9 - 7 2 4 0 ( 0 1 ) 0 0 0 8 4 - 4

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1. Introduction Growth hormone (GH) is essential for postnatal somatic growth and maintenance of lean tissue at maturity in livestock. In animal industries, increased concentrations of GH are of economic importance because they are associated with faster growth, less fat stores and, in the dairy industry, more efficient milk production in dairy cows. Specifically, GH stimulates longitudinal bone growth [1], and growth of muscle [2], decreases adipose tissue mass, and improves lactation in ruminants [3]. Growth hormone is synthesized in somatotrope cells in the anterior pituitary gland as a 190 amino acid peptide in swine and as a 191 amino acid peptide in sheep and cattle [4 – 6]. Secretion of GH from perifused somatotropes is episodic, demonstrating that in the absence of external factors, pulsatile secretion is an inherent property of somatotropes [7]. However, the release of neurohormones from and communication with neurotransmitters in the hypothalamus are necessary to increase the secretion of GH. Indeed, basal and episodic secretion of GH from perifused somatotropes is higher when coupled in series with hypothalamic slices than when perifused alone [7]. The importance of the hypothalamus in regulating the secretion of GH can be demonstrated in vivo. The hypothalamus communicates with the anterior pituitary gland via hypophysial-portal blood vessels, which transport secreted factors from the external layer of the median eminence to the anterior pituitary gland. Disconnection of the hypophysial-stalk from the anterior pituitary gland decreases the secretion of GH, and slows the growth of swine and ruminants [8 –11]. Growth hormone is secreted in episodes or pulses with a frequency of approximately 30 min in swine [12,13] to 6 h in sheep, cattle and deer [14 –17]. A physiological explanation for episodic secretion of GH has long been sought. To date, two neurohormones, growth hormone-releasing hormone (GHRH) and somatostatin (SS) are central to our understanding of GH secretion. GHRH stimulates, whereas SS inhibits the secretion of GH from somatotropes via activation or inhibition, respectively, of adenylate cyclase, the enzyme catalyzing production of 3⬘, 5⬘-cyclic adenosine monophosphate (cAMP), which is the rate limiting step in the signal transduction cascade involving protein kinase A [18]. Tannenbaum and Ling proposed a model for regulation of pulsatile secretion of GH in 1984 [19] in which GHRH and SS are secreted reciprocally into the hypophysial-portal vessels. While administration of GHRH stimulates and SS inhibits the secretion of GH in vivo and in vitro, no study has convincingly demonstrated that GHRH and SS are secreted reciprocally, or that they regulate all endogenous pulses of GH [20 –25]. To date, there is no integrated understanding of how secretion of GH is regulated, especially in domestic animals. Multiple factors regulate the secretion of GH and this subject is regularly reviewed [26 –31]. This review focuses on neurohormones and neurotransmitters regulating the secretion of GH in domestic animals, although data from other species will be cited where appropriate.

2. Relationship between secretion of GHRH, SS, and GH GHRH is synthesized predominantly as a 44 amino acid peptide in neurons located in the arcuate nucleus (ARC) of the hypothalamus [32–35,195]. Most GHRH axons project termi-

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nals to the external layer of the median eminence, where it is secreted into hypophysial-portal blood and carried to the anterior pituitary gland [34 –36]. Short and long GHRH receptor isoforms have been cloned from human anterior pituitary glands [37]. The short form predominates and signals via cAMP, while the long form binds GHRH, but does not stimulate the production of cAMP [37]. GHRH receptor isoforms have not been studied in domestic animals. SS is synthesized predominantly in the brain as a peptide of 14 amino acids (SS-14), the isoform secreted into hypophysial-portal vessels, but also as a peptide of 28 amino acids (SS-28) and a high molecular weight isoform [38]. There are numerous populations of SS neurons throughout the brain, but in the hypothalamus, SS neurons are located predominantly in the periventricular nucleus (PeVN) and ARC [34,39,40]. Moreover, most (70 to 80%) SS terminals in the median eminence originate from SS neurons in the PeVN [41– 43]. There are five SS receptor subtypes. All are present in anterior pituitary glands of rats and sheep [44 – 47]. Current understanding of episodic secretion of GH evolved from the studies of Tannenbaum and Ling [19] and Plotsky and Vale [48]. In those hallmark studies, it was observed that temporal secretion of GH was predictable in rats. Concentrations of GH increased at 1100 h and decreased at 1300 h. Injection of GHRH failed to stimulate secretion of GH at 1300 h compared with 1100 h, unless SS was neutralized with antibody. From this study Tannenbaum and Ling [19] proposed that GHRH and SS are secreted alternately to stimulate and inhibit, respectively, the secretion of GH in rats. This reciprocal relationship between the secretion of GHRH and SS was supported later when GHRH and SS were measured in portal blood collected from the severed ends of disconnected hypophysial stalks of anesthetized rats [48]. In this study it was observed that concentrations of GHRH increased while those of SS decreased, but peak concentrations of GH occurred an hour later, suggesting delayed signaling between changes in the secretion of GHRH and SS and the secretion of GH. This study suffered two difficulties in interpretation. Firstly, GH was measured in another group of rats because hypophysial stalks were severed in the group in which GHRH and SS were measured. Secondly, anesthesia could have altered the secretion of GHRH and SS. The need to establish the relationship between GHRH, SS and GH in unanesthetized animals with hypophysial stalks connected to the anterior pituitary gland lead to the development of a surgical approach to gain access to and collect blood from hypophysial-portal vessels in sheep and swine. Several studies demonstrated that episodic secretion of GHRH and SS in hypophysial-portal blood do not always occur reciprocally with respect to each other and often were not synchronized with the secretion of GH [13,49 –51]. The best correlation of secretion occurred between GH and GHRH and ranged from 48% to 78%, but only where the percent of GH pulses began with or immediately after a pulse of GHRH [13,51]. When secretion of SS was included, the percent of GH pulses that occurred with increased secretion of GHRH and decreased secretion of SS was low, ranging from 26% to 48% [13,51]. Furthermore, in the study of Frohman et al. [49] there was no relationship between secretion of GH and SS. In fact, Frohman et al. [49] suggested that best relationships between GHRH, SS and GH could be explained by chance alone.

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Fig. 1. Effect of meal-feeding on concentrations of GH in serum from 0800 to 1340 h in steers fed between 1000 and 1200 h (indicated by the vertical dashed lines). Redrawn from Gaynor et al. [54].

3. Activity of GHRH and SS neurons during a single episode of GH secretion To further evaluate the relationship between GHRH and SS in the regulation of episodic secretion of GH, we assessed the activity of GHRH and SS neurons and compared them with concentrations of GH during a single surge in GH secretion. To do this it was necessary to synchronize secretion of GH among animals. Synchronized secretion of GH was achieved by feeding steers for a 2-h period each day (meal-feeding). Typically, GH is secreted in a single pulse before feeding in this model (Fig. 1) [10,52–54]. In addition, basal and GHRH-induced secretion of GH are temporarily reduced after, compared with before feeding in fed and sham-fed steers and sheep (Fig. 2) [10,52,53,55].

Fig. 2. Effect of iv injection of bGHRH (0.2 ␮g/kg body weight) on concentrations of GH in serum of steers one hour before (0900) or one hour after feeding (1300 h) (from McMahon et al. [55]).

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Fig. 3. Percent of active GHRH neurons in the ARC and SS neurons in the PeVN, using percent of neurons containing nuclei that are immunoreactive for Fos and Fos-related antigens (Fos/FRA) as a marker of neuronal activity. Symbols indicate differences from 0700 h (*, P ⬍ 0.05) for GHRH and from 0900 h (**, P ⬍ 0.01; *, P ⬍ 0.05) for SS. Adapted from McMahon et al. [55].

Activity (using presence of immediate-early gene proteins Fos and Fos-related antigens as markers of neuronal activity) of GHRH neurons in the ARC and of SS neurons in the PeVN decrease during feeding and remain low for at least an hour after feeding (Fig. 3) [55]. We concluded that decreased basal and GHRH-induced secretion of GH during and after feeding is associated with decreased activity of GHRH and SS neurons. Therefore, at least in cattle, activity of GHRH and SS neurons are not reciprocally regulated and temporary refractoriness of somatotropes after feeding is not due to increased activity of SS neurons. These data also demonstrate that there are regional changes in populations of SS neurons. For example, activity of SS neurons in the PeVN decreased, while those in the ARC remained unaltered from before to after feeding. It has been argued that decreased basal and GHRH-induced secretion of GH is due to increased concentrations of insulin after feeding. Indeed, Bassett [56] demonstrated an inverse relationship between insulin and GH after feeding. However, blockade of insulin release does not prevent decreased basal and GHRH-induced secretion of GH in steers after feeding [57].

4. Interaction between GHRH and SS at somatotropes GHRH and SS actions on somatotropes depends on the type of somatotrope, particularly in swine, where somatotropes can be separated into two groups based on their density and function. The two groups of somatotropes are designated as high or low density, depending on their separation and grouping after centrifugation on a percoll gradient [58]. GHRH and SS have different actions on these somatotrope populations; GHRH stimulates secretion of GH from both populations, while SS inhibits GHRH-induced secretion of GH from lowdensity somatotropes and stimulates secretion of GH from high-density somatotropes [59].

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Therefore, it could be argued that episodic secretion of GH should coincide with episodic secretion of SS as well as GHRH. However, episodic secretion of GH is as weakly associated with increased secretion of SS as it is with increased secretion of GHRH and/or decreased secretion of SS in swine [13] (discussed in the previous section). High and low density populations of somatotropes have not been studied in ruminants.

5. Intercommunication between GHRH and SS neurons Despite the failure to demonstrate consistent, reciprocal secretion of GHRH and SS accounting for all episodes of GH secreted, there is communication between GHRH and SS neurons in the hypothalamus. Indeed, SS inhibits the secretion of GHRH while GHRH stimulates the secretion of SS from perifused bovine hypothalami [60]. However, the anatomical nature of this communication is poorly understood at present. The location of GHRH and SS neurons is similar among swine, sheep, cattle and rodents. Furthermore, the limited information on pathways of GHRH and SS axons in livestock species suggests that they are similar to that in rats [34]. Therefore, it is necessary to consider pathways identified in rats. In rats, SS synapses are found on GHRH neurons, but it is not known whether these originate from SS neurons in the ARC or PeVN [61– 64]. While GHRH axons synapse on SS dendrites in the PeVN, they account for less than 10% of GHRH fibers [64 – 66]. Populations of GHRH and SS neurons can be functionally separated into two groups: those that secrete GHRH and SS into hypophysial-portal blood, and those that communicate between GHRH and SS neurons. Furthermore, the low percent of GHRH neurons projecting to the PeVN, suggests that either there is limited communication between GHRH and SS neurons, or that this communication involves interneurons such as neuropeptide Y and galanin. Therefore, other factors regulate secretion of GH in addition to GHRH and SS. For the remainder of this review, the best understood neurotransmitters and neuropeptides affecting the secretion of GH will be discussed.

6. Growth hormone-releasing peptides (GHRPs) GHRPs are synthetic enkephalin derivatives in tri, tetra, penta, hexa, or heptapeptide configurations, from which a growing number of non-peptide analogues have been formulated [67,68]. Initial screening studies showed that GHRPs stimulate the secretion of GH [69 –71]. Three GHRPs, GHRP-1, -2 and -6 stimulate the secretion of GH in sheep, cattle and swine in vivo and in vitro [11,72,73,85]. Ironically, receptors that bind GHRPs were isolated in anterior pituitary glands and hypothalami before the endogenous hormones were isolated [74 –78]. While much literature has been published on the synthetic GHRPs over the past 20 years, the endogenous hormone called ghrelin, where ghre is derived from the proto-IndoEuropean root of the word grow, was only isolated in the past year [79]. Ghrelin is a 28 amino acid peptide initially isolated from rat stomach. Later neurons containing ghrelin were identified in the ARC [79]. Ghrelin stimulates secretion of GH and is competitively blocked by a GHRP receptor antagonist [79]. More recently, a 27 amino acid

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peptide differing in one amino acid (glutamine) from ghrelin was isolated from rat stomach and designated des-Gln14-ghrelin [80]. The bioactivity of both ghrelin peptides is attributed to an octanoyl group on a serine residue (Ser3), the third amino acid from the N-terminus. Because ghrelin shares little sequence similarity with other GHRPs, and the bioactivity of ghrelin requires octanoylation of Ser3, it is likely that other endogenous GHRPs exist. In this regard, signal transduction varies among GHRPs. For example GHRP-2 receptors signal via cAMP-PKA and inositol 1,4,5-triphosphate (InsP3)- 1,2-diacylglycerol (DAG) pathways, while GHRP-6 receptors activate phospholipase C to produce InsP3 and DAG [72,81– 84,196]. GHRP-6 synergizes with GHRH to stimulate greater secretion of GH [73,81]. Indeed, the combined treatment of GHRH and GHRP-6 stimulates equal and massive secretion of GH before and after feeding in steers, suggesting that GHRP-6 overcomes the refractoriness of somatotropes to GHRH after feeding [86]. GHRPs also increase the expression of immediate-early genes in the ARC and, in this regard, GHRP-6 stimulates the secretion of GHRH into hypophysial-portal blood of sheep as well as the secretion of GHRH from bovine hypothalamic slices [86 – 89]. Therefore, GHRPs act directly at somatotropes to stimulate the secretion of GH and indirectly via stimulation of GHRH secretion. 6.1. Dopamine Dopamine is a catecholamine synthesized from tyrosine in neuronal populations located in the hypothalamus (regions A11 to A15) and brainstem (regions A8 to A10) in swine, sheep and cattle [90 –94]. Dopamine receptors are classified into five types named D1 to D5 that are broadly separated into two categories: D1-like and D2-like [95]. Stimulation of D1-like receptors increases the activity of SS neurons in the PeVN before feeding [96] and increases the secretion of SS from perifused hypothalamic slices [97]. Therefore, it is not surprising that stimulation of D1-like receptors decreases basal and GHRH-induced secretion of GH before feeding in meal-fed steers [96]. Stimulation or inhibition of D2-like receptors does not alter the secretion of SS or GHRH from bovine hypothalamic slices in vitro [97]. However, dopamine or activation of D2receptors inhibits basal and GHRH-induced release of GH from cultured sheep somatotropes [98,99]. Therefore, dopamine inhibits the secretion of GH via stimulating the secretion of SS via D1-like receptors and blocking the secretion of GH from somatotropes via D2-receptors. 6.2. Norepinephrine Norepinephrine is a catecholamine synthesized from dopamine in neurons located in regions A1 to A7 in the brainstem in swine, sheep and cattle [90 –94]. Receptors are termed adrenergic and are divided into ␣- and ␤-classes, both of which regulate the secretion of GH. Alpha-adrenergic receptors are classified into ␣1 and ␣2, with further subclasses within each class [95]. Activation of ␣1-adrenergic receptors inhibits the secretion of GH when injected into the PeVN, suggesting increased secretion of SS into hypophysial-portal blood [100]. In contrast, activation of ␣2-adrenergic receptors stimulates the secretion of GH in sheep and cattle [99 –102]. In vitro studies demonstrate that ␣2-adrenergic regulation of GH occurs in both the hypothalamus and anterior pituitary gland. For example, activation of ␣2-adrenergic

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receptors stimulates the secretion of GHRH, but not SS, from perifused hypothalamic slices and hypophysial stalks [103; McMahon et al. unpublished]. Ironically, stimulation of ␣2adrenergic receptors decreases the activity of SS neurons in the PeVN, but does not alter the activity of GHRH or SS neurons in the ARC [104]. Therefore, it is likely that ␣2-adrenergic receptor agonists act, in part, to decrease the activity of a subset of SS neurons in the PeVN that inhibit secretion of GHRH. In this regard it relevant to consider that ␣2-adrenergicinduced secretion of GH is lower after compared with before feeding in cattle. It was noted earlier that activity of SS neurons in the PeVN is reduced after feeding. Thus, decreased ␣2-adrenergic-induced secretion of GH after feeding is possibly due to the inability of ␣2-adrenergic agonists to further reduce activity of SS neurons in the PeVN [102; McMahon et al. unpublished]. Therefore, activation of ␣2-adrenergic receptors stimulates the secretion of GH by decreasing the activity of SS neurons in the PeVN, and directly stimulating the secretion of GHRH from hypophysial stalks. At somatotropes, activation of ␣2-adrenergic receptors either has no effect (bovine) [105] or decreases (sheep) [99] basal and GHRH-induced secretion of GH from somatotropes. The discrepancy between the effects of activation of ␣2-adrenergic receptors in cattle and sheep may be related to the techniques used. The perifusion studies of Gaynor et al. [105] measured basal secretion of GH at the detection limit of the assay, while Soyoola et al. [99] measured accumulated secretion of GH and GHRH-induced secretion of GH following treatment with an ␣2adrenergic agonist in static culture. If the differences in the rates of secretion are small, the latter technique is more sensitive in detecting decreased basal secretion of GH due to the accumulated difference over hours as opposed to minutes in perifusion studies. Therefore, it is possible that activation of ␣2-adrenergic receptors increases the secretion of GHRH into hypophysial-portal vessels, but inhibits basal and GHRH-induced secretion of GH at somatotropes. Furthermore, different populations of norepinephrine neurons could regulate the secretion of GH via separate actions on GHRH and SS neurons and at somatotropes. In support of the latter, norepinephrine is secreted into hypophysial-portal blood in sheep and, therefore, when transported to somatotropes could regulate secretion of GH in conjunction with other neurotransmitters [106]. Activation of ␤-adrenergic receptors inhibits the secretion of GH, possibly via increased secretion of SS into hypophysial-portal vessels. Indeed, blockade of ␤-adrenergic receptors stimulates the secretion of GH and prevents norepinephrine and epinephrine-induced decreases in secretion of GH in sheep [107]. Beta-adrenergic-induced secretion of SS is also thought to occur in humans because activation of ␤-adrenergic receptors decreases GHRHinduced secretion of GH [108]. 6.3. Serotonin (5-HT) 5-HT is an indoleamine synthesized from tryptophan in the caudal medulla oblongata (B1 to B3, S1 and S2), and rostral brainstem (B5 to B9, S3, and S4) in sheep [90,93,109]. Serotonergic receptors are currently divided into seven subclasses that are designated 5-HT1 to 5-HT7 [95]. The role of each 5-HT receptor subtype in regulating the secretion of GH is not known. However, activation of 5-HT receptors with the non-specific agonist quipazine stimulates the secretion of GH in cattle via an action mediated in the hypothalamus rather than at somatotropes [54,105,110]. In addition, quipazine induces equivalent secretion of GH before and after feeding in cattle, but

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does not alter the secretion of GHRH or SS from perifused bovine hypothalamic slices [54; Radcliff et al. unpublished]. In addition, stimulation of 5-HT and ␣2-adrenergic receptors stimulates greater secretion of GH before feeding than stimulation of either receptor alone in cattle [105]. Therefore, 5-HT probably acts through an intermediate neurotransmitter to stimulate the secretion of GH via a GHRH and SS independent mechanism. In contrast to cattle, 5-HT suppresses the secretion of GH in sheep because depleting concentrations of 5-HT at presynaptic terminals via a re-uptake enhancer increases the secretion of GHRH and GH [111]. 6.4. Thyrotropin-releasing hormone (TRH) TRH is a tri-peptide (Glu-His-Pro) synthesized in the parvicellular and magnocellular neurons of the paraventricular nucleus in most species, and is found in isolated cells in the perifornical and lateral hypothalamus in humans [112,113]. Distribution is similar in cattle and there is intense immunostaining of TRH fibers where they terminate in the median eminence [McMahon et al. unpublished]. TRH stimulates the secretion of GH in cattle [114] and in sheep [115–117]. In addition, TRH stimulates equal release of GH before and after feeding in meal-fed steers, suggesting that somatotropes are not refractory to TRH after feeding [Radcliff et al. unpublished]. TRH synergizes with GHRH both in vivo and in vitro to stimulate the secretion of GH in cattle, but not sheep, and has little effect alone on somatotropes in vitro in both species [115,118 –119]. Insensitivity of somatotropes to TRH-induced secretion of GH in vitro may be explained, in part, through the signal transduction pathway of TRH. Stimulation of TRH receptors increases cytosolic InsP3 and DAG, rather than acting via the cAMP/PKA pathway of GHRH [120,121]. 6.5. Acetylcholine (ACh) ACh is synthesized from acetyl coenzyme A and choline. ACh receptors are classified as either muscarinic or nicotinic [95]. Increased activation of muscarinic receptors via neostigmine-induced inhibition of cholinesterase (the enzyme hydrolyzing ACh), stimulates the secretion of GHRH into hypophysial-portal blood of sheep, without affecting the secretion of SS [122,123]. Furthermore, pyridostigmine, another cholinesterase inhibitor, enhances GHRP6-induced secretion of GH in sheep [124]. While evidence supports a role for ACh to stimulate the secretion of GHRH, other data suggest that ACh decreases the secretion of SS in sheep, rats and humans [125–127]. Indeed, cholinesterase inhibitors are used in clinical settings to block the secretion of SS in tests designed to determine the ability of GHRH to stimulate maximal secretion of GH [128,129]. Although GHRH and neostigmine induce greater secretion of GH when injected together than when injected individually in sheep and swine [122,130], neostigmine increases the secretion of GHRH, but does not alter concentrations of SS in hypophysialportal blood [122,123]. Therefore, synergy between the secretory actions of GHRH and cholinesterase inhibitors occurs via pathways other than SS in sheep. 6.6. Neuropeptide Y (NPY) Described in 1984, NPY is a 36 amino acid peptide that is a member of the pancreatic peptide family of peptides [131]. All members of this peptide family have tyrosine (Y)

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Fig. 4. Effect of NPY on concentrations of GHRH (top) and SS (bottom) released from parasagittal slices of bovine hypothalami (600 ␮m thick) complete with hypophysial-stalk. Slices (n ⫽ 12) were perifused for 20 min (indicated by the solid bar) with vehicle (MEM␣ medium), or NPY from 10⫺10 to 10⫺6 M. Pooled SEM ⫽ 58.7 pg/ml for GHRH and 26.1 pg/ml for SS.

residues at C- and N-termini. NPY is located throughout the brain, but the highest density of neurons is in the ARC [93,132,133]. There are six subtypes of NPY receptors designated Y1 to Y6 and their activation typically inhibits adenylate cyclase [134]. A known appetite stimulant in sheep [135,136], NPY also stimulates the secretion of GH in sheep and cattle [137,142]. This is consistent with observations in some humans (up to 60%) with acromegaly [138,139], but differs from rats, in which NPY inhibits the secretion of GH via stimulating the secretion of SS [140,141]. Although NPY stimulates the secretion of GH in cattle and sheep, peak concentrations are delayed up to 45 min post-administration [137,142]. This delayed time-response is similar in humans with acromegaly [138,139]. One possible explanation for this comes from the finding that NPY stimulates the secretion of both GHRH and SS from perifused bovine hypothalamic slices, suggesting that there is competition at somatotropes between GHRH to stimulate and SS to inhibit release of GH (Fig. 4) [143]. Although concurrent secretion of GHRH and SS occurs in vitro, suggesting conflicting signals at somatotropes, such concurrent secretion may not occur endogenously. Rather, different subpopulations of NPY neurons may mediate secretion of GHRH and SS independently, either via the same or different receptor subtypes. A current hypothesis is that NPY mediates negative feedback of GH on somatostatin

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neurons [144]. In this feedback loop, GH stimulates NPY neurons in the ARC, which, in turn, stimulate SS neurons in the PeVN, to secrete SS into hypophysial-portal blood. In support of this hypothesis, GH receptors are found on NPY neurons in the ARC, but not on GHRH neurons [144,145]. Furthermore, GH increases expression of the immediate-early gene Fos in NPY neurons in the ARC and in SS neurons in the PeVN [146,147]. 6.7. Galanin Galanin, a 29 amino acid peptide, was first described in 1983 after its isolation from porcine intestinal mucosa and is named after the N- and C-terminal amino acids, glycine and alanine, respectively [148]. Galanin neurons have since been detected in the brain with high densities in many hypothalamic regions, notably in the medial preoptic area, infundibular nucleus, paraventricular nucleus, PeVN, and with intensely stained fibers in the external layer of the median eminence [149 –151]. There are two galanin receptor subtypes, GalR1 and GalR2 [152]. Galanin stimulates the secretion of GH in sheep and cattle as it does in rats [153–156]. Furthermore, increased secretion of GH in underfed sheep is associated with increased intensity of immunostained galanin terminals in the median eminence [157]. Studies in rats show no binding sites for galanin in the anterior pituitary gland and galanin does not stimulate the secretion of GH from cultured anterior pituitary cells [158]. Therefore, galanin is thought to regulate secretion of hypophysiotrophic hormones. Indeed, galanin stimulates the secretion of GHRH from perifused hypothalamic slices and both GHRH and SS from perifused median eminence fragments from rats [159,160]. Galanin-induced secretion of GHRH and SS has not been studied in domestic species. It is possible that galanin also regulates the negative feedback of GH. In this regard, GH increases the expression of galanin mRNA, and the absence of GH reduces galanin mRNA [161,162]. Galanin axons innervate SS neurons in the PeVN where galanin receptor mRNA is also expressed [149,161,163]. 6.8. Leptin Basal and GHRH-induced secretion of GH is markedly reduced in obese animals and this is partially due to resistance to GHRH at somatotropes [197–200]. GH plays a vital role in regulating body weight by decreasing the synthesis of lipids [201,202] and, therefore, decreased concentrations of GH would increase synthesis of lipids. In a negative-feedback loop, adipocytes, in turn, secret leptin, which communicates the amount of stored lipid to the brain [165]. Leptin is, therefore, thought to act as a lipostat in regulating body weight, a concept proposed in 1953 by Kennedy [164]. In support, concentrations of leptin are higher in obese than lean humans and sheep [166,167] and leptin reduces appetite and body weight in rodents [168 –170]. Therefore, persistent obesity may result not only from resistance to GHRH, but also from resistance to leptin [171,172]. Leptin is also a neurotransmitter with neurons and receptors located in the hypothalamus and anterior pituitary glands of mice, rats, humans and sheep [173–176]. Furthermore, the brain is a source for circulating concentrations of leptin, perhaps originating from cells in the anterior pituitary gland [177]. Thus, leptin may have functions in addition to signaling the

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amount of stored fat. Intracerebroventricular injection of leptin stimulates secretion of GH in swine and rats, but not in sheep [178 –180]. The mechanism by which leptin induces the secretion of GH is not well understood at present. It is likely that NPY and SS are involved because leptin decreases basal and NPY-induced secretion of SS from and expression of SS in cultured fetal rat hypothalamic cells [181]. Furthermore, leptin decreases NPY mRNA and increases the secretion of GH in fasted rats, when secretion of GH is decreased [182]. Leptin-induced secretion of GH is reduced in the presence of antibody to GHRH, suggesting that leptin stimulates the secretion of GH via increased secretion of GHRH and decreased secretion of SS [183]. In support of these observations, leptin receptor mRNA is located on NPY neurons in the ARC in rats and sheep [184,185]. Leptin does not alter secretion of GH acutely at somatotropes. However, GHRH-induced secretion of GH is decreased from sheep somatotropes after 24-h exposure to leptin [186].

7. Amino acid neurotransmitters Activation of amino acid neurotransmitters stimulates the secretion of GH. Amino acid neurotransmitters are divided into two categories: excitatory, which depolarize cells, and inhibitory, which hyperpolarize cells in the central nervous system [95]. Excitatory amino acids are glutamic acid, aspartic acid, cysteic acid, and homocysteic acid, while inhibitory amino acids are ␥-aminobutyric acid (GABA), glycine, taurine, and ␤-alanine [95]. Aspartate and glutamate are the most potent amino acids that stimulate the secretion of GH in sheep, and n-methyl-d, l-aspartate (NMDA), an agonist of aspartic and glutamic acids stimulates the secretion of GH in sheep and swine [187–189]. NMDA stimulates the secretion of GHRH from perifused swine hypothalami and from stalk/median eminence explants, but did not induce the secretion of GH in swine also given antisera to GHRH [188,190]. Therefore, NMDA stimulates the secretion of GH via stimulating the secretion of GHRH. However, this does not rule out the possibility that NMDA also decreases the secretion of SS [188]. Intravenous and intracerebroventricular injection of GABA stimulates the secretion of GH in sheep [191]. Moreover, SS does not block GABA-induced secretion of GH in sheep, suggesting that GABA-induced secretion of GH is independent of SS [191]. Furthermore, GABA-induced secretion of GH may be independent of GHRH because SS should block the actions of GHRH.

8. Feedback autoregulation of GH Constitutive episodic secretion of GH in vitro suggests that somatotropes regulate the secretion of GH [7]. In vivo, however, GH is thought to inhibit the secretion of GH via increasing the secretion of SS. In this feedback loop, galanin and NPY are thought to be mediators of GH on SS neurons (discussed above). However, intracerebroventricular injections of GH do not alter the secretion of GH in sheep, suggesting that GH does not play a negative feedback role [192]. GH does, however, stimulate the synthesis and secretion of insulin-like growth factor I (IGF-I), which inhibits the secretion of GH at somatotropes, but

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Fig. 5. Summary of the actions and interactions of neurohormones and neurotransmitters regulating secretion of GHRH and SS and of GH in livestock species. Stimulatory and inhibitory actions are indicated by (⫹) and (⫺) symbols, respectively. The ? indicates an as yet uncharacterized pathway through which TRH and GABA act to stimulate secretion of GH. NE ⫽ norepinephrine, D ⫽ dopamine, and other abbreviations are as used in the text.

not when injected into lateral ventricles [193,194]. Therefore, there are GH-dependent and independent negative feedback mechanisms regulating the secretion of GH. Furthermore, IGF-I, but not GH, mediates GH-dependent negative feedback at somatotropes in sheep.

9. Summary and conclusions Multiple neurotransmitters, neurohormones and pathways regulate the secretion of GH and these are summarized in Fig. 5. The principal regulators of GH secretion are GHRH, which stimulates the secretion, and SS, which inhibits the secretion of GH. GHRH and SS are secreted episodically, but despite communication between GHRH and SS neurons, secretion of GHRH is not reciprocal to secretion of SS and the interaction between these two peptides does not account for all episodes of GH released. Therefore, while many of the factors discussed in this review act via SS and GHRH, some like GHRPs, 5-HT, TRH, and GABA appear to regulate the secretion of GH independently of SS and GHRH. While much is understood about individual neurotransmitters, little is understood about how these neurotransmitters interact to regulate all episodes of GH secreted into the blood of domestic animals.

Acknowledgment The United States Department of Agriculture National Research Initiative Grant 9603287 supported this review.

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