Feedback Regulation of Growth Hormone Synthesis and Secretion in Fish and the Emerging Concept of Intrapituitary Feedback Loop ☆ ⁎ Anderson O.L

http://www.paper.edu.cn

Comparative Biochemistry and Physiology, Part A 144 (2006) 284–305

Review Feedback regulation of growth hormone synthesis and secretion in fish and the emerging concept of intrapituitary feedback loop ☆ ⁎ Anderson O.L. Wong , Hong Zhou, Yonghua Jiang, Wendy K.W. Ko

Department of Zoology, University of Hong Kong, Pokfulam Road, Hong Kong, P.R. China Received 29 July 2005; received in revised form 21 November 2005; accepted 21 November 2005 Available online 9 January 2006

Abstract

Growth hormone (GH) is known to play a key role in the regulation of body growth and metabolism. Similar to mammals, GH secretion in fish is under the control of hypothalamic factors. Besides, signals generated within the pituitary and/or from peripheral tissues/organs can also exert a feedback control on GH release by effects acting on both the hypothalamus and/or anterior pituitary. Among these feedback signals, the functional role of IGF is well conserved from fish to mammals. In contrast, the effects of steroids and thyroid hormones are more variable and appear to be species-specific. Recently, a novel intrapituitary feedback loop regulating GH release and GH gene expression has been identified in fish. This feedback loop has three functional components: (i) LH induction of GH release from somatotrophs, (ii) amplification of GH secretion by GH autoregulation in somatotrophs, and (iii) GH feedback inhibition of LH release from neighboring gonadotrophs. In this article, the mechanisms for feedback control of GH synthesis and secretion are reviewed and functional implications of this local feedback loop are discussed. This intrapituitary feedback loop may represent a new facet of pituitary research with potential applications in aquaculture and clinical studies. © 2005 Elsevier Inc. All rights reserved.

Keywords: Growth hormone; Luteinizing hormone; Feedback control; Gene expression; Autocrine/paracrine interactions; Gonadotrophs; Somatotrophs; Signal transduction; Pituitary; Fish

Contents

1. Introduction ...... 284 2. Feedback regulation of GH synthesis and secretion in mammals ...... 285 3. Feedback regulation of GH synthesis and secretion in fish ...... 288 4. Intrapituitary feedback loop for GH regulation in fish model ...... 293 5. Conclusion...... 297 Acknowledgements ...... 298 References ...... 298

☆ From the Symposium “Comparative Neuroendocrinology—Integration of 1. Introduction Hormonal and Environmental Signals in Vertebrates and Invertebrates” presented at the 15th International Congress of Comparative Endocrinology, Growth hormone (GH) is an important pituitary hormone May 23–28, 2005, at Boston, MA, USA (Organizer: Dr. Vance Trudeau, known to regulate body growth and metabolism. In University of Ottawa, Canada). mammals, GH release is under the control of hypothalamic ⁎ Corresponding author. Room 4S-12, Kadoorie Biological Sciences Building, Department of Zoology, University of Hong Kong, Pokfulam Road, Hong regulators, hormones released from target organs/peripheral Kong, P.R. China. Tel.: +852 2299 0863; fax: +852 2299 9114. tissues, feedback regulation by GH itself, and growth E-mail address: [email protected] (A.O.L. Wong). factors/cytokines produced locally within the pituitary

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(Bluet-Pajot et al., 1998; McMahon et al., 2001; Muller et 2. Feedback regulation of GH synthesis and secretion in al., 1999). There is also increasing evidence suggesting that mammals local interactions among pituitary cells via the release of pituitary hormones can modulate the secretory functions in In mammals, GH release is under the dual control of GH- somatotrophs (Schwartz, 2000). The physiological relevance releasing hormone (GHRH) and somatostatin (SRIF) (Fig. 1). as well as the signal transduction mechanisms for these Within the hypothalamus, GHRH and SRIF neurons (from the phenomena, however, is still poorly understood. Recently, arcuate and periventricular nuclei, respectively) directly inner- our studies on GH autoregulation in the carp pituitary have vate the external layers of the median eminence (Leshin et al., revealed the presence of an intrapituitary feedback loop that 1994), and “180° out-of-phase” secretion of the stimulatory can regulate GH release and GH gene expression by local GHRH and inhibitory SRIF into the hypophyseal portal blood interactions between gonadotrophs and somatotrophs. This determines the pulsatile pattern of GH release (Wagner et al., feedback loop may represent a novel mechanism in fish 1998). At the pituitary level, GHRH stimulates GH release and models maintaining basal GH release and pituitary GH gene expression via the adenylate cyclase (AC)/cAMP/ MAPK responsiveness to stimulation by hypophysiotropic factors. PKA and/or PI3K/Ras/P42/44 pathways (Pombo et al., In this article, the mechanisms for feedback control of GH 2000; Wong et al., 1995). GHRH-induced GH gene expression synthesis and secretion will be summarized and the also involves CREB phosphorylation (Bertherat, 1997) and up- functional implications as well as the post-receptor regulation of Pit-1 gene expression (Chung et al., 1998). Unlike signaling mechanisms for this local feedback loop will be GHRH, SRIF inhibits GH release by AC inactivation to discussed. suppress cAMP production (Narayanan et al., 1989), inhibition

Fig. 1. Feedback regulation of GH release in mammals. In the pituitary of mammals, GH release from somatotrophs is under the dual control by GHRH and SRIF. The two regulators are released by the respective neurons in the hypothalamus and delivered to the anterior pituitary via the hypophyseal portal blood system. GH release from the pituitary can exert a negative feedback on somatotrophs by three separate routes, namely (i) long-loop feedback via indirect actions of IGF-I produced in the liver, (ii) short-loop feedback by direct actions of GH acting at the hypothalamus, and (iii) ultra-short feedback by local actions of GH acting within the pituitary. GH released from the pituitary and/or produced locally in the gonad can stimulate/potentiate steroidogenesis and sex steroids in circulation can exert both positive and negative effects on somatotrophs, either directly at the pituitary level or indirectly via actions within the hypothalamus. GH can also modulate energy homeostasis in mammals, which may have an effect on the secretion of ghrelin from the stomach and leptin from white adipocytes. These hormones not only play a role in appetite control but can also act at the pituitary level to induce GH release from somatotrophs. a For short-loop feedback, GH can enter the brain by receptor-mediated transcytosis at the choroids plexus and/or by retrograde transport via the portal blood system. b For ultra-short feedback, GH can act directly on somatotrophs and/ or indirectly via local production of IGF-I at the pituitary level. c Although the stomach represents the major source of ghrelin in systemic circulation, local production of ghrelin has been reported in the hypothalamus as well as in the pituitary. 中国科技论文在线 http://www.paper.edu.cn

286 A.O.L. Wong et al. / Comparative Biochemistry and Physiology, Part A 144 (2006) 284–305 of Na+ (Kato and Sakuma, 1997) and Ca2+ channel activities 1989; Jansson et al., 1985). The influence of sex steroids on GH (Kato, 1995), and membrane hyperpolarization caused by synthesis, however, is still controversial, as stimulatory, activation of inwardly rectifying K+ current (Sims et al., 1991). inhibitory, and no effects have been reported (for review, see Although SRIF can also inhibit GHRH release from the Chowen et al., 2004). Both testosterone and estrogen, and to a hypothalamus (West et al., 1997), SRIF dose not affect GH less extent for progesterone, are known to modify the pusatile production/gene expression at the pituitary cell level (Fukata et pattern of GH release in vivo, either by changing the pulse al., 1985; Tanner et al., 1990). Based on the extensive studies in frequency (Yonezawa et al., 2005) and/or pulse amplitude the rat as well as in other animal models, it is commonly (Crowne et al., 1997; Genazzani et al., 1993). Given that accepted that GHRH and SRIF neurons in the hypothalamus gonadal steroids, e.g. testostrone, can regulate the gene represent the major target sites within the central nervous expression of GHRH in the arcuate nucleus (Zeitler et al., system for feedback control of GH synthesis and secretion 1990) and SRIF in the periventricular nucleus (Argente et al., (McMahon et al., 2001; Muller et al., 1999). 1990), these modulatory effects probably are mediated through The somatotropic and metabolic effects of GH are mediated central actions within the hypothalamus. Recently, increasing mainly by insulin-like growth factor (IGF) released from the evidence has cumulated suggesting that ghrelin from the liver (Isaksson, 2004; Muller et al., 2003). Except during the stomach (Kojima et al., 1999) and leptin from white adipose neonatal phase, IGF-I but not IGF-II is the dominant form of tissue (Zhang et al., 1994) may serve as a link between pituitary IGF expressed (Nakae et al., 2001) under the stimulatory functions and energy homeostasis. Apart from their primary role influence of GH via the JAK2/STAT5b pathway (Woelfle et al., in appetite control, these two hormones are also involved in GH 2003). IGF-I in systemic circulation is known to exert a long- regulation and can be regarded as “signals” from the periphery loop feedback on GH synthesis and secretion (Daughaday, regulating somatic growth based on the energy status of the 2000; Le Roith et al., 2001). The site of action for IGF appears body (Pombo et al., 2001). to be species-specific. Direct actions of IGF-I at the pituitary Ghrelin, a 28 a.a. acylated peptide produced in the X/A- level without a hypothalamic component have been reported in like cells (or “ghrelin cells”) of the stomach, is an orexigenic the sheep (Fletcher et al., 1995) whereas the central actions factor that can induce food intake and increase weight gain associated with increased GHRH and reduced SRIF release and overall adiposity (Kojima and Kangawa, 2005). It can from the hypothalamus have been clearly demonstrated in the also enhance GH pulsatility in vivo (Tannenbaum et al., rat (Becker et al., 1995). IGF-I treatment in vivo is also effective 2003) by forming a three-peptide regulatory ensemble with in stimulating SRIF but attenuating GHRH mRNA expression GHRH and SRIF (Veldhuis and Bowers, 2003). Within the in the rat hypothalamus (Ghigo et al., 1997). At the pituitary hypothalamus, ghrelin increases GHRH pulse frequency level, IGFs can bind to type I IGF receptors (or IGF-I receptors) (Fletcher et al., 1996) and GHRH release into hypophyseal (Weber et al., 1992) and to a less extent to insulin receptors portal blood without affecting SRIF secretion (Tannenbaum (Yamashita and Melmed, 1986) to inhibit GH release and GH and Bowers, 2001). At the pituitary level, ghrelin stimulates gene expression (Morita et al., 1987; Yamashita and Melmed, GH release via GHS-1a receptors coupled to the PLC/IP3/ 1987). In rat pituitary cells or pituitary cell lines, IGFs can block PKC pathway and [Ca2+]i mobilization (Ueno et al., 2005). the stimulatory effects on GH mRNA expression induced by Activation of pituitary GHS-1a receptors can also increase GHRH or by activation of the cAMP- and PKC-dependent GH mRNA expression (Yan et al., 2004), which may be pathways (Morita et al., 1987). These inhibitory actions are mediated by the stimulatory actions of ghrelin on Pit-1 gene exerted directly at the level of GH promoter through activation expression (Garcia et al., 2001). Although ghrelin has no MAPK of the P42/44 (Voss et al., 2000) and IRS/PI3K cascades effects on cAMP synthesis, it can potentiate the cAMP (Niiori-Onishi et al., 1999) and occur concurrently with a drop responses induced by GHRH (Cunha and Mayo, 2002), in GHRH receptors (Sugihara et al., 1999) and Pit-1 gene which may account for the synergistic action of ghrelin and expression (Castillo and Aranda, 1997). IGF-I expression has GHRH on GH release in vivo (Hataya et al., 2001). Although also been reported in somatotrophs, corticotrophs and follicu- the stomach represents a major source of ghrelin in circulation lostellate cells (Schwartz, 2000), and pituitary IGF-I mRNA (Leonetti et al., 2003), ghrelin expression is also detected in expression can be up-regulated by high levels of circulating GH hypothalamic neurons in areas adjacent to the third ventricle (Fagin et al., 1988). The physiological role of this locally between the arcuate, ventromedial, dorsomedial, and para- produced IGF-I in GH regulation, however, has yet to be ventricular nuclei (Cowley et al., 2003). Given that (i) the determined (for reviews on endocrine vs. autocrine/paracrine projection of these neurons to the median eminence and (ii) IGF, see Adams, 2002; Ohlsson et al., 2000). presence of ghrelin in hypophyseal portal blood have not Besides IGF, hormones released from peripheral tissues are been demonstrated, it is still unclear if ghrelin can serve as a also known to modulate GH secretion. In the gonad, GH can act hypophysiotropic factor in mammals. Recently, ghrelin as a “co-gonadotropin” to stimulate steroidogenesis (Hull and expression at the pituitary level, especially in somatotrophs, Harvey, 2002) while sex steroids in circulation can modify GH lactotrophs and thryotrophs, has been reported in the rat release and GH gene expression with effects acting on both the (Caminos et al., 2003). In the same animal model, pituitary hypothalamus and anterior pituitary (Chowen et al., 2004). In expression of ghrelin, both at the protein and transcript levels, general, testosterone enhances and estradiol reduces basal and can be up-regulated by GHRH treatment (Kamegai et al., GHRH-stimulated GH release at the pituitary level (Hertz et al., 2004). These findings raise the possibility that ghrelin may 中国科技论文在线 http://www.paper.edu.cn

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also act as an autocrine/paracrine factor at the pituitary level expression in the lateral hypothalamus (Yoshizato et al., to amplify the somatotroph responsiveness to GHRH 1998). To our knowledge, the physiological role of brain GH stimulation (Zizzari et al., 2005). in regulating GHRH and SRIF secretion/expression has not Unlike ghrelin, leptin secreted from white adipocytes is a been previously examined (for a recent review on brain GH, see potent inhibitor of food intake (Macajova et al., 2004) and its Harvey and Hull, 2003). effect on GH release appears to be species-specific, being Besides the hypothalamic actions, an ultra-short feedback by stimulatory in the rat (Sone and Osamura, 2001) and pig (Saleri GH acting locally at the pituitary level via autocrine/paracrine et al., 2005) and inhibitory in human (Pombo et al., 2001). In the mechanisms has also been reported. In the rat, GH receptors are rat, leptin can increase GH pulse amplitude (Tannenbaum et al., ubiquitously expressed in the anterior pituitary (Fraser and 1998) by suppressing SRIF tone in the median eminence (Saleri Harvey, 1992), indicating that somatotrophs may serve as the et al., 2004). Using push–pull perfusion, leptin infusion into the target cells for endogenous GH. This idea is supported by the brain can increase GHRH but suppress SRIF release in the findings that GH treatment can attenuate GH secretion in bovine hypothalamus (Watanobe and Habu, 2002). At the pituitary pituitary cells (Rosenthal et al., 1991). These observations are level, leptin can induce GH synthesis and secretion via OB-Rb also consistent with the earlier reports that somatotroph cell receptors (Lloyd et al., 2001), presumably by coupling with the lines (e.g., GH3 cells) are known to secrete autocrine/paracrine MAPK MAPK JAK2/STAT5b, IRS/PI3K, and P42/44 /P38 signaling factor(s) to inhibit GH release (Lapp et al., 1989; Stachura et al., cascades (Otero et al., 2005). Recently, the secondary coupling 1990). Recently, transgenic mice lacking GH receptor expres- MAPK MAPK of P42/44 /P38 with L-type VSCC activation has been sion or with expression of a GH antagonist have been shown to reported in leptin-induced Ca2+ rise in porcine somatotrophs exhibit histological features in somatotrophs typical of secretory (Glavaski-Joksimovic et al., 2004), confirming that the GH- hyperactivity. Apparently, the level of “secretory hyperactivity” releasing effect of leptin is Ca2+ dependent. In the rat pituitary, is much more intense in the mice lacking GH receptors leptin is also expressed in gonadotrophs, somatotrophs, compared to the one with GH antagonist (Asa et al., 2000). The thyrotrophs, and folliculostellate cells (Jin et al., 2001; Sone marked difference in the histological changes in somatotrophs et al., 2001). Given that (i) leptin can stimulate NO production observed in these two cases has been interpreted as a supporting in the pituitary (Baratta et al., 2002) and (ii) NO donors and evidence in vivo for the idea of GH autoinhibition at the cGMP analogs can increase GH release in pituitary cell cultures pituitary level. Although the functional coupling of protein (Pinilla et al., 1999), an autocrine/paracrine component of GH kinases in the JAK/MAPK and JAK/IRS/PI3K cascades has regulation by leptin-induced NO production at the pituitary been reported for GH receptors (Kopchick and Andry, 2000; level has also been proposed (Sone and Osamura, 2001). Zhu et al., 2001), the signaling mechanisms mediating the In mammals, GH released from the pituitary by itself can inhibitory effects of ultra-short feedback on GH release are still exert a short-loop feedback on its own synthesis and secretion in unknown. Since there have been no previous studies on the somatotrophs by acting within the hypothalamus. In this case, autocrine/paracrine actions of GH on GH gene expression, it is GH can penetrate the blood–brain barrier presumably through not sure if GH ultra-short feedback can also affect GH synthesis receptor-mediated transcytosis at the choroid plexus (Cocu- at the pituitary cell level. lescu, 1999) and/or by retrograde bloodflow from the pituitary In mammals, there are also reports that do not support the to the brain (Paradisi et al., 1993). In the rat, the presence of GH idea of GH ultra-short feedback. For examples, GH treatment in the cerebrospinal fluid has been confirmed by radioimmu- is not effective in altering basal GH release in rat pituitary noassay (Temeli, 1984). Subsequent activation of GH receptors cells (Richman et al., 1981) or in purified rat somatotrophs in the hypothalamus alters the functionality of the arcuate and (Kraicer et al., 1988). The cause of the discrepancy compared periventricular nuclei to stimulate SRIF but inhibit GHRH to the study in bovine pituitary cells (Rosenthal et al., 1991) release into hypophyseal portal blood (Bertherat et al., 1993). is unclear but may be related to species-specific variations. In These modulatory effects, at least partly, are mediated by NPY the rat, pituitary transplanted under the renal capsule has been interneurons (Peng et al., 2001) and c-fos gene expression in the used as a model system to study GH release in vivo in the arcuate areas (Kamegai et al., 1994). Using the GHRH promoter absence of hypothalamic influences (Adler et al., 1983). In for transgenic studies, human GH gene was targeted to GHRH these studies, a normal range of GH levels in blood can be neurons in the hypothalamus to induce dwarfism in the rat by detected after grafting of the whole pituitary or pituitary local feedback of GH actions (Flavell et al., 1996). This short- fragments into the kidney capsule. In static cultures of loop feedback of GH can be blocked by central administration pituitary cells, a progressive increase in basal GH secretion is of a GH antagonist (Nass et al., 2000) or by brain infusion of commonly observed for days to weeks in the absence of GH- antisense against GH receptor (Pellegrini et al., 1996). For SRIF releasing factors (for a review of the literatures, see Rousseau neurons in the periventricular areas, there is increasing evidence et al., 2001). Since a similar phenomenon can also be noted suggesting that GH can induce SRIF production by stimulating in static incubation experiments under serum-free culture STAT5b expression and phosphorylation (Bennett et al., 2005). conditions (Oosterom et al., 1985), the gradual rise in GH In recent years, it has been shown that GH is also expressed in release as a result of serum factors in culture medium is the brain, especially in the areas covering the putamen, unlikely. If ultra-short feedback indeed is a part of the thalamus, hippocampus, and hypothalamus (Nyberg, 2000). In physiological mechanisms regulating GH secretion, it will be the rat, brain injection of GHRH can elevate GH gene rather difficult to interpret the results of these in vivo and in 中国科技论文在线 http://www.paper.edu.cn

288 A.O.L. Wong et al. / Comparative Biochemistry and Physiology, Part A 144 (2006) 284–305 vitro studies because the local actions of endogenous GH 3. Feedback regulation of GH synthesis and secretion in should have inhibited basal GH release at the pituitary level. fish Recently, there has been increasing evidence for local interactions of hormonal factors in the pituitary to modulate Neuroendocrine regulation of GH release in fish is quite pituitary functions (Schwartz, 2000). These paradoxical different from that of mammals. This difference can be traced observations regarding the ultra-short feedback by GH may back to the unique organization of the hypothalamo-pituitary suggest the possible existence of an autocrine/paracrine axis in fish models. Unlike mammals, a functional hypophyseal component at the pituitary level maintaining the spontaneous portal blood system is absent and the anterior pituitary of secretion of GH from somatotrophs irrespective of the modern-day bony fish (or teleosts) is directly innervated by potential autoinhibition by GH release. nerve fibers from the hypothalamus (Gorbman, 1995; Kah et al., The autocrine/paracrine actions of GH not only can be 1993). Furthermore, the endocrine cells in the anterior pituitary noted at the pituitary level but also in peripheral tissues/ of bony fish also exhibit a clear pattern of zonal distribution organs. In mammals, especially in the rat, GH is expressed in (Fig. 2), which is at variance with the random distribution found tissues other than the pituitary (Harvey et al., 2000) and this in mammals (Doerr-Schott, 1980). For examples, in goldfish extrapituitary GH can serve as a local growth factor (Ge and Peter, 1994) and carp (Wong et al., 1998b), lactotrophs regulating immune responses, reproductive functions, neuro- are located exclusively in the rostral pars distalis whereas the nal survival, and embryonic development (Harvey and Hull, distribution of somatotrophs and gonadotrophs are restricted to 1997; Harvey et al., 1998). In the gonad, local production of the proximal pars distalis. In some species, e.g., bluefin tuna GH has also been reported, which may represent an (Kagawa et al., 1998), gonadotrophs can also be found along the emergency mechanism to allow for rapid regulation of external rim bordering the neurointermediate lobe. Unlike cellular functions in gonadal tissues that are normally mammals, in which modulation of GH release occurs mainly in regulated by pituitary GH (Hull and Harvey, 2000). At the the hypothalamus by altering GHRH and SRIF secretion (i.e., a pituitary level, besides its role in ultra-short feedback, GH can classic “dual control” model), GH release in bony fish is also affect LH and FSH secretion and probably induce IGF-I regulated directly at the pituitary level by a multitude of production in an autocrine/paracrine manner (Schwartz, neuroendocrine factors (Table 1). This phenomenon is also 2000). Since GH binding sites are ubiquitously expressed in described as the “multifactorial” model for GH regulation in the anterior pituitary (Fraser and Harvey, 1992), it is teleosts (Peng and Peter, 1997). This “multifactorial” complex is conceivable that pituitary cells other than somatotrophs can composed of: (i) neuropeptides [e.g., GnRH (Klausen et al., also serve as the “target cells” for the local actions of GH. 2002; Li et al., 2002), GHRH (Luo and McKeown, 1991b; Recently, the pursuit on the intrapituitary functions of GH has Vaughan et al., 1992), NPY (Peng et al., 1993, 1990), PACAP become more interesting with the findings of “multihormonal” (Montero et al., 1998; Wong et al., 2000), TRH (Kagabu et al., cell types in the pituitary. In the anterior pituitary of the rat 1998; Trudeau et al., 1992), and SRIF (Kwong and Chang, and mouse, about 30% of the cells express two, three, or 1997; Wong et al., 1993c)], (ii) biogenic amines [e.g., dopamine more pituitary hormone mRNAs and most of these “multi- (Melamed et al., 1996; Wong et al., 1993a), serotonin (Wong et hormone mRNA cells” also carry detectable levels of GH al., 1998c), and norepinephrine (Lee et al., 2000; Yunker et al., transcripts. Co-storage of multiple hormone proteins in the 2000)], (iii) excitatory/inhibitory amino acids [e.g., GABA same cell, however, could not be demonstrated in these cell (Trudeau et al., 2000a) and glutamate (Trudeau et al., 1996)], populations (Seuntjens et al., 2002). Unlike the “multi- (iv) steroids [e.g., testosterone (Huggard et al., 1996) and hormone mRNA cells”, other subsets of pituitary cells do estradiol (Melamed et al., 1995b; Zou et al., 1997)], (v) thyroid produce a combination of more than one hormone proteins. hormones [e.g., T3/T4 (Luo and McKeown, 1991a; Moav and For examples, a subset of pituitary cells called mammoso- McKeown, 1992)] and (vi) growth factors [e.g., IGF (Frucht- matotropes expresses both GH and PRL at the protein level man et al., 2001; Kajimura et al., 2002) and activin (Ge and (Frawley and Boockfor, 1991). In the rat, TSH can be co- Peter, 1994)]. These neuroendocrine factors by acting together localized with GH in the secretory granules in a small number integrate the signals from the brain, within the pituitary, and of pituitary cells called thyrosomatotrophs (Horvath et al., from the periphery to modulate GH release according to the 1990). Recently, a subset of pituitary cells with phenotypic physiological status, developmental stages, and seasonal cycle characteristics of gonadotrophs and somatotrophs (both at the of the animal (Fig. 3). In contrast to mammals, GHRH does not transcript and protein levels) has been reported. Since the act as a major GH-releasing factor in fish and PACAP, a receptors for GnRH and GHRH can be detected in these cells, structurally related peptide evolved with GHRH along the it is assumed that they are also responsive to stimulation by glucagon lineage (Sherwood et al., 2000), has been proposed to GnRH and GHRH (Childs, 2000). During the proestrus, these be the “ancestral GHRH” in lower vertebrates (Montero et al., gonadosomatotrophs may transdifferentiate into LH- and 2000). Based on the extensive studies in the goldfish as well as FSH-secreting cells under the influence of estrogen and in other fish species, it is now known that the AC/cAMP/PKA activin (Childs, 2002). Whether the functionality or transdif- pathway (Wong et al., 1994a,c), PLC/IP3/PKC pathway (Chang ferentiation of these “multihormonal somatotrophs” is under et al., 1991; Wong et al., 1994c), calmodulin/CAM kinase II the control of GH and/or IGF-I remains an interesting topic cascade (Chang et al., 2000), [Ca2+]e entry through VSCC for future research. (Jobin and Chang, 1992; Wong et al., 1994b), ryanodine- 中国科技论文在线 http://www.paper.edu.cn

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AB C

RPD RPD RPD

PPD PPD PPD

NIL PRL cells NIL GH cells NIL GTH cells

RPD RPD RPD

PPD PPD PPD

NIL PRL cells NIL GH cells NIL GTH cells

Fig. 2. Zonal distribution of pituitary cells in the anterior pituitary of teleost. Immunostaining of lactotrophs (A), somatotrophs (B), and gonadotrophs (B) was performed in the grass carp pituitary sections using the avidin–biotin–peroxidase complex method with antisera specific for carp PRL (1:100,000), GH (1:500,000), and LH/GTH-II (1:60,000), respectively. Dark field pictures for zonal distribution of the three cell types are presented in the upper panels (original magnification ×50; adapted from Wong et al., 1998b with permission), whereas the corresponding bright field pictures are presented in the lower panels (original magnification ×100). In the carp pituitary, lactotrophs (PRL cells) are located exclusively in the rostral pars distalis (RPD). In contrast, somatotrophs (GH cells) and gonadotrophs (GTH cells) are restricted to the proximal pars distalis (PPD). These three cell types, however, can not be identified in the neurointermediate lobe (NIL).

sensitive [Ca2+]i stores (Johnson and Chang, 2000; Wong et al., gene expression has been reported in the endocrine pancreas 2001), mitochondrial Ca2+ buffering (Johnson and Chang, of rainbow trout (Melroe et al., 2004), the direct effects of 2005), [Na+]e and Na+/H+ antiports (Van Goor et al., 1997), GH in modulating the expression/ secretion of GH-releasing arachidonic acid (Chang et al., 1996), and locally produced factors in the hypothalamus have not been demonstrated in nitric oxide (Uretsky and Chang, 2000) are involved in the fish. Regarding the functional role of IGF, the long-loop signal transduction mechanisms for GH secretion in fish feedback by IGF release from the liver appears to be well models. Regarding the mechanisms for GH synthesis, activation conserved during the course of vertebrate evolution. When of PKA- and PKC-dependent cascades has been shown to compared to mammalian counterparts, the molecular structure increase GH mRNA levels in fish pituitary cells, e.g., in tilapia of IGFs (Moriyama et al., 2000) and IGF-I receptors (Maures (Melamed et al., 1996). Besides, cAMP induction of GH gene et al., 2002) are highly conserved (for a review on molecular transcription in fish is mediated through CRE sites in the GH evolution of IGF and IGF-I receptors, see Wood et al., 2005). promoter (Wong et al., 1996) and the process is dependent on Except in agnatha (e.g., hagfish), in which only one form of Pit-1 expression (Sekkali et al., 1999). These findings are IGF can be found (Nagamatsu et al., 1991), both IGF-I and consistent with the recent reports in mammals that CREB -II are expressed in the liver of adult fish in teleosts and recruitment to its target promoter (e.g., PRL promoter) can be elasmobranchs (Moriyama et al., 2000). Furthermore, GH modulated by Pit-1 (Ferry et al., 2005), probably through direct treatment is known to stimulate IGF secretion and IGF changes in chromatin structures by altering histone acetylation mRNA expression in the liver of fish species, including (Kievit and Maurer, 2005). salmon (Pierce et al., 2004), catfish (Peterson et al., 2005), Unlike mammals, the feedback control of GH synthesis goldfish (Kermouni et al., 1998), common carp (Tse et al., and secretion in fish has not been fully characterized. The 2002), seabream (Carnevali et al., 2005) and rainbow trout direct in vivo evidence for the presence of GH negative (Moriyama, 1995). Recently, the common carp IGF-I gene feedback in fish comes from the transgenic studies. In has been cloned and its promoter activity can be up-regulated transgenic salamon (Mori and Devlin, 1999) and tilapia by GH stimulation (Vong et al., 2003b). Since a putative (Caelers et al., 2005), ectopic expression of GH has been STAT5b binding site can be located in the carp IGF-I shown to cause a reduction in the size of the pituitary gland promoter, it is conceivable that GH-induced IGF-I gene with a drop in pituitary GH mRNA levels. Whether these transcription is mediated via the JAK/STAT pathway. Similar effects are caused by the direct action of GH and/or indirect to mammals, IGFs (both IGF-I and -II) inhibit GH secretion actions via IGF is still unclear. Although GH-induced SRIF (Duval et al., 2002; Fruchtman et al., 2000)andGH 中国科技论文在线 http://www.paper.edu.cn

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Table 1 Table 1 (continued) Multifactorial regulation of growth hormone in fish models Signals within the pituitary References Signals from the brain References Activin Expressed in somatotrophs to induce/maintain 36 Neuropeptides GH release (e.g., goldfish) GnRH Stimulate GH release and GH mRNA expression 1, 2, 3 IGF-I Expressed in gonadotrophs to prevent apoptosis 37 (e.g., goldfish, tilapia, common carp) in somatotrophs (e.g., tilapia) Direct action at the pituitary level (e.g., goldfish, 1, 2, 3 common carp, tilapia) Signals from peripheral organs/tissues References GH response may require IGF-I treatment (e.g., 4 IGFs GH stimulates IGF-I and -II expression in the 38, 39 rainbow trout) liver of adult fish (e.g., carp, seabream) GHRH Mild to weak effect on GH release at the pituitary 5, 6, 7 Inhibit GH release, GH content, and GH mRNA 40, 41, 42 level (e.g., goldfish, rainbow trout) expression (e.g., tilapia, rainbow trout) No effect on GH release in some species (e.g., 8, 9, 10 Direct action at the pituitary level via IGF-I 43 European eel, grass carp, turbot) receptors (e.g., striped bass) No report on GH gene expression in fish Sex steroids Effects tend to vary according to fish species PACAP Stimulate GH release and GH mRNA expression 11, 12 Central actions to affect hypothalamic GH 44, 45 (e.g., goldfish, European eel) regulators (e.g., GnRH and SRIF) Direct action at the pituitary level via PAC-1 11, 13 Pituitary action to induce GH release (e.g., E2 in 46 receptors (e.g., goldfish, common carp) tilapia) Encoded with GHRH in the same gene and 14 Pituitary action to increase GH mRNA 47 proposed to be the ancestral GHRH expression (e.g., T in goldfish) SRIF Inhibit GH release at the pituitary level via SST-2 15, 16 May increase GH production at the translational 48 receptors (e.g., goldfish) level (e.g., E2 in goldfish) Do not affect GH mRNA expression (e.g., tilapia, 17, 18 Modify pituitary expression of various isoforms 49, 50 rainbow trout) of SRIF receptors (e.g., E2 in goldfish) May inhibit GH production at the translational 18 T3/T4 Increase GH secretion directly at the pituitary 51 level (e.g., rainbow trout) level (e.g., rainbow trout) Do not induce post-inhibition GH rebound like 9, 15 Induce GH mRNA expression in pituitary cells 52, 53 mammals (e.g., goldfish, grass carp) (e.g., rainbow trout, common carp) NPY Stimulate GH release directly at the pituitary 19, 20 Stimulate de novo GH synthesis in isolated 7 level (e.g., goldfish) pituitaries (e.g., tilapia) Induce GH release indirectly by GnRH via 20 Glucocorticoid Increase GH release at the pituitary level (e.g., 51 presynaptic Y2 receptors (e.g., goldfish) rainbow trout) TRH Stimulate GH release directly at the pituitary 21, 22 Increase GH mRNA levels in pituitary cells (e.g., 54, 55 level (e.g., goldfish, common carp) tilapia, channel catfish) Increase plasma GH but no effect on GH release 7 Ghrelin Increase GH release and/or GH mRNA level at 56, 57 at the pituitary level (e.g., tilapia) the pituitary level (e.g., tilapia, goldfish) CRH Stimulate GH release at the pituitary level (e.g., 23 GH-releasing actions mimicked by GHRPs and 58, 59 European eel) non-peptide GHS (e.g., catfish, seabream) CCK Stimulate GH release at the pituitary level (e.g., 24 CNP/VNP Increase GH release at the pituitary level (e.g., 60 goldfish) tilapia) Bombesin Stimulate GH release at the pituitary level (e.g. 25 goldfish) References: (1) Klausen et al., 2001; (2) Melamed et al., 1996; (3) Li et al., 2002; (4) Weil et al., 1999; (5) Vaughan et al., 1992; (6) Luo and McKeown, 1991b; (7) Neurotransmitters Melamed et al., 1995a; (8) Montero et al., 1998; (9) Wong et al., 1998b; (10) Dopamine Stimulate GH release and/or GH mRNA 2, 26 Rousseau et al., 2001;(11)Wong et al., 1998a; (12) Montero et al., 1998; (13) expression (e.g., tilapia, goldfish) Xiao et al., 2002; (14) Montero et al., 2000; (15) Wong et al., 1993b; (16) Lin et Direct action at the pituitary level via D1 9, 26 al., 2000; (17) Melamed et al., 1996; (18) Yada and Hirano, 1992; (19) Peng et receptors (e.g., goldfish, grass carp) al., 1990; (20) Peng et al., 1993; (21) Trudeau et al., 1992; (22) Lin et al., 1993a, Indirect action in the brain to suppress SRIF gene 27 b; (23) Rousseau et al., 1999; (24) Himick et al., 1993; (25) Himick and Peter, expression (e.g., goldfish) 1995; (26) Wong et al., 1993a; (27) Otto et al., 1999; (28) Lee et al., 2000; (29) Norepinephrine Inhibit GH release at the pituitary level via α2 28, 29 Yunker et al., 2000; (30) Somoza and Peter, 1991; (31) Wong et al., 1998c; (32) receptors (e.g., goldfish) Trudeau et al., 2000a; (33) Trudeau et al., 2000b; (34) Trudeau et al., 1996; (35) Induce post-inhibition GH rebound, which can be 28 Holloway and Leatherland, 1997; (36) Ge and Peter, 1994; (37) Melamed et al., potentiated by GnRH (e.g., goldfish) 1999; (38) Vong et al., 2003a,b; (39) Carnevali et al., 2005; (40) Perez-Sanchez Serotonin Inhibit GH secretion at the pituitary level via 30, 31 et al., 1992; (41) Kajimura et al., 2002; (42) Fruchtman et al., 2000; (43)

5HT2 receptors (e.g., goldfish) Fruchtman et al., 2002; (44) Breton and Sambroni, 1996; (45) Canosa et al., GABA Reduce serum GH, probably by indirect actions 32, 33 2002; (46) Melamed et al., 1995b; (47) Huggard et al., 1996; (48) Zou et al., through GnRH (e.g., goldfish) 1997; (49) Cardenas et al., 2003; (50) Canosa et al., 2003; (51) Luo and Do not affect GH release at the pituitary level 32 McKeown, 1991a; (52) Moav and McKeown, 1992; (53) Farchi-Pisanty et al., (e.g., goldfish) 1995; (54) Uchida et al., 2004; (55) Peterson and Small, 2005; (56) Kaiya et al., Glutamate Reduce serum GH, probably by subsequent 33, 34 2003a,b,c; (57) Unniappan and Peter, 2004; (58) Drennon et al., 2003; (59) Chan conversion to GABA (e.g., goldfish) et al., 2004a,b; (60) Eckert et al., 2003. Induce GH release at the pituitary level via 35 NMDA receptors (e.g., rainbow trout) 中国科技论文在线 http://www.paper.edu.cn

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GlutamateGlutamate

BombesinBombesin

Fig. 3. Feedback regulation of growth hormone release in fish. In the fish pituitary, GH release from somatotrophs is under the “multifactorial” control of various neuropeptides and neurotransmitters. These stimulatory/inhibitory regulators from the brain can be delivered to the somatotrophs in the anterior pituitary by direct innervation from the hypothalamus. Apart from the signals from the hypothalamus, GH release can be regulated by local signals within the pituitary, including activin. Besides, GH by itself can also induce positive autoregulation on somatotrophs to increase GH synthesis and secretion at the pituitary level. GH released into systemic circulation can act on the liver to increase IGF-I and -II production, which will initiate a long-loop feedback on the pituitary to suppress GH secretion. GH released from the pituitary can also stimulate/potentiate steroidogenesis in the gonad and sex steroids produced will exert both positive and negative effects on GH synthesis and secretion in somatotrophs. Probably, GH can also modulate energy homeostasis in fish, which may have an effect on the secretion of ghrelin from the stomach and leptin from white adipocytes. These hormones not only can regulate food intake in fish models but may also act at the pituitary level and/or hypothalamic level to induce GH release from somatotrophs.

production/gene expression (Fruchtman et al., 2000; Kajimura expression can be located in the optic tectum and hypothal- et al., 2002) through IGF-I receptors expressed in fish amus (Smith et al., 2005). These findings may provide the pituitary cells (Fruchtman et al., 2002). Regarding the signal anatomical basis for future studies on IGF regulation of transduction mechanisms for IGF action, e.g., in striped bass hypophysiotropic factors in fish models. pituitary cells, IGF-I can reduce GH release through Similar to mammals, hormones released from peripheral MAPK S6K activation of PI3K and P42/44 but not P70 (Frucht- tissues are known to modulate GH secretion and synthesis in man et al., 2001). In a recent study in grass carp pituitary fish models. In salmons, GH is involved in the regulation of cells, it has been shown that both IGF-I and -II can inhibit steroidogenesis, spermatogenesis, and oocyte maturation GH gene transcription by up-regulation of calmodulin gene (LeGac et al., 1993). Furthermore, GH receptors are expressed expression and subsequent activation of calmodulin/calci- in the gonad of fish species, including the rainbow trout (Gomez neurin-dependent signaling cascades (Huo et al., 2005). It is et al., 1998) and tilapia (Kajimura et al., 2004). In some cases, also worth mentioning that IGFs has been reported to induce GH can also exert a direct effect on ovarian tissue to induce LH (Huang et al., 1998), FSH (Baker et al., 2000) and PRL testosterone and estradiol production [e.g., seatrout (Singh and release in fish (Fruchtman et al., 2000; Kajimura et al., 2002), Thomas, 1993)] or to potentiate steroidogenesis induced by suggesting that IGF may act on pituitary cells other than gonadotropins [e.g., goldfish (Van der Kraak et al., 1990)]. somatotrophs. Given that no information is available in fish These stimulatory actions are partly mediated by GH induction regarding IGF actions on GH-releasing factors expressed in of aromatase activity in the ovary through cAMP-dependent the hypothalamus, the central actions of IGF in GH feedback mechanisms (Singh and Thomas, 1993). Regarding the signal are still unknown. Recently, IGF-I receptors have been input to the pituitary from the gonad, the effects of sex steroids detected in the brain of brown trout and a high level of on GH release and GH gene expression appear to be species- 中国科技论文在线 http://www.paper.edu.cn

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specific. In tilapia, estradiol but not testosterone can induce GH this case, T3 and T4 treatment, both in vivo and in vitro, can release by acting directly at the pituitary level (Melamed et al., suppress GH secretion, GH content, and GH mRNA expression 1995b). These two hormones, nevertheless, are both effective in in the eel pituitary. These results are comparable to the stimulating GH secretion in common carp pituitary cells inhibitory effects of thyroid hormones on GH release reported (Degani et al., 1998). In the goldfish, estradiol increases GH in reptiles [e.g., turtle (Denver and Licht, 1990)] and birds [e.g., release and pituitary GH content without altering GH mRNA chicken (Denver and Harvey, 1991)] but are at variance with the levels, suggesting that the stimulatory influence on GH stimulatory effects well documented in mammals (Giustina and production may be acting at the translational level (Zou et al., Wehrenberg, 1995). Since TRH [e.g., goldfish (Trudeau et al., 1997). In the same animal model, testosterone can also up- 1992)] and TSH [e.g., tilapia (Melamed et al., 1995a)] are regulate GH mRNA expression by direct actions at the pituitary known to stimulate GH release in fish by acting directly at the level (Huggard et al., 1996). However, gonadal steroids appear pituitary level, the possibility of indirect actions of T3/T4 to to have no pituitary effects on GH gene expression in rainbow inhibit GH secretion by negative feedback on TRH and/or TSH trout (Melamed et al., 1998) and European eel (Rousseau et al., can not be excluded. 2002). In these cases, the amount of GH mRNA expressed in As mentioned earlier, ghrelin from the stomach and leptin pituitary cells prepared from the two species is not affected by from white adipose tissue may represent a novel form of treatment with estradiol or testosterone. Apart from the pituitary “peripheral signals” linking GH regulation and energy homeo- actions, the GH-releasing effects of sex steroids can also be stasis. In burbot, fasting can reduce leptin immunoreactivity in indirect by acting within the brain to modulate the expression of blood with a concurrent drop in liver glycogen content GH-release inhibitors and/or GH-releasing factors. For exam- (Nieminen et al., 2003). Similar treatment in goldfish, however, ples, estradiol is known to increase GnRH content in the brain can elevate serum ghrelin and ghrelin transcript expression in of rainbow trout (Breton and Sambroni, 1996), which is the gut (Unniappan et al., 2004). These findings are consistent consistent with the previous finding that GnRH gene expression with the idea that the release of these two hormones can be in fish (e.g., salmon) can be up-regulated by estrogen receptor modified according to the status of energy balance in the body. binding to EREs in the GnRH promoter (Klungland et al., In recent years, ghrelin has been cloned in fish species, 1993). Recently, estradiol treatment in vivo has been shown to including the goldfish (Unniappan et al., 2002), tilapia (Kaiya et reduce SRIF SST-2 receptor expression in the goldfish pituitary al., 2003c), eel (Kaiya et al., 2003b) and rainbow trout (Kaiya et (Cardenas et al., 2003), suggesting that estrogen may reduce the al., 2003a), and its molecular structure is highly comparable to responsiveness of the pituitary to SRIF inhibition. In the that of mammals (Kojima and Kangawa, 2005). Although the goldfish, interestingly enough, similar treatment also increases size of fish ghrelin (18–20 a.a.) in general tends to be smaller SRIF gene expression in the brain (Canosa et al., 2002) and than that of mammals (28 a.a.), the N-terminal core with an SST-1 and -5 receptor expression in the pituitary (Canosa et al., acyl-modification site at position 3 (S/T residue) is well 2003). Since these changes also occur with a rise in serum GH conserved (for a recent review on fish ghrelin, see Unniappan levels, these results raise the possibility that GH release induced and Peter, 2005). Similar to mammals, ghrelin is expressed in by estrogen may also activate some “feedback mechanisms” for the stomach of fish models [e.g., in rainbow trout (Sakata et al., signal termination by altering the expression levels of SRIF and 2004)] and serves as an orexigenic factor in vivo [e.g., in its receptors along the brain–pituitary axis. goldfish (Unniappan et al., 2004) and tilapia (Riley et al., In fish models, it has been known for a long time that thyroid 2005)]. In fish pituitary cultures (both organ and cell cultures), hormones (T3 and T4), the key regulators of energy metabolism, ghrelin can serve as a potent stimulator for GH secretion, e.g., in can act synergistically with GH to enhance body growth (Eales, rainbow trout (Kaiya et al., 2003a), tilapia (Kaiya et al., 2003c), 1990). In rainbow trout, GH can induce extrathyroidal T3 goldfish (Unniappan and Peter, 2004) and seabream (Chan et production by activating 5′-monodeiodinase activity in the liver al., 2004a). This GH-releasing effect can also occur with [e.g., (MacLatchy et al., 1992) and the process is under T3 in goldfish (Unniappan and Peter, 2004)] or without the autoregulation at the hepatocyte level (Sweeting and Eales, concurrent increase in pituitary GH content or GH mRNA 1992). Besides, the receptors for thyroid hormones can be levels [e.g., in tilapia (Riley et al., 2002) and seabream (Chan et detected in the fish pituitary [e.g., in common carp (Farchi- al., 2004a)]. Ghrelin receptors, namely GHS-1a and -1b Pisanty et al., 1995) and T3/T4 treatment in vitro can induce GH receptors, have been recently cloned in black seabream (Chan release (Luo and McKeown, 1991a), GH de novo synthesis and Cheng, 2004). Functional expression of GHS-1a receptors (Melamed et al., 1995a) and GH transcript expression in fish has revealed that their activation can lead to Ca2+ entry via 2+ MAPK pituitary cells (Moav and McKeown, 1992). These findings are VSCC, [Ca ]i mobilization, IP3 production, and P42/44 in agreement with the previous report that TRE-like motifs can activation (Chan et al., 2004b). Whether these post-receptor be identified in the 5′ promoter of GH gene in fish [e.g., in signaling mechanisms also contribute to the GH-releasing rainbow trout GH1 and GH2 genes (Yang et al., 1997)], effects of fish ghrelin still remains to be determined. suggesting that GH gene transcription is under the control of Unlike ghrelin, the molecular cloning of leptin in fish has not thyroid hormones. Nevertheless, the functional role of T3/T4 in been successful. Although leptin immunoreactivity can be GH regulation is not always stimulatory. Recently, a negative detected in fish models (Johnson et al., 2000), the structural feedback on GH synthesis and secretion by thyroid hormones identity of fish leptin has not been established. Using leptin of has been reported in European eel (Rousseau et al., 2002). In the mammalian origin (e.g., human or mouse leptin), it has been 中国科技论文在线 http://www.paper.edu.cn

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shown that leptin can inhibit food intake in the goldfish (Volkoff idea about the mechanisms by which exogenous GH can et al., 2003) probably through differential regulation of NPY, impart its feedback control on GH release and synthesis, CCK, and CART in the brain (Volkoff et al., 2005). At the especially in commercial fish species. pituitary level, leptin is known to induce hormone release/gene Recently, we have examined the autocrine/paracrine expression of LH [e.g., European eel (Peyon et al., 2001)], FSH mechanisms regulating GH synthesis and secretion in the carp [e.g., rainbow trout (Weil et al., 2003)], somatolactin [e.g., sea species. Grass carp was selected as an animal model as it is a bass (Peyon et al., 2003)], and TSH [e.g., bighead carp key component of the carp polyculture system (Lin and Peter, (Chowdhury et al., 2004)]. However, direct actions of leptin on 1991) and has a high commercial value in Asian countries GH regulation have not been demonstrated in fish. In the [∼3.6 million metric tons/year, equivalent to 12.9% of global goldfish, brain injection of leptin can up-regulate CCK but finfish production and a cash value of 3.05 billion USD (data down-regulate NPY gene expression in the hypothalamus from FAO website)]. Using a static incubation approach, we (Volkoff et al., 2003). In the same animal model, NPY and CCK have shown that treatment with exogenous GH (e.g., porcine nerve fibers are present in the anterior pituitary and play a role GH) could elevate GH release, GH production, and GH mRNA in stimulating GH release (Himick et al., 1993; Peng et al., levels in grass carp pituitary cells (Fig. 4, left panels). 1993). These findings raise the possibility that leptin may Consistent with these findings, the opposite effects could be modify GH secretion in fish through indirect actions on observed by removing endogenous GH using immunoneutra- hypothalamic neuropeptides involved in appetite control. lization with an antiserum for carp GH (Zhou et al., 2004b). In More recently, a “leptin-like” gene has been isolated in the the same study, GH immunoneuralization was also effective in puffer fish using a genomic synteny approach (Kurokawa et al., 2005). Although protein modeling has revealed that the 3-D A structure of this “fish leptin” is comparable to that of mammals, the deduced a.a. sequence is only 13.2% homologous to that of human leptin. If the identity of this “fish leptin” can be further confirmed by functional studies (e.g., by feeding experiments), μ μ it would suggest that the primary structure of leptin has undergone a lot of a.a. substitutions during the evolution from fish to mammals. Whether these sequence modifications can also affect the functionality of the peptide in fish remains an interesting question for future investigations. B 4. Intrapituitary feedback loop for GH regulation in fish model

Unlike long-loop feedback, direct evidence for ultra-short feedback in fish by local actions of endogenous GH is still lacking. To our knowledge, there is only a single report in rainbow trout inferring the possible existence of GH ultra- short feedback (Agustsson and Bjornsson, 2000). In this case, in vitro perfusion of intact trout pituitaries with ovine GH was C found to inhibit basal GH secretion. Since the nerve fibers/ nerve terminals for neurotransmitters and neuropeptides were still intact in this pituitary preparation, the authors of this report stress that their results do not exclude the possibility of indirect actions of GH through local release of GH-release inhibitors (e.g., SRIF). The results of this in vitro perfusion study are also at variance with that of a previous report using primary cultures of rainbow trout pituitary cells. In this previous study, static incubation with bovine GH, unlike the inhibitory action of IGF-I, was unable to cause any changes

in basal GH release in trout pituitary cells (Blaise et al., PorcinePorcine GGHH cconcentrationoncentration ((ng/ml)ng/ml) HCGHCG cconcentrationoncentration ((U/ml)U/ml) 1995). Apparently, the functional role of ultra-short feedback at the pituitary level needs to be further clarified in fish Fig. 4. Effects of exogenous growth hormone (GH) and gonadotropin on (A) GH models. This will be important not only for basic research but release, (B) GH production, and (C) GH mRNA expression in grass carp – also for the potential application of GH in finfish aquaculture. pituitary cells. Pituitary cells were incubated with porcine GH (1 100 ng/ml, left panels) or human chorionic gonadotropin (HCG, 5–40 U/ml, right panels) for Given that recombinant GH has received increasing attention 24 h. Treatment groups denoted by different letters represent a significant as a feed additive for growth promotion in fish farms (Ho et difference at Pb0.05 (ANOVA followed by Fisher's least significance al., 1998; Jin et al., 1999), it will be essential to have a clear difference test). 中国科技论文在线 http://www.paper.edu.cn

294 A.O.L. Wong et al. / Comparative Biochemistry and Physiology, Part A 144 (2006) 284–305 blocking the stimulatory influence on GH mRNA expression the presence of an ultra-short feedback at the pituitary level in induced by GnRH, PACAP, and dopamine agonists. GnRH (Li fish models. et al., 2002), PACAP (Wong et al., 2000), and dopamine (Wong In the grass carp, similar to other teleosts, a clear zonation et al., 1993b) are documented GH-releasing factors in fish that of individual cell types can be identified in the anterior can induce GH secretion by acting directly at the pituitary level. pituitary (Fig. 2). The distribution of somatotrophs and In grass carp pituitary cells, GH-induced GH gene expression gonadotrophs are restricted to the proximal pars distalis. could be achieved by mechanisms acting at two different levels: Within this region, gonadotrophs always exhibit a patchy (i) at the transcriptional level by increasing the expression of distribution with cell clusters embedding in a matrix of GH primary transcripts in the nucleus, and (ii) at the post- somatotrophs (Wong et al., 1998b). The close proximity of transcriptional level by prolonging the half-life (T1/2)ofGH the two cell types appears to be well conserved in bony fish mRNA in the cytoplasm (Zhou et al., 2004a). Using laser [e.g., in goldfish (Ge and Peter, 1994) and tilapia (Melamed capture microdissection, expression of GH receptors in grass et al., 1995a)] and provides the anatomic basis for local carp somatotrophs was confirmed [Fig. 5], indicating that interactions between gonadotrophs and somatotrophs. In our endogenous GH can act in an autocrine/paracrine manner to recent studies, expression of LH receptors has been stimulate GH release and GH gene expression. Since GH- demonstrated in grass carp somatotrophs (Fig. 5), suggesting induced GH mRNA expression at the pituitary cell level could that somatotrophs can serve as the target cells for LH (also MAPK MAPK be blocked by inhibiting JAK2,P42/44 ,P38 , and refered to as GTH-II in teleosts). Using static incubation of PI3K, it is likely that the JAK2/MAPK and JAK2/PI3K carp pituitary cells, exogenous gonadotropin (e.g., HCG) was pathways are involved in the post-receptor signaling events found to stimulate GH release, GH production, and GH coupled to GH receptors expressed in carp somatotrophs (Zhou mRNA expression (Fig. 4, right panels) whereas the opposite et al., 2004a). These results clearly indicate that GH, besides its effects were obtained by removing endogenous LH using an well documented role as an endocrine hormone, can also serve antiserum for carp LH/GTH-II (Zhou et al., 2004b). The as a novel intrapituitary autocrine/paracrine factor maintaining/ stimulatory effect of HCG on GH mRNA expression was regulating (i) basal levels of GH synthesis and secretion and (ii) additive to that of PACAP and dopamine. However, the the sensitivity of somatotrophs to stimulation by hypophysio- stimulatory actions of these two GH-releasing factors could tropic factors. This “positive autoregulation” (Fig. 6), however, be abolished by LH immunoneutralization. In parallel studies, is at variance with the reports in mammals and argues against we have also shown that endogenous LH was required for

A B RT-PCR of LCM-captured Before Capture Immuno-identified GH cells

GH cells Pituitary cells

M Ctrl -RT +RT -RT +RT Laser Pulsed

GHR- (259 bp)

After Capture

LHR- (213 bp)

Captured on Cap

β-Actin- (280 bp)

Fig. 5. Expression of GH and LH receptors in grass carp somatotrophs. (A) Isolation of carp somatotroph by laser capture microdissection (LCM). Somatotrophs in mixed populations of pituitary cells were identified by immunostaining using GH antiserum (1:8000) and captured on LCM HS Caps by laser pulse at 65 mW with a beam size at 7.5 μm in diameter. (B) RT-PCR of GH receptors (GHR) and LH receptors (LHR) in LCM-captured somatotrophs. About 250 somatotrophs were captured on individual caps for RT-PCR using primers for grass carp GHR and LHR, respectively. In this study, RT-PCR of mixed populations of pituitary cells was used as a parallel control, and PCR of β actin was used as an internal control. (Adapted from Zhou et al., 2004a with permission). 中国科技论文在线 http://www.paper.edu.cn

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↑ GHGH ssecretionecretion

↑ GHGH mmRNARNA

↑ GHGH ccontentontent

↑ GHGH mRNAmRNA stabilitystability

↑ GHGH ggeneene ttranscriptionranscription

↑ GHGH mmRNARNA

↑ GHGH pproductionroduction (+)

Fig. 6. Positive autoregulation of GH synthesis and secretion by GH released from carp somatotrophs. In the carp pituitary, locally secreted GH can act in an autocrine/ paracrine manner to stimulate GH release, GH production, and GH mRNA expression in somatotrophs (or GH cells). These stimulatory effects are mediated through GH receptors coupled to the JAK/MAPK and JAK/PI3K pathways. Activation of GH receptors can induce GH production in somatotrophs by increasing GH gene transcription and enhancing GH transcript stability.

activation of GH promoter activity and production of GH the goldfish (Marchant et al., 1989), common carp (Lin et al., primary transcripts. Unlike GH, endogenous LH did not 1993a), and tilapia (Melamed et al., 1995a)]. The paracrine improve GH mRNA stability but rather enhanced the effects of LH on GH release and synthesis observed in the clearance of GH transcripts in grass carp pituitary cells grass carp suggest that local interactions between gonado- (Zhou et al., 2005). These results clearly indicate that LH can trophs and somatotrophs may also contribute to the parallel act as a paracrine factor in the carp pituitary to stimulate GH changes in LH and GH secretion in fish, especially in synthesis and secretion. As reflected by the opposite effects seasonal breeders with overlapping somatic growth and on GH mRNA clearance and GH gene transcription, LH can gonadal growth during the spawning period. also enhance the turnover of GH mRNA, which may allow In grass carp pituitary cells, static incubation with exogenous for a rapid response at the transcript level to stimulation by gonadotropin (e.g., HCG) could activate cAMP production. GH-releasing factors. In rainbow trout, parallel increases in Furthermore, HCG-induced GH mRNA expression was mim- the population size of somatotrophs and gonadotrophs can be icked by stimulating cAMP synthesis and blocked by inhibiting noted during sexual maturation (Weil et al., 1995). In white AC and PKA. In the same study, HCG-induced GH mRNA MAPK suckers (Stacey et al., 1984) and goldfish (Marchant and expression was also sensitive to inhibition of JAK2,P42/44 , MAPK Peter, 1986), a close correlation between LH and GH release P38 and PI3K. Similar inhibitions, except for PI3K, were has been reported during the period of sexual recrudescence all effective in blocking GH mRNA expression induced by and spawning season. A similar correlation at the transcript activation of cAMP synthesis (Zhou et al., 2005). These results, level for these two hormones has been recently documented as a whole, indicate that LH can activate GH gene expression at in gilthead seabream (Meiri et al., 2004). These phenomena, the pituitary level via the AC/cAMP/PKA pathway functionally to a large extent, have been attributed to the stimulatory effect coupled to JAK2 and MAPKs. Apparently, a cAMP-indepen- of GnRH on GH and LH release at the pituitary level [e.g., in dent PI3K component is also involved. Given that (i) both LH 中国科技论文在线 http://www.paper.edu.cn

296 A.O.L. Wong et al. / Comparative Biochemistry and Physiology, Part A 144 (2006) 284–305 and GH can induce GH release in carp pituitary cells and (ii) the incubation approach, GH not only could suppress LH release GH responses to GH and LH appear to share some overlap in but also stimulate LHβ mRNA expression in grass carp pituitary signal transduction (e.g., JAK2, MAPK, and PI3K), it was cells. In parallel studies, LH production and LHβ mRNA levels speculated that the stimulatory actions of LH, at least partly, could be markedly reduced by removing endogenous GH using might be mediated by local release of GH at the pituitary level. immunoneutralization (Zhou et al., 2004b). These results, as a To test the hypothesis, GH immunoneutralization was per- whole, suggest that a local feedback loop may be present in the formed in carp pituitary cells exposed to HCG treatment. In this anterior pituitary of carp species (Fig. 8). Apparently, the case, HCG-induced GH mRNA expression was abolished by “driving force” of the feedback loop comes from LH released removing endogenous GH. In reciprocal experiments, interest- from gonadotrophs, which acts in a paracrine manner to ingly enough, removal of endogenous LH by immunoneutra- stimulate GH release from neighboring somatotrophs. Locally lization also blocked the stimulatory effects of GH on GH secreted GH then acts in an autocrine/paracrine manner to mRNA expression (Zhou et al., 2004b). These results indicate induce GH secretion and GH gene expression in somatotrophs. that LH and GH can interact in an autocrine/paracrine manner to Meanwhile, GH can also exert a negative feedback through modulate GH gene expression at the pituitary cell level. To paracrine actions to suppress LH release in adjacent gonado- further examine the dynamic interactions of the two hormones trophs. In this system, GH not only acts as an intrinsic “signal at the protein level, a perfusion approach was used to test the amplifier” to magnify the stimulatory effects of LH on acute effect of gonadotropin on GH release and vice versa (Fig. somatotrophs, but also serves as a local growth factor to 7). In carp pituitary cells under column perfusion, HCG was maintain/stimulate the gene expression and protein synthesis of effective in inducing a rapid rise in GH release. However, in LH in gonadotrophs. This local feedback loop formed by reciprocal experiments, GH was found to be inhibitory for basal functional interactions of gonadotrophs and somatotrophs may LH secretion. This inhibitory action was rapid and long lasting, represent a novel mechanism setting up the basal tones of GH especially under high doses of exogenous GH. Using a static secretion and GH gene expression at the pituitary level, which

FractionFraction nnoo ((55 mmin/in/ ffraction)raction) FractionFraction nnoo ((55 mmin/in/ ffraction)raction)

Fig. 7. Rapid kinetics of the reciprocal interactions of growth hormone and gonadotropin in carp pituitary cells. Acute effects of increasing doses of (A) human chorionic gonadotropin (HCG, 30–50 U/ml) on GH release and (B) porcine GH (10–1000 ng/ml) on LH release from grass carp pituitary cells under column perfusion. In these experiments, salmon GnRH (sGnRH) was used as a positive control and drug treatments were routinely fixed at 15 min as indicated by the vertical bars. The kinetics of hormone release before, during, and after HCG/GH stimulation is presented on the left, whereas the corresponding data for sGnRH treatment are presented on the right. Data presented are expressed as mean±SEM (N=4) and the average pretreatment GH and LH level was 28.4±1.9 and 1.44±0.2 ng/ml, respectively. (Adapted from Zhou et al., 2004b with permission). 中国科技论文在线 http://www.paper.edu.cn

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↑

(+) ↑

↑ transcriptiontranscription

(+) ↑ (-) ↑ stimustimulalationtion

↑

↓ ↑ β

↓ ↑

Fig. 8. Intrapituitary feedback loop for GH regulation in the grass carp by local interactions of gonadotrophs and somatotrophs. In the carp pituitary, LH released from gonadotrophs (or GTH cells) by acting in a paracrine manner can stimulate GH secretion, GH production, and GH mRNA expression in neighboring somatotrophs (or GH cells). The stimulatory effects of LH are mediated by LH receptors coupled to both cAMP-dependent (e.g., JAK/MAPK) and cAMP-independent signaling mechanisms (e.g., PI3K). After LH receptor activation, LH can induce GH production by increasing GH gene transcription and maintain the responsiveness of somatotrophs to exogenous stimulatons (e.g., by GH-releasing factors) by enhancing the turnover rate of GH transcripts. The stimulatory actions of LH on GH synthesis and secretion can be further amplified by positive autoregulation by GH acting at the level of somatotrophs. GH released from somatotrophs, however, can exert a negative feedback to inhibit LH release in gonadotrophs. Meanwhile, GH is also required for the maintenance of LH production by up-regulating LHβ mRNA expression. can be further modified by the regulatory signals from the GH-releasing factors (Chang et al., 2000)]. In addition, some of hypothalamus. the recently identified orexigenic factors in fish not only can maintain their functions in appetite control (Volkoff et al., 2005) 5. Conclusion but also play a role in regulating GH release and GH gene expression in the fish pituitary [e.g., ghrelin (Unniappan and Similar to mammals, GH release in fish is under the control Peter, 2004)]. Regarding the feedback mechanisms for GH of a multitude of regulating factors. Some of these factors are regulation, the long-loop feedback through IGF production in well conserved in terms of their regulatory functions [e.g., SRIF the liver appears to be well conserved from fish to mammals as a GH-release inhibitor (Lin and Peter, 2001)] whereas the (Moriyama et al., 2000). In contrast, the ultra-short feedback by others are unique to fish species [e.g., GnRH and dopamine as local actions of GH acting at the pituitary level may not be 中国科技论文在线 http://www.paper.edu.cn

298 A.O.L. Wong et al. / Comparative Biochemistry and Physiology, Part A 144 (2006) 284–305 present in fish models. Based on our recent studies in the grass Agustsson, T., Bjornsson, B.T., 2000. Growth hormone inhibits growth hormone carp, we have shown that endogenous GH can act on secretion from the rainbow trout pituitary in vitro. Comp. Biochem. Physiol. C 126, 299–303. somatotrophs to induce GH release and GH gene expression. Argente, J., Chowen-Breed, J.A., Steiner, R.A., Clifton, D.K., 1990. This “positive autoregulation” by GH constitutes a signal Somatostatin messenger RNA in hypothalamic neurons is increased by amplification step for an intrapituitary feedback loop formed by testosterone through activation of androgen receptors and not by local interactions between gonadotrophs and somatotrophs. aromatization to estradiol. Neuroendocrinology 52, 342–349. This feedback loop, by autocrine/paracrine communications via Asa, S.L., Coschigano, K.T., Bellush, L., Kopchick, J.J., Ezzat, S., 2000. Evidence for growth hormone autoregulation in pituitary somatotrophs in LH and GH release, may play a crucial role in maintaining (i) GH antagonist-transgenic mice and GH receptor-deficient mice. Am. J. basal levels of GH synthesis and secretion and (ii) the pituitary Pathol. 156, 1009–1015. responsiveness to stimulation by GH-releasing factors. These Baker, D.M., Davies, B., Dickhoff, W.W., Swanson, P., 2000. Insulin-like findings not only shed light on a novel mechanism for GH growth factor I increases follicle-stimulating hormone content and regulation, but also provide a functional account for the gonadotropin-releasing hormone-stimulated FSH release from coho salmon pituitary cells in vitro. Biol. Reprod. 63, 865–871. evolution of a close anatomical relationship between gonado- Baratta, M., Saleri, R., Mainardi, G.L., Valle, D., Giustina, A., Tamanini, C., trophs and somatotrophs in teleosts. It is also worth mentioning 2002. Leptin regulates GH gene expression and secretion and nitric oxide that production of fish lines with GH transgene has been used a production in pig pituitary cells. Endocrinology 143, 551–557. means to enhance the growth performance in commercial fish, Becker, K., Stegenga, S., Conway, S., 1995. Role of insulin-like growth factor I e.g., in Atlantic salmon (Du et al., 1992), common carp (Chen et in regulating growth hormone release and feedback in the male rat. Neuroendocrinology 61, 573–583. al., 1993), and channel catfish (Dunham et al., 1999). The Bennett, E., McGuinness, L., Gevers, E.F., Thomas, G.B., Robinson, I.C., research in this area, however, has been focused on the directed Davey, H.W., Luckman, S.M., 2005. Hypothalamic STAT proteins: expression of GH transgene in the liver to increase IGF regulation of somatostatin neurones by growth hormone via STAT5b. J. production [e.g., with the use of liver-specific methallothionein Neuroendocrinol. 17, 186–194. or antifreeze protein promoters (Chen et al., 1996)]. Our novel Bertherat, J., 1997. Nuclear effects of the cAMP pathway activation in somatotrophs. Horm. Res. 47, 245–250. findings of GH autoregulation in a carp species raise the Bertherat, J., Timsit, J., Bluet-Pajot, M.T., Mercadier, J.J., Gourdji, D., Kordon, possibility that the pituitary can also serve as a potential “target C., Epelbaum, J., 1993. Chronic growth hormone (GH) hypersecretion site” for GH transgene. This is particularly important judging induces reciprocal and reversible changes in mRNA levels from hypotha- from the findings that GH can maintain the pituitary lamic GH-releasing hormone and somatostatin neurons in the rat. J. Clin. – responsiveness to stimulation by GH-releasing factors. This Invest. 91, 1783 1791. Blaise, O., Weil, C., Le Bail, P.Y., 1995. Role of IGF-I in the control of GH phenomenon may also have clinical implications in patients secretion in rainbow trout (Oncorhynchus mykiss). Growth Regul. 5, with pituitary tumor or nasopharyngeal carcinoma. In these 142–150. patients, post-irradiation hypopituitarism is a common sequela Bluet-Pajot, M.T., Epelbaum, J., Gourdji, D., Hammond, C., Kordon, C., 1998. after radiotherapy and/or cranial irradiation. Using irradiated rat Hypothalamic and hypophyseal regulation of growth hormone secretion. – pituitary cells as a model, GH treatment was found to be Cell. Mol. Neurobiol. 18, 101 123. Breton, B., Sambroni, E., 1996. Steroid activation of the brain–pituitary effective in preventing cell death, maintaining secretory complex gonadotropic function in the triploid rainbow trout Oncorhynchus capacity, and restoring pituitary responsiveness to stimulation mykiss. Gen. Comp. Endocrinol. 101, 155–164. by GHRH, GnRH, TRH and CRH (Chiarenza et al., 2000). The Caelers, A., Maclean, N., Hwang, G., Eppler, E., Reinecke, M., 2005. local actions of GH in maintaining/restoring the normal Expression of endogenous and exogenous growth hormone (GH) mRNA responsiveness and functionality of pituitary cells may represent in a GH-transgenic tilapia (Oreochromis niloticus). Transgenic Res. 14, 95–104. a new facet of pituitary research that will have significant Caminos, J.E., Nogueiras, R., Blanco, M., Seoane, L.M., Bravo, S., Alvarez, C. impacts on biotechnology development and clinical studies. V., Garcia-Caballero, T., Casanueva, F.F., Dieguez, C., 2003. Cellular distribution and regulation of ghrelin messenger ribonucleic acid in the rat Acknowledgements pituitary gland. Endocrinology 144, 5089–5097. Canosa, L.F., Lin, X., Peter, R.E., 2002. Regulation of expression of somatostatin genes by sex steroid hormones in goldfish forebrain. The present study was supported by RGC (HK) and CRCG Neuroendocrinology 76, 8–17. grants (HKU) to A.O.L.W. Financial support from the Canosa, L.F., Lin, X., Peter, R.E., 2003. Effects of sex steroid hormones on the Department of Zoology (HKU) to H.Z. and Y.J. in the form expression of somatostatin receptors SST-1 and SST-5 in goldfish pituitary of postgraduate studentships is also acknowledged. Special and forebrain. Neuroendocrinology 78, 81–89. thanks are given to Drs. R.E. Peter and J.P. Chang (University of Cardenas, R., Lin, X., Canosa, L.F., Luna, M., Aramburo, C., Peter, R.E., 2003. 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