Peripheral regulation of the growth hormone-insulin-like growth factor system in fish and other vertebrates

Comparative Biochemistry and Physiology, Part A 163 (2012) 231–245

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Review

Peripheral regulation of the growth hormone-insulin-like growth factor system in fish and other vertebrates Katie M. Reindl, Mark A. Sheridan ⁎ Department of Biological Sciences, North Dakota State University, Fargo, ND 58108, USA

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Article history: Received 22 January 2012 Received in revised form 3 August 2012 Accepted 7 August 2012 Available online 14 August 2012 Keywords: Fish Growth hormone binding protein Growth hormone receptor Insulin-like growth factor binding protein Insulin-like growth factor-1 receptor

a b s t r a c t The growth hormone (GH)-insulin-like growth factor (IGF) system plays a major role in coordinating the growth of vertebrates including fish. Considerable research on the regulation of growth has focused on the production and secretion of GH from the pituitary. This review will synthesize recent work on regulating extrapituitary aspects of the GH–IGF system, which includes GH binding proteins (GHBP), GH receptors (GHR), IGF binding protein (IGFBP), and IGF receptors (IGFR). These components are widely distributed and they interact to coordinate growth as well as a host of other biological processes such as metabolism, osmoregulation, reproduction, behavior, and immunity. The GH–IGF system of fish is particularly interesting and complex because it consists of multiple subtypes of GHRs, IGFRs, and IGFBPs that arose through gene duplication events associated with the evolution of the teleost lineage. Peripheral regulation of the GH–IGF system results from adjusting peripheral sensitivity to GH and IGFs as well as from modulating the bioavailability and actions of GH and IGFs in target cells. Numerous chemicals, including hormones such as growth hormone, insulin, somatostatin, and sex steroids as well as a variety of transcription factors, proteases, and phosphatases, regulate the synthesis and activity of GHRs, GHBPs, IGFRs, and IGFBPs as well as the synthesis, secretion, and bioavailability of IGFs. In addition, numerous environmental factors such as nutritional state, photoperiod, stress, and temperature have dramatic effects on the expression and activity of peripheral components of the GH/IGF system. The complex regulation of these system components appears to be both organism- and tissue-specific. © 2012 Elsevier Inc. All rights reserved.

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Introduction . . . . . . . . . . . . . . . . . . . . . Growth hormone receptor . . . . . . . . . . . . . . 2.1. Regulation of growth hormone receptor synthesis 2.2. Regulation of growth hormone receptor activity . Growth hormone binding protein . . . . . . . . . . . 3.1. Regulation of GHBP expression and release . . . 3.2. Release of GHBP . . . . . . . . . . . . . . . . Insulin-like growth factors . . . . . . . . . . . . . . 4.1. Regulation of IGF synthesis . . . . . . . . . . . 4.2. Regulation of IGF secretion . . . . . . . . . . . 4.3. Regulation of IGF activity . . . . . . . . . . . Insulin-like growth factor receptors . . . . . . . . . . 5.1. Regulation of IGFR expression . . . . . . . . . 5.2. Regulation of IGFR activity . . . . . . . . . . .

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Abbreviations: cAMP, cyclic adenosine monophosphate; ERK, extracellular signal-regulated kinase; E2, 17β-estradiol; GH, growth hormone; GHR, growth hormone receptor; GHBP, growth hormone binding protein; HNF, hepatocyte nuclear factor; IGF, insulin-like growth factor; IGFBP, insulin-like growth factor binding protein; IGFR, insulin-like growth factor receptor; IRS, insulin receptor substrate; JAK, janus-activated kinase; MAPK, mitogen activated protein kinase; P13K, phosphatidyl inositol 3 kinase; TACE, TNF-α converting enzyme; T3, thyroid hormone triiodothyronine; T4, thyroid hormone thyroxine; SOCS, suppressor of cytokine signaling; STAT, signal transducer and activator of transcription. ⁎ Corresponding author. Tel.: + 1 701 231 8110; fax: + 1 701 231 7149. E-mail address: [email protected] (M.A. Sheridan). 1095-6433/$ – see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cbpa.2012.08.003

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Insulin-like growth factor binding proteins . 6.1. Regulation of IGFBP synthesis . . . . 6.2. Regulation of IGFBP secretion . . . . 6.3. Regulation of IGFBP activity . . . . 7. Summary and conclusions . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . .

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1. Introduction The growth of vertebrates including fish is primarily mediated through the growth hormone (GH)/insulin-like growth factor (IGF) system. The classical view of the GH/IGF system holds that circulating GH stimulates the synthesis and secretion of IGF-1 from the liver and other sites (e.g., muscle, gill, etc.) and IGF-1, in turn, stimulates cell growth and differentiation in a variety of target tissues via distinct type 1 IGF receptors (IGFR1) (Le Roith et al., 2001; Wood et al., 2005; Laviola et al., 2007). The availability and actions of GH and IGF-1 are influenced by GH binding proteins and IGF binding protein (IGFBPs), respectively (Baumann et al., 1988; Duan and Xu, 2005). In addition, local production of IGF-1 is important, and GH and IGFBPs have direct, non-IGF-1 dependent effects (Butler and LeRoith, 2001; Duan and Xu, 2005; Wood et al., 2005). The GH–IGF system of teleost fish is particularly complex as a result of a genome duplication associated with their evolution, and multiple forms of GH, GH receptors (GHRs), and IGFR1s have been described (Reinecke et al., 2005). Until recently, most work on the regulation of growth focused on the production and release of GH from the pituitary and other sites (Harvey and Hull, 1997; Harvey et al., 2000; Chang and Wong, 2009). Given the complexity of the GH–IGF system and the observation that there are tissue-specific differences in growth, it is becoming increasingly clear that the regulation of growth also occurs at levels other than GH production/release. Accordingly, this review will focus on peripheral aspects of growth regulation, including adjustment of peripheral sensitivity to GH and IGF-1 as well as modulation of GH and IGF-1 actions in target cells. The emphasis will be on teleost fish, but information from other vertebrates is included so as to provide a more complete picture, especially where data in fish are minimal or absent. 2. Growth hormone receptor The biological actions of growth hormone are mediated by the transmembrane growth hormone receptor (GHR). GHR is a cytokine receptor composed of an extracellular domain, a single transmembrane domain, and an intracellular domain (Postel-Vinay and Finidori, 1995). In mammals, the binding of growth hormone to its receptor causes rapid activation of the tyrosine kinase JAK2 (Han et al., 1996) and subsequent activation of second messengers including signal transducer and activator of transcription (STATs), mitogenactivated protein kinases (MAPKs), insulin receptor substrates (IRSs), protein kinase C, phospholipase C (PLC), phospholipase A2, phosphatidyl inositol-3 kinase (PI-3K), and diacylglycerol (DAG) (Carter-Su et al., 1996). Characterization of GHRs has been completed in over 100 species, including 25 species of fish (Reindl et al., 2009; Ellens and Sheridan, in press). Two forms of GHR are found in mammals as a result of differential processing of the mRNA or protein (Talamantes and Ortiz, 2002). Multiple GHRs derived from distinct mRNAs have been described in many species of fish; however, it is not clear if the GHRs have similar or distinct functions (Saera-Vila et al., 2007). The nomenclature for teleost GHR is somewhat confusing. The terms “GHR1” and “GHR2” for naming of the multiple GHR subtypes in fish

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was first adopted in the tetraploid salmonids, and this convention continued for other teleosts (e.g. eel, grouper, tilapia) (Ozaki et al., 2006, Li et al. 2007, Ma et al. 2007). There has emerged two distinct clades, sometimes referred to as a GHR “type 1” (sometimes written type I) and GHR “type 2” (sometimes written type II), respectively (cf. Saera-Vila et al., 2005; Ozaki et al., 2006), with both of the original salmonid GHR1 and GHR2 subtypes contained within the “type 2” clade. The nomenclature became more complex following the characterization of what appeared to be a distinct somatolactin receptor (SLR) from masu salmon based on 125I-somatolactin (SL) binding (Fukada et al. 2005) that claded with type 1 GHRs. Fukamachi and Meyer (2007) suggested that this clade (type 1 GHR clade) represents SLRs and that the other major clade (the type 2 GHR) represents GHRs (which includes the GHR1 and GHR2 of salmonids) and that SLR is a teleost-specific paralog of GHR that arose during the fish-specific genome duplication (FSGD) event. However, designation of non-salmonid type 1 GHRs as SLRs may be premature. Physiological concentrations of SL or prolactin could not displace labeled GH from recombinant eel GHR1(Ozaki et al., 2006). In addition, neither zebrafish SLα nor SLβ interacted with GHR1 in His-tag pulldown assays or were able to activate GHR1-mediated signaling processes or promoter activities (Chen et al., 2011). It is possible, then, that SL binding to the type 1 GHR of salmon may be a derived feature. To resolve the confusion in nomenclature, we recently proposed a system that uses numbers to designate the different GHR types that arose in the actinopterygian lineage (associated with FSGD or 3R); hence, in the teleosts there would be GHR1s (we suggest abandonment of the term SLR to avoid confusion) and GHR2s. The addition of different letters would be added to distinguish paralogues associated with 4R duplication events (e.g., salmonid tetraploidization). This will necessitate changes to existing names (which we have done already for our GeneBank designations for trout GHRs). So, what were previously referred to as rainbow trout GHR1 and GHR2 (which were both in the type 2 GHR clade), are now GHR2a and GHR2b, respectively (cf. GenBank accession nos. NM_001124535 and NM_001124731). A similar scheme is proposed for the GHR1s. Whereas salmonids appear to have lost a gene following their 4R event and possess a single GHR1 (GHR 1 is proposed to be used in preference to SLR so as to avoid confusion and to better represent the evolutionary origins of this gene), other species retained both GHR1 paralogues, which should be designated GHR1a and GHR1b [e.g., Jian carp, Cyprinus carpio var. Jian GHR1a (ADC35573) and GHR1b (ADC35574)]. For clarity, we will use this new nomenclature system for the remainder of this paper. A proposed phylogeny of the GHR family appears in Fig. 1. In fish and other vertebrates, GHR expression is most abundant in liver; however, GHR mRNA and protein are expressed in numerous extrahepatic tissues (Mathews et al., 1989; Harvey et al., 1998; Ballesteros et al., 2000; Very et al., 2005; Pierce et al., 2007). In rainbow trout, GHR1 is more abundant in brain than GHR2, and GHR2 is more abundant in spleen and pancreas than GHR1 (Very et al., 2005). In tilapia, GHR1 expression is the highest in fat, liver, and muscle, indicating a possible role in metabolism while GHR2 expression is highest in muscle, heart, testis, and liver, indicating possible roles in both growth and metabolism (Pierce et al., 2007). In

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Ancestral GHR?

Ganthostome GHR ?

Sarcopterygian GHR

Actinopterygian GHR FSGD

Teleost GHR2 (or type II GHR)

Tetrapod GHR

lungfish GHR

Teleost GHR1 (or Type I GHR)

tetraploidization Salmonid GHR2a

Salmonid GHR2b

Figure 1. Proposed phylogeny of the growth hormone receptor (GHR) family. GHR2 (or type II) is a teleost-specific paralog of GHR1 (or type I) that resulted from a whole genome duplication event, the fish-specific genome duplication (FSGD), the timing of which is uncertain (see Ellens and Sheridan, in press). Several subsequent duplication events gave rise to GHR subtypes in certain teleost lineages, such as the salmonids which possess two GHR2 subtypes, GHR2a and GHR2b.

seabream, GHR2 expression is much higher than GHR1 expression in many tissues such as gonad, kidney, muscle, pituitary, and spleen (Jiao et al., 2006). It is clear that GHR1 and GHR2 have distinct expression patterns in various fish tissues, but it is unclear if the two receptors have distinct or overlapping cellular functions. Experiments with cloned teleost GHRs have suggested that the two distinct GHRs operate through specific signaling mechanisms to elicit biological responses. Reporter transcription assays with seabream GHRs revealed that the two receptor subtypes were able to initiate activation of Spi 2.1 and β-casein promoters, but only GHR1 stimulated c-fos promoter activity (Jiao et al., 2006). Ligand binding studies with rainbow trout GHRs revealed that the two receptors subtypes bind preferentially to GH rather than prolactin or somatolactin, but GHR1 had a significantly higher affinity for GH than did GHR2 (Reindl et al., 2009). Additionally, both receptor subtypes were able to bind to prolactin, although to a lesser extent than binding to GH. Therefore, GHR1 and GHR2 appear to activate overlapping signaling cascades, but not identical ones. Further, the two receptor types are able to bind multiple ligands which could lead to various biological effects. Recent data suggest that cloned trout GHR1 preferentially activates STAT5 while GHR2 activates ERK and Akt signaling pathways (Reindl et al. 2011). In summary, GHRs are expressed in multiple tissue types, and there is some evidence that the different GHR isoforms differentially link to cell signaling cascades (Kittilson et al., 2011). Based on available information, it is not yet possible to determine if different GHR isoforms in fish may be responsible for triggering a specific subset of biological responses. Future experiments using fish cells that have been made deficient of specific GHR subtypes (via small interfering RNA) will shed light on this interesting issue. We will next discuss what regulates the synthesis and activity of GHR, most of which is known regarding hepatic GHR. 2.1. Regulation of growth hormone receptor synthesis Numerous hormones and transcription factors regulate the synthesis of GHR (Fig. 2). Growth hormone, insulin, IGF, somatostatin, and estrogen treatment have all been shown to affect GHR mRNA expression in a variety of tissues from vertebrates. Environmental factors such as nutritional status, photoperiod, temperature, and salt or fresh water also influence GHR expression in various tissues from fish. GH has been shown to affect GHR expression in several species, but the results are conflicting. GH-transgenic fish have displayed increased growth responses in salmon (Devlin et al., 1994) and mud loaches (Nam et al., 2001) and decreased growth in carp (Zhang et al., 1990) and tilapia (Hernandez et al., 1997). A GH-transgenic zebrafish model using hemizygous and homozygous genotypes revealed that

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body mass, GHR and IGF-1 mRNA expression, and condition factor were reduced in homozygous compared to hemizygous zebrafish (Figueiredo et al., 2007). In isolated rainbow trout hepatocytes, GH treatment resulted in a 2.5 to 3-fold increase in the transcription rate of GHR1 and GHR2 (Very and Sheridan, 2007a). However, in vivo treatment of black seabream with seabream GH did not alter hepatic GHR1 or GHR2 mRNA levels (Jiao et al., 2006). The variable changes in GHR expression in response to GH treatment that is observed in fish species have also been noted in other vertebrates. In rat liver, chronic GH therapy increased GHR levels while acute GH treatment decreased GHR (Baxter and Zaltsman, 1984; Maiter et al., 1988). The differential responses of various organisms to GH treatment may be due to chronic versus acute effects or differences in the tissue type or species examined. Together, these results suggest that differential regulation of GHR subtypes occurs in various tissues in response to GH. Several other hormones besides GH are involved in regulating GHR expression in various species. These hormones include cortisol, insulin, somatostatin, and thyroid hormones. In vivo cortisol treatment of black seabream resulted in increased hepatic GHR1, but not GHR2 levels (Jiao et al., 2006). Cortisol treatment increased GHR1 and GHR2 mRNA synthesis in the liver and gill of rainbow trout (Norbeck and Sheridan, 2010). Dexamethasone (a potent synthetic glucocorticoid) also increased GHR mRNA expression in cultured hepatocytes from coho salmon (Pierce et al., 2005a). Bovine insulin decreased GHR levels, whereas glucagon and T3 had no effect on GHR mRNA expression in salmon hepatocytes (Pierce et al., 2005a). However, bovine insulin increased expression of GHR mRNAs in liver, gill, and muscle tissue of rainbow trout in vitro (Norbeck and Sheridan, unpublished observations)—actions consistent with the effects of insulin on GHR expression in mammals (Birzniece et al., 2009). In isolated rainbow trout hepatocytes, somatostatin treatment decreased steady state levels of GHR by increasing receptor internalization and decreasing transcription rates (Very and Sheridan, 2007a). The mechanism of somatostatin-inhibited hepatic GHR transcription involved activation of the ERK and PI-3K/Akt pathways (Hagemeister and Sheridan, 2008; Sheridan and Hagemeister, 2010). Sex steroids such as 17β-estradiol (E2) and testosterone also influence the expression of GHR mRNAs. In vivo treatment of black seabream with E2 resulted in reduced levels of hepatic GHR1 and GHR2 (Jiao et al., 2006). Injection of E2 into male tilapia resulted in decreased GHR mRNA levels in liver, but had no effect on the expression in testes (Davis et al., 2007, 2008). Similarly, E2 decreased levels of GHR1 and GHR2 mRNAs in primary hepatocyte cultures from rainbow trout, but had no effect on the expression of GHRs in the gill (Norbeck and Sheridan, 2011). Meanwhile, in vivo treatment of black seabream with testosterone resulted in decreased hepatic GHR2, but not GHR1 levels (Jiao et al., 2006), and in vitro experiments with rainbow trout tissues showed that testosterone treatment increased GHR1 and GHR2 mRNAs in the liver and gill (Norbeck and Sheridan, 2011). The results with sex steroids suggest that estrogen and testosterone have opposing effects on GHR expression in liver and extrahepatic tissues. Environmental factors such as the nutritional state of an organism have a strong effect on the expression of GHRs in a species-specific and tissue-specific manner (Fig. 2). During fasting, hepatic GHR transcript levels decreased in several fishes; masu salmon (Fukada et al., 2004), black seabream (Deng et al., 2004), cat fish (Small et al., 2006; Peterson et al., 2009), gilthead sea bream (Saera-Vila et al., 2005), rainbow trout (Norbeck et al., 2007), and striped sea bass (Picha et al., 2008a). However, no changes in GHR transcript levels were observed in the liver of tilapia under fasting conditions (Pierce et al., 2007). Fasting also reduced GHR mRNA expression in the gills of rainbow trout (Norbeck et al., 2007). In contrast, fasting increased expression of GHR 1 and 2 mRNAs in muscle of tilapia (Pierce et al., 2007) and of GHR2 mRNA in muscle of gilthead sea bream and striped bass (Saera-Vila et al., 2005; Picha et al., 2008a). In addition, GHR2a, but not GHR2b, transcript levels increased and 125I-GH binding

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Figure 2. Regulation of the GH/IGF system in the periphery of fish by hormones and environmental factors. A host of hormones (cort = cortisol, dex = dexamethasone, E2 = 17βestradiol, GH = growth hormone, glu = glucagon, ins = insulin, IGF = insulin-like growth factor, SS = somatostatin, T = testosterone, T3 = triiodothyronine, T4 = thyroxine) and environmental factors (fast = fasting, photo = length of photoperiod, re-fed = re-feeding, stress, temp = temperature) influence the expression, secretion, and binding of GH/IGF system components in the gills, heart, liver, adipose, and skeletal muscle of various fish. The IGFs and IGFBPs shown inside the tissues and the GHRs and IGFRs on the tissue surface represent mRNAs that were synthesized in response to a given treatment. The IGFs and IGFBPs shown outside the tissues represent proteins that were secreted in response to a given treatment.

capacity was enhanced in the adipose of rainbow trout under fasting conditions (Norbeck et al., 2007). Fasting is also known to elevate plasma levels of GH in several species of fish (Norbeck et al., 2007; Picha et al., 2008b; Reinecke, 2010). During fasting, high levels of circulating GH and high expression of GHR on the surface of muscle cells and adipocytes could spare protein and promote mobilization of lipids, respectively; whereas, reduced expression of hepatic GHR would attenuate GH sensitivity and result in reduced IGF production. Therefore, during fasting conditions, the function of GH may switch from growth-promoter to metabolic regulator. Given the influence of fasting on reducing GHR abundance in gill, it is conceivable that nutritional restriction cold compromise SW adaptability given the role of GH in this process (McCormick, 2001); in fact, reduced GHR expression in gill induced by somatostatin accompanied reduced seawater adaptability of rainbow trout (Poppinga et al., 2007). Re-feeding generally restores the fasting-associated changes in the GH/IGF system; plasma GH decreases, plasma IGF increases, and hepatic GHR and IGF-1 mRNAs increase. For example, re-feeding of rainbow trout for 2 weeks following a 4-week fast resulted in decreased plasma GH levels, elevated hepatic GHR1 and GHR2 mRNAs, but decreased GHR1 and no change in GHR2 levels in adipose (Norbeck et al., 2007). Compensatory growth following refeeding of hybrid striped bass was accompanied by increased expression of GHR in liver and return to pre-fast levels of GHR1 mRNA in muscle (Picha

et al., 2008a). Moreover, over feeding increased hepatic GH binding in gilthead seabream (Perez-Sanchez et al., 1995). In addition to nutritional status, salinity is another environmental factor that affects the GH/IGF system. Adaptation to seawater is a requirement for many salmonids. In post-smolt coho salmon, transfer of fish into half seawater resulted in increased basal levels of hepatic GHR mRNA as well as increased plasma IGF-1 and 41-kDa IGFBP (IGFBP-3) compared to fish transferred to freshwater (Shimizu et al. 2007). Similarly, rainbow trout acclimated to 20% seawater, showed increased expression of hepatic GHR1 and GHR2 as well as gill GHRs compared to freshwater fish (Poppinga et al., 2007). After 24 h, the levels of GHRs begin to decline in seawater- transfer fish. These data demonstrate the importance of the GH/IGF system in seawater adaptation and suggest that up-regulation of the system components occurs in a higher salinity environment. Together, the results from these studies suggest that GHR has tissue-specific roles, where liver GHR is involved in growth, and adipose GHR is involved in metabolism. Further, there appears to be some species-specific responses to fasting as hepatic GHR mRNA levels are decreased in many, but not all fish species, in response to food deprivation. Finally, differences in GHR1 and GHR2 expression under fasting suggest that these receptors have unique functions. Further studies are needed to tease apart these functions in different organisms possessing multiple GHR isoforms and in different tissues.

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The specific mechanisms by which hormones or environmental factors trigger GHR gene expression in fish are not yet clear. In mammals, it is known that certain transcription factors regulate the GHR gene (Schwartzbauer and Menon, 1998). Sp family transcription factors (Sp1 and Sp3) have been linked to increased GHR promoter activity in mice (Yu et al., 1999). Inhibition of Sp1 and Sp3 by TNF-α decreased transcription of the GHR gene (Denson et al., 2001). Another transcription factor, MSY-1, inhibited GHR synthesis in adult mice (Schwartzbauer et al., 1998). It is not yet clear if the GH signaling elements such as MAPKs, JAKs, STATs, etc. interact with these transcription factors to regulate GHR expression. In other words, it is not clear if GHR can activate signaling pathways and transcription factors that influence its own expression. In addition to GHR mRNA expression, the ability of GH to bind to its receptor and the turn-over of the receptors on the cell surface are major factors influencing GH/GHR signaling. 2.2. Regulation of growth hormone receptor activity GHR activity requires ligand binding. A number of different methods have been employed to assess ligand binding, from use of microsomal membrane fractions, to whole cell binding assays, to expression of receptors in cell lines. Each method has relative merits in a particular experimental context; there also may be drawbacks. For example, the microsomal fraction includes receptors that were located on the surface of cells as well as those in intracellular compartments. Moreover, some binding studies examined “free” binding (i.e., assays performed on preparations in which some receptors may have been previously occupied by hormone), while other studies examined “total” binding (i.e., treatment of preparations to remove hormone prior to conducting assays, typically with agents such as MgCl2); the results between the two measures can be quite different. For example, hypophysectomy (Hx) of coho salmon had no effect on GH binding to untreated (free) hepatic microsomes compared to sham-operated controls, whereas binding to treated (total) microsomes was reduced in Hx fish compared to controls (Gray et al., 1992). As a result, interpretation of GH binding data requires consideration of the methods employed. GH binding has been studied in fish in the presence of several hormones and under variable environmental conditions. Treatment of coho salmon in vivo with bovine GH decreased GH “free” binding to hepatic microsomes; however, bovine IGF-1, thyroxine (T4), and cortisol did not affect hepatic “free” GH binding (Gray et al., 1992). Testosterone increased free GH binding in microsomes prepared from liver, gill, and muscle of rainbow trout, whereas 17β-estradiol decreased such free binding in hepatic microsomes, but had no effect in membranes prepared from gill or muscle (Norbeck and Sheridan, 2011). Fasting decreased GH free binding in hepatic microsomes from coho salmon (Gray et al., 1992) and rainbow trout (Norbeck et al., 2007) as well as GH binding (type not specified) in hepatic membranes from black seabream (Deng et al., 2004). Interestingly, fasting increased free GH binding to microsomes from trout adipose tissue (Norbeck et al., 2007). Re-feeding of 4-week fasted rainbow trout resulted in increased GH binding in the liver and a return toward pre-fast levels of GH binding in the adipose (Norbeck et al., 2007). GHR activity is also regulated by proteases that cleave the receptor from the cell surface, mechanisms that internalize the receptor, and by phosphatases that interrupt signal transduction events (FloresMorales et al., 2006). Various hormones have been found to affect GHR internalization including GH, insulin, and somatostatin. Acute GH exposure of CHO cells transfected with rainbow trout GHRs resulted in rapid internalization of both GHR1 and GHR2; however, more GHR2 was internalized than GHR1 (Reindl et al., 2009). Whereas, prolonged GH treatment of those cells resulted in increased GHR1 and GHR2 expression on the cell surface. Insulin had a suppressive effect on GHR internalization in a human hepatoma cell

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line (Leung et al., 2000) while somatostatin increased GHR internalization in isolated rainbow trout hepatocytes (Very and Sheridan, 2007a). Receptor internalization through endocytosis is one of the major mechanisms mediating the activity of the GHR. However, if GHR is internalized, it does not necessarily get degraded. The GH/GHR complex can localize to the nucleus where it may activate a series of signal transduction cascades and have direct effects on gene expression (Lobie et al., 1994). In addition to hormones, phosphatases regulate GH/GHR signaling by causing dephosphorylation of the receptor tyrosine kinases. In mammals, suppressors of cytokine signaling (SOCS) family members such as SOCS-1 to SOCS-7 and cytokine-inducible SH2-containing protein are proteins that interfere with GH signaling (Wilkinson et al., 2004; Flores-Morales et al., 2006). SOCS-1 and SOCS-3 can deactivate GHR signaling through dephosphorylation of the tyrosine kinases on the GHR, JAK2, and STATs (Starr et al., 1997). Interestingly, GH stimulates the expression of SOCS-3, a negative regulator of GHR activity (Adams et al., 1998). GH that is not bound to its receptor will likely be bound to GH binding proteins (GHBP). Therefore, GHBPs play an important role in regulating GH-mediated activity.

3. Growth hormone binding protein Under normal physiological conditions, a large portion (40–50%) of circulating GH in mammals is predicted to be bound to growth hormone binding protein (GHBP) (Baumann et al., 1988; Edens and Talamantes, 1998). Three forms of GHBP exist in mammals, including circulating, membrane-associated, and intracellular GHBP. The function of circulating GHBP is somewhat contradictory in that it has been shown to both potentiate and inhibit the growth-promoting effects of GH (Clark et al., 1996; Barnard and Waters, 1997). GH that is bound to GHBP is protected from proteolytic degradation and its availability to cells is prolonged (Turyn et al., 1997). This may be due to an increased half-life of the protected/bound GH. At the same time, GHBP decreases the cellular response to GH by competing with GHR for binding to GH and limiting its bioavailability (Lim et al., 1990; Mannor et al., 1991). The opposing effects of serum GHBP on GH action may depend on the relative plasma concentrations of GH and GHBP and the physiological condition of the organism (Barnard and Waters, 1997). The functions of membrane-associated and intracellular GHBPs are not clear. The intracellular GHBP may be used to transport GH to the nucleus where it influences transcription. The membrane-associated GHBP may serve as a negative regulator of GHR activity by sequestering excess GH at the cell surface (Gonzalez et al., 2007). Like GHR, the majority of GHBP is produced by the liver (Amit et al., 2000); however, GHBP is also expressed in many extrahepatic tissues of vertebrates (Tiong and Herington, 1991; Lobie et al., 1992; Barnard et al., 1994). GHBP is also abundant in cytoplasmic and nuclear regions, suggesting GHBP has both extracellular and intracellular functions (Lobie et al., 1992). Intracellular GHBP may be locally synthesized and used to transport GH inside the cell for transcriptional regulation (Lobie et al., 1992). This coincides with the fact that GH has been reported in the nucleus where it may directly influence gene regulation. The GHBP produces different transcriptional effects depending on its location in a cell. Endogenous GHBP localized in the nucleus was able to stimulate STAT5-mediated transcription in response to cytokine receptor stimulation, whereas exogenous GHBP inhibited the cellular response to GH (Graichen et al., 2003). Of the GH/IGF system components present in fish, the least is known regarding GHBP. GHBPs have been identified in rainbow trout (Sohm et al., 1998), goldfish (Zhang and Marchant, 1999), and Chinese sturgeon (Liao and Zhu, 2004; Liao et al., 2009), but the regulation of GHBPs in fish is poorly studied. The majority of what we know about GHBPs comes from studies with other vertebrates.

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3.1. Regulation of GHBP expression and release

4. Insulin-like growth factors

GHBP is generated through two distinct mechanisms; proteolytic cleavage of GHR or alternative splicing of the pre-mRNA for GHR/GHBP (Leung et al., 2004). In humans, the metalloprotease TNF-α converting enzyme (TACE) has been shown to proteolytically cleave membranebound GHR into GHBP, and this process was regulated by protein kinase C (Alele et al., 1998; Zhang et al., 2000; Schantl et al., 2004). In rodents, however, GHBP is generated through alternative splicing of the primary mRNA transcript which codes for GHR (Baumbach et al., 1989; Sotiropoulos et al., 1993; Edens and Talamantes, 1998). GHBP is generated through both alternative splicing and proteolytic cleavage in humans and monkeys (Dastot et al., 1996; Martini et al., 1997). It is unclear how fish GHBP is generated. Because GHBP is derived from alternative splicing of the GHR gene or through proteolytic cleavage of GHR, the expression of GHBP is likely under many of the same influences described for GHR. In the case of alternative splicing, GHBP could be generated independently of GHR expression, but in the case of proteolytic cleavage, GHR is required for GHBP production (Amit et al., 2000). As seen with GHR synthesis, GH, E2, insulin, and thyroid hormone all affect plasma levels of GHBP, but the exact mechanisms are not clear. GH treatment of hypophysectomized rats resulted in increased GHBP mRNA in spleen, hypothalamus, brain cortex, and brainstem, but not in liver (Hull and Harvey, 1998). Treatment of GH-deficient patients with GH resulted in a slight increase in GHBP plasma levels (Roelen et al., 1999). E2 in combination with GH treatment increased expression of GHBP mRNA in mouse hepatocytes (Contreras and Talamantes, 1999), and increased plasma levels of GHBP in rats (Carmignac et al., 1993). However, GHBP levels in dwarf rats or hypophysectomized rats did not respond much to E2 treatment, suggesting that GH is needed in up-regulation of GHBP by estradiol. Insulin produces tissue-specific responses in GHBP expression. In the liver and heart of diabetic rats, insulin did not alter GHR or GHBP mRNA expression, but it did reduce GHBP expression in the kidney (Menon et al., 1994). In the plasma of mammals, low levels of GHBP are associated with type I diabetes and low levels of IGF-1; however, high levels of GHBP attend hyperinsulinemia and obesity (Birzniece et al., 2009). Finally, T4 treatment of infants born with congenital hypothyroidism, resulted in increased serum GHBP levels (Cassio et al., 1998). In summary, GH, E2, insulin, and thyroid hormone all have the ability to alter the levels of GHBP, with GH, E2, and T4 increasing GHBP levels and insulin decreasing GHBP levels. Once the binding proteins have been synthesized, they are subject to factors that regulate their release from a cell.

Insulin-like growth factors (IGFs) are the primary mediators of the growth-promoting effects of GH in fish and other vertebrates and have been shown to operate in an autocrine, paracrine, and endocrine manner (Le Roith et al., 2001; Wood et al., 2005). IGFs affect many processes such stimulation of protein synthesis and inhibition of proteolysis; cell proliferation, differentiation, survival and migration; and tissue maintenance (Daughaday and Rotwein, 1989; Fryburg, 1994; Fryburg et al., 1995; Le Roith et al., 2001; Wood et al., 2005; Allard and Duan, 2011). The correlation between organismal growth and plasma IGF-1 is strong, and Picha et al. (2008b) make a convincing argument for plasma IGF-1 as a biomarker of growth in fish. The liver is the primary site for IGF transcription in fish and other vertebrates; however, expression of IGF is well documented in nearly all extrahepatic tissues of fetal, juvenile, and adult vertebrates (D'Ercole et al., 1980; Schwander et al., 1983; Jones and Clemmons, 1995; Wood et al., 2005). In juvenile fish, IGF-1 mRNA expression has been demonstrated in a number of tissues including; muscle, spleen, fat, intestine, liver, heart, testes, ovary, kidney, pituitary, and brain (Duguay et al., 1992; Duan and Plisetskaya, 1993; Shamblott and Chen, 1993; Biga et al., 2004). In adult fish, an ubiquitous tissue distribution of IGF-1 mRNA is observed (Tse et al., 2002; Gabillard et al., 2003; Aegerter et al., 2004; Caelers et al., 2004). Although it is often assumed that the plasma pool of IGF-1 is derived principally from the liver, and in most studies in fish IGF-1 mRNA expression is directly related to IGF-1 secretion in vitro (cf. Reindl et al. 2011) and plasma IGF-1 levels (cf. Norbeck et al., 2007), contributions to the plasma from extrahepatic sites and storage of IGF-1 message and/or protein are possible (cf. Reinecke, 2010). There is evidence that IGF-1 is stored in mammalian pancreatic islets (Jevdjovic et al., 2005). As a result, it is conceivable that IGF biosynthesis and release are independently regulated, and we have opted to discuss the regulation of these processes separately below. The first fish IGF-2 gene was characterized in chum salmon (Palamarchuk et al., 1997). Since then, other fish IGF-2s have been characterized including rainbow trout (Shamblott et al., 1998). Zebrafish have two IGF-2 isoforms, IGF-2a and IGF-2b, which display varying patterns of expression during zebrafish development suggesting the isoforms have distinct functions (White et al., 2009). The evolution of insulin-related peptides is reviewed by Caruso and Sheridan (2011). Given that IGFs are expressed in so many different tissues, it is not surprising to find that IGF has growth-promoting actions independent of GH. 4.1. Regulation of IGF synthesis

3.2. Release of GHBP The release of GHBPs from a cell and their presence in the plasma will influence the level of plasma GH available for GHR binding. Very little is known regarding regulation of GHBP release in fish. A study using a human hepatoma cell line revealed that GH treatment can inhibit the release of GHBP (Harrison et al., 1995). Activation of protein kinase C enhanced the release of human GHBP from lymphoblasts, and cyclohexamide did not inhibit the enhanced release of GHBP, suggesting that new protein synthesis was not involved (Saito et al., 1998). One study in fish has demonstrated that freshwater to saltwater transfer can influence GHbinding capacity. Rainbow trout transferred into saltwater showed a fourfold change in GH-binding capacity to GHBP (Sohm et al., 1998). Further studies are needed to evaluate the regulatory mechanisms responsible for GHBP expression, secretion, and activity in fish. The regulation of GHR and GHBP expression and activity has been discussed. We will now turn our attention to IGF, IGFR, and IGFBP to complete the discussion on the GH/IGF system in the peripheral tissues of vertebrates.

GH is the principal regulator of IGF synthesis in a wide variety of tissues from fish and other vertebrates (Piwien-Pilipuk et al., 2002; Wood et al., 2005)(Fig. 2). GH treatment in vivo and in vitro stimulates IGF-1 and IGF-2 mRNA synthesis in a variety of tissues in fish. In vivo experiments show that injection of GH increases hepatic IGF-1 and/or IGF-2 mRNA levels in redbanded seabream (Ponce et al., 2008), common carp (Tse et al., 2002; Vong et al., 2003), rainbow trout (Shamblott et al., 1995), and channel catfish (Peterson et al., 2005). GH injection also increased IGF mRNA levels in extrahepatic tissues such as brain, gill, intestines, pyloric ceca, and kidney of various fishes (Sakamoto and Hirano, 1993; Shamblott et al., 1995; Tse et al., 2002; Vong et al., 2003), but did not have an effect on IGF expression in catfish muscle (Peterson et al., 2005), kidney, or gill of rainbow trout (Shamblott et al., 1995), or gill of Mozambique tilapia (Kajimura et al., 2001). Similarly, in vitro studies show that treatment of isolated hepatocytes with GH results in elevated levels of IGF. IGF transcript levels were elevated in response to GH treatment in primary hepatocytes isolated from rainbow trout (Shamblott et al., 1995; Hagemeister and Sheridan,

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2008; Reindl et al., 2011), tilapia (Kajimura et al., 2001), coho salmon (Pierce et al., 2005b, 2009), silver seabream (Leung et al., 2008), and common carp (Tse et al., 2002). Together, these results suggest that IGF synthesis occurs in many different tissue types, and IGF mRNA expression is partly regulated by GH in many of these tissues. The mechanism by which GH stimulates IGF expression in fish and other vertebrates seems to be through activation of the JAK/STAT pathway. GH-bound GHR interacts with JAK2 and leads to phosphorylation of numerous transcription factors (STATs) that alter IGF gene expression and influence tissue growth (Teglund et al., 1998). STAT-3 and ‐5 and hepatocyte nuclear factor (HNF)-1α and -3β are all transcription factors involved in IGF gene expression (Kulik et al., 1995; Nolten et al., 1996; Meton et al., 1999; Frost et al., 2002). It has been shown that HNF-3β, along with the transcription factors Sp1 and C/EBPβ, activate the IGF-2 gene promoter in chum salmon liver (Palamarchuk et al., 1999, 2001). Further support for activation of IGF2 gene expression by C/EBP has been demonstrated in rainbow trout where treatment of trout livers with GH resulted in increased C/EBP and enhanced IGF-2 gene expression (Shamblott et al., 1998). In other vertebrates, GH-mediated IGF-1 transcription has been shown to occur via activation of the cAMP-dependent protein kinase A (PKA) pathways (Umayahara et al., 1997, 1999; Billiard et al., 2001; Rotwein et al., 2002). IGF-1 synthesis can be both GH-dependent and GH-independent at various life stages and in different tissue types. In early development, IGF synthesis and secretion appear to be largely GH-independent (Butler and LeRoith, 2001). In addition to GH, hormones such as insulin, somatostatin, cortisol, and thyroid hormones influence IGF-1 and IGF-2 mRNA expression in liver and extrahepatic tissues (Fig. 2). Insulin treatment of GHstimulated hepatocytes isolated from coho salmon resulted in decreased levels of IGF-1 mRNA (Pierce et al., 2005a); however, IGF-2 mRNA levels were elevated (Pierce et al., 2009). Somatostatin (SS) is a key inhibitor of GH synthesis and secretion, and it has also been shown to alter hepatic IGF-1 transcription in fish (Sheridan and Hagemeister, 2010). SS inhibited IGF-1 transcription in rainbow trout hepatocytes (Very et al., 2008a). The mechanism by which SS reduced IGF-1 mRNA involved activation of the MAPK and Akt pathways (Hagemeister and Sheridan, 2008). Treatment of primary hepatocytes isolated from coho salmon with glucagon decreased IGF-1 (Pierce et al., 2005a). Glucagon and dexamethasone increased IFG-2 mRNA levels, whereasT3 decreased IGF-2 levels in isolated salmon hepatocytes (Pierce et al., 2009). However, variable changes in IGF expression have been obtained when fish hepatocytes are treated with T3 or T4. In cultured silver seabream hepatocytes, T4 treatment resulted in increased IGF-1 mRNA levels and no change in IGF-1 with T3 treatment (Leung et al., 2008). T3 treatment resulted in increased hepatic levels of IGF-1 in tilapia both in vitro and in vivo (Schmid et al., 2003) and in zebrafish and amphioxus in vitro (Wang and Zhang, 2011). Consistent with its growth-inhibiting effects, cortisol treatment of hepatocytes isolated from silver seabream resulted in a decrease in IGF-1 mRNA levels (Leung et al., 2008). Conversely, cortisol-fed fish did not show changes in liver IGF-I mRNA expression compared to controls; however, cortisol treatment did decrease plasma IGF-1 levels (Peterson and Small, 2005). In other tissue types, cortisol increases IGF synthesis. For example, in rainbow trout, cortisol treatment increased IGF-1 and IGF-2 mRNA levels in the gill (Norbeck and Sheridan, 2010). The sex steroids E2 and testosterone have opposing effects on IGF mRNA expression (Fig. 2). In vitro or in vivo treatment of tilapia with E2 decreased IGF-1 mRNA expression in the liver, but not testes (Riley et al., 2004; Davis et al., 2007, 2008). Conversely, E2 treatment of tilapia increased IGF-1 and IGF-2 expression in the gonad possibly via up-regulation of HNF-3 β (Huang et al., 2007). In vivo treatment of gilthead seabream with E2 resulted in decreased basal and GHstimulated IGF-1 and IGF-2 levels (Carnevali et al., 2005). Similarly, E2 treatment reduced IGF-1 and IGF-2 mRNA levels in the liver and gills of rainbow trout (Norbeck and Sheridan, 2011). In contrast to E2,

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testosterone or dihydroxytestosterone treatment typically increases IGF expression in fish. Testosterone treatment of liver and gill tissue isolated from rainbow trout resulted in increased levels of IGF-1 and IGF-2 in both tissue types (Norbeck and Sheridan, 2011). Further, dihydroxytestosterone treatment increased hepatic IGF-1 in male fish, but decreased IGF-1 expression in female fish (Riley et al., 2004; Davis et al., 2007). The variable responses of the GH/IGF system components to sex steroid treatment may be due to differences among species or across tissues, or influences from the environment such as stress, photoperiod, temperature, or nutritional status. In addition to various hormones, the availability of food and the resulting nutritional status of an organism can influence the expression and activity of the GH/IGF system (Fig. 2). Fish are frequently exposed to extended periods of starvation. The effects of fasting on the GH/IGF system in fish have been reviewed recently (Reinecke, 2010). Overall, fasting reduces IGF-1 levels in fish by influencing both IGF-1 mRNA expression and the presence of IGF-1 protein in the serum. Prolonged fasting resulted in reduced hepatic IGF-1 mRNA in numerous fish species including: catfish (Small et al., 2006; Peterson and Waldbieser, 2009), chinook salmon (Pierce et al., 2005b), coho salmon (Duan and Plisetskaya, 1993), grouper (Pedroso et al., 2006), rabbitfish (Ayson et al., 2007), rainbow trout (Chauvigne et al., 2003; Norbeck et al., 2007), and tilapia (Uchida et al., 2003; Fox et al., 2006). Interestingly, in hybrid striped bass, fasting increased hepatic IGF-1 mRNA in the face of reduced plasma levels of IGF-1, following a period of refeeding that was attended by compensatory growth, hepatic IGF-1 mRNA expression declined in association with increased plasma levels of the hormone (Picha et al., 2006). A few studies have looked at IGF-1 mRNA expression in non-hepatic fish tissues following fasting. Similar to liver tissues, IGF-1 mRNA is decreased in the gill and adipose of fasted rainbow trout (Norbeck et al., 2007) and skeletal muscle of catfish (Peterson and Waldbieser, 2009). However, no change in IGF-1 expression was found in the kidney, spleen, ovary, intestines, and gill of coho salmon fasted for 4 weeks (Duan and Plisetskaya, 1993). Interestingly, fasting resulted in reduced levels of IGF-1 mRNA in the liver and muscle of catfish, but no change in IGF-2 levels, suggesting that IGF-1 and IGF-2 are differentially regulated by nutritional status (Chauvigne et al., 2003; Peterson and Waldbieser, 2009). These studies on fasting provide further evidence for a role of GH outside of growth-promotion and suggest that nutritional status plays a key role in regulating the expression and function of the GH/IGF system components. Further, the results suggest that IGF-1 and IGF-2 are differentially regulated by nutritional status, and IGF-1 and ‐2 may differentially influence muscle growth after fasting (Peterson and Waldbieser, 2009). Other environmental determinants such as temperature, photoperiod, and confinement stress can influence the expression and activity of the GH/IGF system. Increased temperatures lead to increased growth of fish. Rainbow trout reared at temperatures of 8, 12, and 16 °C showed greater growth at the higher temperatures (Gabillard et al., 2003). Additionally, the higher temperatures produced elevated plasma IGF-1 levels, and elevated hepatic IGF-1 mRNA levels, but no change in hepatic or plasma IGF-2 mRNA. Further, muscle IGF-1 mRNA decreased, and IGF-2 mRNA in muscle was not affected by temperature (Gabillard et al., 2003). Photoperiod has been shown to modulate the production and secretion of GH/IGF system components. Rainbow trout exposed to a longer photoperiod showed elevated growth and increased plasma IGF-1 levels (Taylor et al., 2005). Further, handling and confinement stress reduced circulating levels of GH, IGF-1, and IGF-2 in Atlantic salmon, and IGF-1 and IGF-2 levels in rainbow trout (Wilkinson et al., 2006). 4.2. Regulation of IGF secretion Many of the same hormones (GH, insulin, somatostatin, glucocorticoids, and sex steroids) that influence IGF mRNA expression also

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influence IGF secretion from those cells. GH is the principal regulator of IGF-1 secretion in fish (Wood et al., 2005). GH administration, both intraperitoneally and orally, elevated plasma IGF-1 levels in rainbow trout (Moriyama, 1995). Circulating IGF-1 levels also rose in catfish injected with bGH (Peterson et al., 2005). Somatostatin, which decreases IGF-1 mRNA levels in trout liver, also reduced plasma IGF1 levels in rainbow trout (Very et al., 2008a). Glucocorticoids, such as cortisol, decrease plasma level IGFs in fish (Kajimura et al., 2003; Dyer et al., 2004). Cortisol-fed fish did not show changes in liver IGF-I mRNA expression compared to controls; however, cortisol treatment did decrease plasma IGF-1 levels (Peterson and Small, 2005). Testosterone or 11-ketotestosterone injection of coho salmon resulted in elevated levels of plasma IGF-1, but no effect on plasma GH (Larsen et al., 2004). Finally, E2 immersion of Atlantic salmon resulted in decreased plasma IGF-1 levels (Lerner et al., 2007). Environmental determinants also affect the circulating levels of IGF-1 in fish. In rainbow trout, fasting stimulated increased plasma GH levels and decreased plasma IGF-1 levels (Norbeck et al., 2007). A similar decrease in plasma IGF-1 levels has been observed in fasted coho salmon (Duan, 1998), catfish (Small et al., 2006), Arctic charr (Cameron et al., 2007), and tilapia (Uchida et al., 2003; Fox et al., 2006). Upon re-feeding, the circulating IGF-1 levels increased in rainbow trout (Chauvigne et al., 2003) and coho salmon (Shimizu et al., 2009). In contrast, re-feeding resulted in no change in plasma IGF-1 levels in Atlantic salmon compared to only fasted fish (Wilkinson et al., 2006). It is interesting to note that despite elevated levels of circulating GH in fasted fish, IGF-1 levels are reduced both at a tissue level and in circulation. Photoperiod also affects the presence of GH/IGF in circulation. In trout, exposure to longer light periods resulted in elevated growth and increase levels of plasma IGF-1 (Taylor et al., 2005). GH is known to display distinct expression patterns in response to seasonal changes and day length. The alteration in GH and IGF-1 levels in response to photoperiod may form the basis for the varied growth patterns observed under these conditions (Bjornsson, 1997). 4.3. Regulation of IGF activity The cellular effects of IGFs are mediated through various receptors. IGFs can bind to both IGFRs and insulin receptors. IGF-1 binds to the insulin receptor to mediate metabolic effects such as glucose and amino acid uptake, and glycogen and lipid synthesis (Binoux, 1995). Whereas, IGF-1 binds to IGFR1 to mediate anabolic effects such as cell proliferation, protein and nucleic acid synthesis, and to decrease proteolysis (Boulware et al., 1992). The influence of IGFs on cellular processes relies on the expression of the cell surface receptors. 5. Insulin-like growth factor receptors There are two types of insulin-like growth factor receptors (IGFRs) in vertebrates, type 1 (IGFR1) and type 2 (IGFR2), that are part of a rather heterogeneous family of receptors that includes INS receptors (IR) and relaxin receptor as well as the IGFRs (Caruso and Sheridan, 2011). Although the two types of IGFRs appear to have arisen from a common ancestor, they are structurally distinct; IGFR1s, like IRs, belong to the tyrosine kinase receptor subfamily similar in structure to the insulin receptor, whereas IGFR2s do not possess tyrosine kinase activity and belong to the mannose-6-phosphate receptor family (Caruso and Sheridan, 2011). IGFR1s have been characterized from several species of fish, and two isoforms (IGFR1A and IGFR1B) have been described in salmonids (Chan et al., 1997) and Japanese flounder (Nakao et al., 2002). IGFR2, which is bifunctional in mammals playing a role in lysosomal enzyme trafficking and regulating extracellular IGF-2 levels (Wood et al., 2005), was first identified in fish by competitive binding, cross-linking, and immunoprecipitation with a mammalian IGFR2 antibody in the embryos of brown trout (Mendez et al., 2001). Subsequent genomic analysis has confirmed the existence of IGFR2s in several species of fish; IGFR2s have been annotated in the e! Ensemble database for fugu,

medaka, stickleback, Tetraodon, and zebrafish (cf. Caruso and Sheridan, 2011). In zebrafish, two distinct cell-specific promoters result in two different IGFR2 subtypes (Tsalavouta et al., 2009). The IGFRs can bind to several different ligands including IGF-1, IGF-2, and insulin; however, the affinity for IGFs is much higher than for insulin in all species (Wood et al., 2005). Further, the affinity of IGFR1 for IGF-1 is typically greater than IGF-2, and the affinity of IGFR2 for IGF-2 is higher than the affinity for IGF-1, including in fish (Jones and Clemmons, 1995; Mendez et al., 2001; Hawkes and Kar, 2004). However, ligand binding assays done with zebrafish cells showed IGF-1 and IGF-2 bind to the IGFR1 with similar affinities; 1.9 and 2.6 nM, respectively (Pozios et al., 2001). IGF-1 binding to IGFR1 activates a series of phosphorylation events that lead to many anabolic effects such as enhanced protein and nucleic acid synthesis, decreased protein degradation, increased cell proliferation, cell survival, and differentiation (Wood et al., 2005). In fish and mammals, IGFR1 signals through many different pathways including IRS-1, Shc/MAPK, 14-3-3/Raf, and PI3K/Akt to elicit these effects (Peruzzi et al., 1999; Pozios et al., 2001; Wood et al., 2005). The dependence of organisms on IGFR1 expression for growth and survival is evidenced by studies using IGFR1 double knock-out mice. These mice display markedly reduced growth (45% of normal size) and do not survive after birth (Liu et al., 1993). The binding of IGF-2 to IGFR2 results in internalization and degradation of IGF-2 rather than signal transduction in mammals (Oka et al., 1985). The significance of IGFR2s in fish remains to be determined. IGFRs are widely expressed in vertebrate tissues (Yakar et al., 1999; Maures et al., 2002). IGFR1 mRNA expression has been demonstrated in a number of tissues from juvenile salmonids including; muscle, spleen, fat, intestine, liver, heart, testes, ovary, kidney, pituitary, and brain (Duguay et al., 1992; Duan and Plisetskaya, 1993; Shamblott and Chen, 1993; Biga et al., 2004). IGFR1 expression was present in numerous tissues of the developing shi drum, including chondrocytes, gills, heart, skin, and lateral muscle (Radaelli et al., 2003). As mentioned above, IGF1 is expressed in many of these same tissues where it could have autocrine or paracrine effects on growth outside of the liver. IGFR2 expression has been detected in numerous tissues including heart, thymus, and kidney during embryonic development of mammals (Senior et al., 1990; Funk et al., 1992). IGFR2 was detected in oocytes, whole embryo and juvenile muscle of brown trout (Mendez et al., 2001) and in zebrafish throughout early-stage embryos and in the brain region of late-stage embryos (Nolan et al. 2006). 5.1. Regulation of IGFR expression Several internal and external factors influence the expression of IGFRs (Fig. 2). GH, IGF, insulin, insulin, thyroid hormone, and steroids have been found to affect IGFR1 expression in a variety of vertebrates and tissues. IGF-1 and insulin treatment decreased IGFR1 expression in trout cardiomyocytes (Moon et al., 1996). Insulin increased IGFR1A and 1B mRNA expression in the gills of rainbow trout (Very et al., 2008b). Cortisol treatment of rainbow trout also resulted in increased expression of IGFR1A and 1B in the gills (Norbeck and Sheridan, 2010). Testosterone increased expression of IGFR1A and 1B in the gill of rainbow trout, but E2 had no effect (Norbeck and Sheridan, 2011). Somatostatins inhibited the expression of IGFR1A and IGFR1B mRNAs in rainbow trout gill filaments (Very and Sheridan, 2007b; Hanson et al., 2009). Environmental factors such as the nutritional status and rearing temperature have influences on IGFR expression in fish. Rainbow trout fasted for 2 or 6 weeks showed a tissue-specific response in IGFR1A and IGFR1B mRNA expression patterns. In cardiac muscle, fasting (2 and 6 weeks) resulted in elevated levels of IGFR1A mRNA and elevated levels of IGFR1B mRNA (6 weeks only), and enhanced IGF binding (Norbeck et al., 2007). However, no change in IGFR mRNA was observed in skeletal muscle and IGFR1 levels were reduced in the gill of fasted fish. Upon re-feeding, the IGFR mRNA levels returned to

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levels seen in continuously fed animals; IGFR1A and IGFR1B levels dropped in the cardiac muscle and IGFR1 levels increased in the gill of rainbow trout. These results demonstrate that the nutritional state of an organism affects the expression of IGFRs in a tissue-specific manner. Further, fasting promotes the metabolic actions of GH rather than the growth-promoting actions (Norbeck et al., 2007). Temperature did not affect IGFR1A or IGFR1B mRNA expression in the muscle of rainbow trout; however, IGF-1 binding was reduced in muscle suggesting that turnover, but not synthesis, of the receptor is influenced by temperature (Gabillard et al., 2003). The mechanisms by which these hormones induce IGFR expression have yet to be delineated. It is known that certain signaling cascades appear to be linked to IGFR gene expression. Activation of Akt increased IGFR1 expression, and inhibition of Akt decreased IGFR1 expression in human pancreatic cancer cells (Tanno et al., 2001). The transcription factor E2F1 induced IGFR1 gene expression in human prostate cancer cells (Schayek et al., 2010). In addition to IGFR mRNA abundance, receptor presence on the cell surface plays an important role in regulating IGF function. 5.2. Regulation of IGFR activity Similar to GHRs, the activity of IGFRs is influenced by factors such as phosphatases and receptor internalization. In mammals, the IGFR can be dephosphorylated by proteins, such as Src-homology 2containing phosphotyrosine phosphatase-2 (SHP-2), which influence how long the receptor remains active and able to initiate signaling cascades. Recruitment of SHP-2 to IGFR1 causes dephosphorylation of the receptor and reduces the biological actions of IGF. In murine bone marrow 32D cells, SHP-2 inhibits IRS-1 signal transduction through dephosphorylation events (Myers et al., 1998). In porcine vascular smooth muscle cells, the αVβ3 integrin plays an important role in IGFR1 activity by altering the rate of recruitment of SHP-2 to the IGFR1 (Maile and Clemmons, 2002). The suppressor of cytokine signaling (SOCS)-2 has also been shown to interact with and negatively regulate the activity of IGFR1 (Dey et al., 1998). Receptor internalization can occur by two different mechanisms; ligand-dependent and ligand-independent internalization. In liganddependent internalization, IGF-1 and IGF-2 are the major regulators of IGFR1 and IGFR2 expression on the cell surface. IGF-1 binding to IGFR1 stimulated receptor internalization in glial progenitor cells (Romanelli et al., 2007). IGF-1 stimulated IGFR internalization and degradation through Grb10/Nedd4 which mediated ubiquitination of IGFR and receptor internalization (Monami et al., 2008). Tyrosine kinase activity is necessary for ligand-dependent IGFR1 internalization (Yamasaki et al., 1993). A single tyrosine substitution in the kinase domain of IGFR1 inhibited IGF-1 mediated receptor phosphorylation and internalization (Stannard et al., 1995). Therefore, IGF-1 binding to IGFR1 triggers internalization of the complex and attenuates signal transduction events. IGFR2 internalization is similarly enhanced by IGF-1 treatment. In addition to IGF-1, IGF-2, insulin, and EGF all increased localization of the IGFR2 from internal membranes to the cell surface in human fibroblasts (Braulke et al., 1989). In rat adipocytes, insulin increased the number of IGFR2s on the surface and enhanced the rate of internalization of bound receptors (Oka et al., 1985). The ability of IGFs to bind to their receptors is regulated by their binding proteins. 6. Insulin-like growth factor binding proteins Insulin-like growth factor binding proteins (IGFBPs) are key players in the GH/IGF system where they modulate the distribution and bioavailability of IGFs (Cohick and Clemmons, 1993a; Wood et al., 2005; Rodgers et al., 2008). Six IGF binding proteins (IGFBP-1-6) have been identified in vertebrates ranging from fish to mammals, and their origin and evolution have been recently reviewed (Daza et al., 2011). It should

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be noted that upon more extensive phylogenetic analysis, what was originally described as an IGFBP-3 in trout (Kamangar et al., 2006) should be classified as a paralog of IGFBP-2, yielding two IGFBP-2s in this species (Rodgers et al., 2008). The major portion of circulating IGFs is bound to IGFBPs, and in mammals approximately 75% of circulating IGF-1 is bound to IGFBP-3 and the acid labile unit, a glycoprotein that is bound to the binding protein (Jones and Clemmons, 1995). In teleost fish, there are typically three IGFBPs detected in plasma based on ligand binding analysis with molecular masses of 20–25, 28–32, and 40–45 kDa, respectively; however, the identity of these is not clear and is often confused (Wood et al., 2005; Shimizu et al., 2011a). Recent work in salmon characterizes the 22-, 28-, and 41-kDa IGFBPs as IGFBP1a, IGFBP1b, and IGFBP2b, respectively (Shimizu et al., 2011a, 2011b). Local production of IGFBPs may serve as a means for tissue-specific regulation of IGF action (Duan, 2002). IGFBPs such as IGFBP-3 and IGFBP-5 also have biological functions independent of IGFs that include mitogenesis, gene regulation, and cell migration (Andress and Birnbaum, 1992; Jones et al., 1993; Mohan and Baylink, 2002; Wood et al., 2005; Rodgers et al., 2008). The IGF-independent effects of IGFBPs add to the complexity of an already complex GH/IGF system that is ubiquitously expressed and serving many different functions in various tissues. IGFBPs are produced in a wide variety of cell types including liver, muscle, connective tissue, bone, brain, intestine, ovary, and kidney in a variety of different vertebrates (Cohick and Clemmons, 1993a; Ferry et al., 1999; Wood et al., 2005). In zebrafish, IGFBP-1 and ‐2 mRNA expression was highest in the liver, but IGFBP-1 was absent in extrahepatic tissues while IGFBP-2 was detected in the brain, intestine, muscle, fin, and eye (Duan et al., 1999; Maures et al., 2002). IGFBP1a was widely distributed in tissues of salmon (e.g., brain, pituitary, gill, heart, kidney, stomach, intestine, spleen, pyloric cecum, and muscle), whereas IGFBP1b was expressed almost exclusively in liver (Shimizu et al., 2011a). These results show that IGFBPs are synthesized in a variety of tissue types, further suggesting that autocrine and paracrine regulation of growth occurs in these tissues.

6.1. Regulation of IGFBP synthesis Unlike the GHBPs which are derived from proteolytic cleavage of the GHR or alternative splicing of the mRNA that codes for GHR, IGFBPs are not homologous with IGFRs (Kelley et al., 2002). However, gene expression of IGFBPs is regulated by many of the same hormones and growth factors that regulate GHR expression (Fig. 2). Further, the regulation of IGFBP expression appears to be cell type-specific in different organisms (Cohick and Clemmons, 1993a; Wood et al., 2005). In mammals, GH, insulin, and glucocorticoids are the major hormones that regulate IGFBP expression and secretion. Typically, insulin inhibits IGFBP gene expression while glucocorticoids stimulate expression. Fish show a similar but distinct IGFBP-1 expression in response to metabolic hormones. In isolated salmon hepatocytes, dexamethasone and glucagon both increased IGFBP-1 mRNA levels, GH decreased levels, triiodothyronine (T3) had no effect, and, surprisingly, insulin slightly increased IGFBP-1 mRNA in liver cells (Pierce et al., 2006). While GH decreased IGFBP-1 in salmon hepatocytes, GH increased IGFBP-3 mRNA expression in liver from tilapia (Cheng et al., 2002). These results are not unlike those observed in other vertebrates where growth hormone has variable effects on the expression of the different IGFBPs (Albiston and Herington, 1992; Kachra et al., 1994; Lemmey et al., 1997). Nutritional status also influences IGFBP expression in fish. In catfish, fasting increased hepatic IGFBP-1, decreased IGFBP-3 mRNA levels, but had no effect on IGFBP-2 levels. Re-feeding did not restore IGFBP-1 or IGFBP-3 levels to those seen in the control fish. The results suggest that IGFBP-1 may have a role in catabolism while IGFBP-3 may play more of a role in somatic growth (Peterson and Waldbieser, 2009). Further, IGFBP-2 may be growth inhibitory (Shimizu et al., 2003).

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6.2. Regulation of IGFBP secretion The secretion of IGFBPs is regulated by many of the same hormones that encourage their synthesis. Glucocorticoids and GH influence the levels of circulating IGFBP. Similar to changes in mRNA expression of IGFBP-1, dexamethasone increased secretion of IGFBP-1 from isolated salmon hepatocytes, GH decreased secretion, and insulin had no effect (Pierce et al., 2006). Glucocorticoids inhibit somatic growth in many vertebrate species. One mechanism of growth-inhibition may be through cortisol's effects on the GH/IGF system. Channel catfish fed cortisol diets weighed 50% less than fish fed control diets. A ca. 20-kDa IGFBP (IGFBP1?) was detected in the plasma from cortisol-fed fish, but not in controls (Peterson and Small, 2005), indicating that cortisol may inhibit growth by increasing secretion of IGFBP and attenuating the effects of IGF-1. Similarly, a low-dose injection of cortisol into tilapia resulted in an increase in plasma IGFBPs of four different molecular weights (24, 28, 30, and 32 kD, the identities of which are not clear), but no change in IGF-1 mRNA levels (Kajimura et al., 2003). Direct transfer of salmon parr from fresh water to seawater increased levels of both IGFBP1a and IGFBP1b in plasma (Shimizu et al., 2011a); however, how this relates to sweater adaptation or alterations in plasma levels of GH or cortisol that accompany such (McCormick, 2001) are not clear. 6.3. Regulation of IGFBP activity Mammalian plasma IGFBP-1 has a short half-life in serum due to its Pro-Glu-Ser-Thr (PEST) region on its N-terminus, a region associated with protein high turn-over rates (Julkunen et al., 1988). The half-life of human recombinant IGFBP-1 in athymic mice was about 2.5 h (Yee et al., 1996). Salmon IGFBP-1 does not contain the PEST region, and may have a different half-life than mammalian IGFBP-1 (Shimizu et al., 2005). The concentration of IGFBPs in the serum is regulated by proteases. IGFs are able to both promote and inhibit IGFBP degradation in the serum by allowing or interfering with proteolysis. IGF-1 has been shown to inactivate IGFBP-4 by encouraging its proteolysis (Cohick and Clemmons, 1993b; Kamyar et al., 1994; Duan and Clemmons, 1998). IGFBP-4 protein levels, but not mRNA levels, were down-regulated in SMC treated with IGF-1 and ‐2, but not insulin, demonstrating that IGFs lead to the degradation of serum IGFBPs (Kamyar et al., 1994). Conversely, IGFs bind to secreted IGFBP-5 and prevent the degradation of this binding protein by proteases (Camacho-Hubner et al., 1992). In human keratinocytes, matrix metalloproteinase 19 (MMP19) degraded IGFBP-3 (Sadowski et al., 2003). Further study is needed to better understand how proteases influence IGFBP activity. 7. Summary and conclusions The growth hormone/insulin-like growth factor system plays an integral role in the regulation of vertebrate growth. The components of this system are ubiquitously expressed in vertebrates suggesting that growth regulation can occur at a local level independent of pituitary GH. The peripheral regulation of the GH/IGF system is complex due to the numerous isoforms of the ligands, receptors, and binding proteins; tissue-wide expression and variation in expression among tissues; and varying expression throughout growth and development. Fish, in particular, possess multiple isoforms of the GH/IGF ligands, receptors, and binding proteins, and these isoforms exhibit distinct expression patterns and functions. In this review, we have described the regulation of the synthesis, secretion, and activity of the GH/IGF ligands, receptors, and binding proteins in the periphery of vertebrates. Based on the current literature, we have created a model that represents our current understanding of the regulation of the GH/IGF system by various hormones and environmental factors in the

peripheral tissues of fish (Fig. 1). In general, GH promotes somatic growth by up-regulating GHRs, increasing IGF synthesis and secretion, and increasing IGFBP-3 and decreasing IGFBP-1 synthesis and secretion from the liver. Insulin has an opposing effect on the system by decreasing GHRs and IGF-1, and increasing IGFBP-1 synthesis in the liver. E2 and testosterone also have opposing regulatory effects on the GH/IGF system. Similar to insulin, E2 diminishes GHR expression and IGF synthesis and secretion in the liver while testosterone treatment, similar to GH, elevates GHRs, IGFs, and IGFBP-3 expression. Cortisol inhibits growth by decreasing IGF-1 mRNA expression and secretion and by stimulating IGFBP-1 expression and release from liver cells. Interestingly cortisol increases GHR expression in both the liver and gills, and cortisol treatment results in elevated IGF and IGFR expression in the gills. These data provide evidence for tissue-specific responses of the GH/IGF system to various hormones (GH, cortisol, insulin, E2, etc.) which may be a mechanism to influence alternative biological responses such as growth versus osmoregulation or reproduction. Environmental factors also influence the GH/IGF system in peripheral organs. Fasting down-regulates GHRs in the liver and gill; IGF-1 in the liver, gill, and skeletal muscle; but up-regulates GHR1 in adipose suggesting a switch from growth promotion to metabolism of lipids. It is interesting to note that IGF-1 synthesis decreased in the adipose under fasting conditions. Although our knowledge of the GH/IGF system has been expanded in recent years, there are several areas where more work is needed. Clearly the focus has been on pituitary GH and hepatic GHR and IGF (Fig. 1). Additional studies are needed in order to understand the influence of the GH/IGF system in tissues such as heart, skeletal muscle, gill, adipose, and reproductive organs. There appears to be tissuespecific responses to various hormones and environmental factors as evidenced by opposing responses to cortisol in the gill compared to liver and to fasting in adipose compared to the liver. Further exploration of these tissues is needed to identify the molecular mechanisms by which a given treatment will affect the GH/IGF system and the function of that tissue. While some of the signaling cascades responsible for mediating the expression and function of the GH/IGF system have been identified, but much more work will be required to identify the complex molecular mechanisms by which various hormones and other influences affect GH/IGF ligand, receptor, and binding protein expression and function at a local level. Additionally, future studies will be needed to decipher the specific functions of the different isoforms of the ligands, receptors, and binding proteins. For example, the functions of the six different IGFBPs have not been determined. Because the binding proteins are under differential regulation by various factors such as GH and IGF, certain IGFBPs may enhance IGF function while other IGFBPs may serve to inhibit IGF-directed growth. Also, the roles of the different GHR isoforms in fish have not been identified, although there is evidence to suggest that the GHRs have both overlapping and unique functions with GHR1 linking to STAT signaling and GHR2 linking to ERK and Akt signaling (Reindl et al., 2009; Kittilson et al., 2011). Additionally, there is very little known about the GHBPs. GHBPs of four molecular weights have been identified in fish, but these have not been fully characterized. It is still unclear how GHBPs are generated in fish and the regulation of their expression and activity by hormones and environmental factors is poorly studied. In conclusion, many tissues are capable of self-regulating the expression and activity of the GH/IGF system components, giving this system much more function than just endocrine. The abilities of GH and IGF to promote a variety of biological functions (growth, metabolism, reproduction, etc.) may depend on the tissue-specific hormonal and environmental factors present. Future studies on the autocrine and paracrine effects of the GH/IGF system in peripheral tissues are needed to link the different isoforms of the GH/IGF system components to particular biological responses under a given physiological condition.

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