Scholarly article on topic 'Activation of somatostatin 2 receptors in the brain and the periphery induces opposite changes in circulating ghrelin levels: functional implications'

Activation of somatostatin 2 receptors in the brain and the periphery induces opposite changes in circulating ghrelin levels: functional implications Academic research paper on "Veterinary science"

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Academic research paper on topic "Activation of somatostatin 2 receptors in the brain and the periphery induces opposite changes in circulating ghrelin levels: functional implications"

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ENDOCRINOLOGY

REVIEW ARTICLE

published: 11 January 2013 doi: 10.3389/fendo.2012.00178

Activation of somatostatin 2 receptors in the brain and the periphery induces opposite changes in circulating ghrelin levels: functional implications

Andreas Stengel1 * and Yvette Taché2*

' Division Psychosomatic Medicine and Psychotherapy, Department of Medicine, Obesity Center Berlin, Charité, Universitätsmedizin Berlin, Berlin, Germany 2 Digestive Diseases Division, CURE: Digestive Diseases Research Center, Center for Neurobiology of Stress and Women's Health, Department of Medicine, VA Greater Los Angeles Health Care System, University of California at Los Angeles, Los Angeles, CA, USA

Edited by:

Hubert Vaudry, University of Rouen, France

Reviewed by:

Rafael Vazquez-Martinez, University of Cordoba, Spain

Francisco Gracia-Navarro, University of Cordoba, Spain

*Correspondence:

Andreas Stengel, Division Psychosomatic Medicine and Psychotherapy, Department of Medicine, Obesity Center Berlin, Charité, Universitätsmedizin Berlin, Luisenstr. 13a, 10117 Berlin, Germany. e-mail: andreas.stengel@charite.de; Yvette Taché, Digestive Diseases Division, CURE: Digestive Diseases Research Center, Center for Neurobiology of Stress and Women's Health, Department of Medicine, VA Greater Los Angeles Health Care System, University of California at Los Angeles, CURE Building 115, Room 117, 11301 Wilshire Boulevard, Los Angeles, CA 90073, USA. e-mail: ytache@mednet.ucla.edu

Somatostatin is an important modulator of neurotransmission in the central nervous system and acts as a potent inhibitor of hormone and exocrine secretion and regulator of cell proliferation in the periphery. These pleiotropic actions occur through interaction with five G protein-coupled somatostatin receptor subtypes (sst1 -5) that are widely expressed in the brain and peripheral organs. The characterization of somatostatin's effects can be investigated by pharmacological or genetic approaches using newly developed selective sst agonists and antagonists and mice lacking specific sst subtypes. Recent evidence points toward a divergent action of somatostatin in the brain and in the periphery to regulate circulating levels of ghrelin, an orexigenic hormone produced by the endocrine X/A-like cells in the rat gastric mucosa. Somatostatin interacts with the sst2 in the brain to induce an increase in basal ghrelin plasma levels and counteracts the visceral stress-related decrease in circulating ghrelin. By contrast, stimulation of peripheral somatostatin-sst2 signaling results in the inhibition of basal ghrelin release and mediates the postoperative decrease in circulating ghrelin. The peripheral sst2-mediated reduction of plasma ghrelin is likely to involve a paracrine action of D cell-derived somatostatin acting on sst2 bearing X/A-like ghrelin cells in the gastric mucosa. The other member of the somatostatin family, named cortistatin, in addition to binding to sst1-5 also directly interacts with the ghrelin receptor and therefore may simultaneously modulate ghrelin release and actions at target sites bearing ghrelin receptors representing a link between the ghrelin and somatostatin systems.

Keywords: X/A-like cell, somatostatin receptor subtypes, antagonist, cortistatin

ghrelin cell, somatostatin receptor agonists and

INTRODUCTION

In 1972, Guillemin's group - while searching for additional releasing factors in hypothalamic extracts after their identification of thyrotropin-releasing hormone (TRH) - identified a novel negative regulator of pituitary somatotropic cells releasing growth hormone (GH; Brazeau etal., 1973). The cyclo peptide was named somatostatin (somatotropin release-inhibiting factor, SRIF), in keeping with its hypophysiotropic action (Guillemin, 2011). Somatostatin was found to be expressed in two biologically active isoforms: the tetradecapeptide somatostatin-14 (Brazeau etal., 1973) and the amino terminally extended octacosapep-tide somatostatin-28 generated by differential post-translational processing from a common precursor molecule (Pradayrol etal., 1980). Thereafter, a flow of articles in rodents and humans established the ubiquitous distribution of somatostatin in various brain areas (Finley etal., 1981; Johansson etal., 1984; Uhl etal., 1985) and peripheral organs including the gastrointestinal tract (Costa etal., 1977; Walsh, 1994). This was followed by the identification and characterization of five distinct, high-affinity, specific somatostatin receptors (sst) encoded by five distinct genes (Gahete etal., 2010a). Structurally, these receptors belong to the so-called

"superfamily" of membrane G protein-coupled (GPC) receptors. The ssti - 5 have distinct as well as overlapping patterns of distribution in the brain (Fehlmann et al., 2000; Spary et al., 2008) and gut (Schafer and Meyerhof, 1999; Ludvigsen et al., 2004; Corleto et al., 2006) with a prominent expression of sst2 in the gastrointestinal tract (Sternini etal., 1997). Studies using new pharmacological tools, namely selective sst subtype agonists and antagonists (Grace et al., 2006; Cescato et al., 2008; Erchegyi et al., 2008,2009; Table 1 ) point toward the role of different sst1 -5 in mediating the large spectrum of somatostatin biological actions, mostly inhibitory in nature. Multiple effects of somatostatin can also result from the ability of sst to form both homodimers or heterodimers (sst5 with sst1 or dopamine D2 receptor, sst2a with sst3, D2 or ^ opioid receptor subtype 1) resulting in the activation of different intra-cellular signaling cascades (Rocheville etal., 2000; Baragli etal., 2007; Siehler etal., 2008).

Of interest to neuroendocrinologists, somatostatin's inhibitory action on pituitary GH release was soon extended to a wide range of hypophyseal hormones including prolactin, thyrotropin (thyroid-stimulating hormone, TSH), and adrenocorticotropic hormone (ACTH; Brown etal., 1984; Bertherat etal., 1995;

Table 1 | Structure and receptor binding affinity of somatostatin and somatostatin receptor agonists.

Peptide

Structure

Receptor binding affinity (IC50, nM)a

Somatostatin-14 (Viollet etal., 1995) Somatostatin-28 (Viollet etal., 1995)

Octreotide (Grace etal., 2008) ODT8-SST

(Erchegyi etal., 2008) Cortistatin-17 (Fukusumi etal., 1997) sst1 agonist (Erchegyi etal., 2009) sst2 agonist (Grace etal., 2006) sst2 antagonist (Cescato etal., 2008)

Ala-Gly-c[Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser- 0.1-1.5 Cys]-OH

Ser-Ala-Asn-Ser-Asn-Pro-Ala-Met-Ala-Pro-Arg-Glu-Arg- 0.1-4.7 0.4-5.2 0.2

Lys-Ala-Gly-c[Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-

Thr-Ser-Cys]-OH

H-(D)-Phe2-c[Cys3-Phe7-DTrp8-Lys9-Thr10-Cys14]- >1K 1.9 ± 0.3 39 ± 14

Thr15(ol)

des-AA1-2-4-5-12-13-(DTrp8)-SST 270 ± 3.4 41.0 ± 8.7 13.0 ± 3.2

1.0-1.6 0.2-2.2

0.3-1.1 0.05-0.19

>1K 5.1 ± 1.1

1.8 ± 0.7 46.0 ± 27.0

Asp-Arg-Met-Pro-cyclo-[Cys-Arg-Asn-Phe-Phe-Trp-Lys- 0.3-7.0 0.6-0.9 0.4-0.6 0.5-0.6 0.3-0.4

Thr-Phe-Ser-Ser-Cys]Lys

des-AA1-4-6-10-12-13-[DTyr2,D-Agl(NMe,2naphtoyl)8, 0.19 ± 0.04 >1K IAmp9]-SST-Thr-NH2

des-AA1,4-6,11-13-[DPhe2,Aph7(Cbm),DTrp8]-Cbm- >1K 7.5-20 SST-Thr-NH2

des-AA1,4-6,11-13-[pNO2- >1K 2.6 ± 0.7 384.0 ± 97.0 >1K >1K

Phe2,DCys3,Tyr7,DAph(Cbm)8]-SST-2Nal-NH2

158.0 ± 14.0 27.0 ± 75 >1K

942-1094 872-957 109-260

Receptor affinities were derived from competitive radioligand displacement assays in cells stably expressing the cloned human receptor using 125 /-[Leu8 DTrp22 Tyr25] SST-28 (Grace etal., 2006, 2008; Cescato etal., 2008; Erchegyi etal., 2008, 2009) except for somatostatin-14 (Viollet etal., 1995), somatostatin-28 (Viollet etal., 1995), and cortistatin (Fukusumi etal., 1997).

Shimon etal., 1997) as well as a large number of hormones secreted from endocrine cells of the gastrointestinal tract including gastrin (Lloyd etal., 1997), cholecystokinin (CCK; Shiratori etal., 1991), secretin (Shiratori etal., 1991), gastric inhibitory peptide (GIP; Pederson etal., 1975), and neurotensin (Rokaeus, 1984), and from the pancreas glucagon (Marco etal., 1983; Strowski etal., 2000), insulin (Pederson etal., 1975; Marco etal., 1983; Strowski etal., 2000), and pancreatic polypeptide (PP; Marco etal., 1983). Studies to characterize the somatostatin receptor subtypes established that sst2 is primarily involved and, to a smaller extent, sst5 in the broad inhibitory effects of somato-statin on endocrine secretion (Lloyd etal., 1997; Strowski etal., 2000; de Heer etal., 2008). Of clinical relevance was also the compelling evidence that the majority of neuroendocrine tumors (NETs) expressed increased levels of sst2 leading to the development of radiolabeled peptides and peptide receptor radionuclides as diagnostic and therapeutic tools respectively for NETs (van der Hoek etal., 2010; Culler etal., 2011; Giovacchini etal., 2012; Jawiarczyk et al., 2012).

In the past decade, a significant breakthrough came from the identification of a 28-amino-acid octanoylated peptide, ghrelin in the endocrine cells of the gastric mucosa as the cognate ligand for the GH-secretagogue receptor 1a (GHS-R1a, later renamed ghrelin receptor, GRLN-R; Kojima etal., 2001; Davenport etal., 2005). Ghrelin's interaction with the GRLN-R represents a third independent regulatory pathway controlling the pulsatile release of pituitary GH besides the GH-releasing hormone (GHRH) and

somatostatin (Kojima etal., 2001; Malagon etal., 2003; Kineman and Luque, 2007).

Consistent with ghrelin, being predominantly produced by the endocrine cells of the stomach (Ariyasu etal., 2001), recent studies also documented that gastrointestinal NETs released ghrelin (Corbetta etal., 2003; Tsolakis etal., 2004). Therefore the regulation of ghrelin release by somatostatin will be of clinical relevance. The present review focuses on recent evidence that somatostatin signaling in the brain and the periphery exerts opposite influence on circulating ghrelin levels. The sst receptor subtype(s) involved and functional relevance of somatostatin-induced altered ghrelin plasma levels in the context of orexigenic and gastric prokinetic actions of the peptide (Kojima and Kangawa, 2005) will also be addressed.

SOMATOSTATIN AND ITS RECEPTORS: EXPRESSION AND MODULATION OF FEEDING BEHAVIOR AND GASTROINTESTINAL MOTILITY

EXPRESSION OF SOMATOSTATIN AND sst

Somatostatin is expressed throughout the brain except in the cerebellum (Finley etal., 1981; Johansson etal., 1984). Peptide distribution has been investigated byimmunohistochemistryindi-cating the expression in the cortex, limbic system, central nucleus of the amygdala, sensory structures, hypothalamus (including the arcuate, ventromedial, and paraventricular nucleus), and the peri-aqueductal central gray (Finley etal., 1981; Johansson etal., 1984; Moga and Gray, 1985). Similarly, sst receptor mRNA expression

is widely detected in the rat brain including the deep layers of the cerebral cortex, bed nucleus of the stria terminalis, basolateral amygdaloid nucleus, medial amygdaloid nucleus, paraventricu-lar thalamic nucleus, medial preoptic nucleus, dorsomedial and ventromedial hypothalamic nucleus, arcuate and paraventricu-lar nucleus of the hypothalamus, substantia nigra, dorsal raphe nucleus, granular layer of the cerebellum, locus coeruleus, nucleus of the solitary tract, and the dorsal motor nucleus of the vagus nerve (Fehlmann etal., 2000; Spary etal., 2008). The wide distribution of the ligand along with the receptors is consistent with the pleiotropic action of the sst signaling systems.

Somatostatin is widely expressed in the gastrointestinal tract and the pancreas, namely in endocrine mucosal D cells scattered within the stomach, small and large intestine, and in 8-cells of the pancreatic islets of Langerhans (Walsh, 1994). In addition, somatostatin is also detected in neurons of the gut enteric nervous system within both the submucosal and myenteric plexus (Costa et al., 1977). Similar to the ligand, sst receptor subtypes are widely expressed in the gastrointestinal tract. In rats, mRNA expression of sst1, sst2, sst3, and sst4 is detected in the small and large intestine without any clear predominance to one segment (Schafer and Meyerhof, 1999). The sst1 is the predominant form in gastrointestinal tract of mice, whereas the sst5 was almost undetectable (Schafer and Meyerhof, 1999). In human colon, a differential expression has been reported with sst2 mRNA expression on circular smooth muscle cells and sst1 -3 mRNA on longitudinal muscle layer cells (Corleto et al., 2006). Interestingly, in the pancreas protein expression of all sst1 -5 receptor subtypes has been identified on every major endocrine cell type, namely a, p, 8, and PP cells with a differential expression pattern between species (Ludvigsen etal., 2004).

BRAIN ACTIONS OF SOMATOSTATIN

The first function assigned to somatostatin was the inhibition of GH release (Brazeau etal., 1973). Now somatostatin is recognized to exert several central extrapituitary actions such as the regulation of other pituitary endocrine hormones especially those responsive to stress, parasympathetic and sympathetic outflow, thermogenesis, visceral functions, and behaviors. Namely, intracerebroventricular (icv) injection of somatostatin-28 inhibited the tail suspension stress-induced rise of circulating ACTH (Brown etal., 1984). This effect was mimicked by the stable pan-somatostatin agonist, ODT8-SST but not by somatostatin-14 (Brown et al., 1984). The sst2 seems to play a pivotal role in these regulatory processes as sst2 receptor knockout mice display an increased ACTH release compared to their wild type littermates (Viollet etal., 2000).

With regard to the central actions of somatostatin to affect visceral functions, recent studies have focused on the gastrointestinal tract. ODT8-SST injected intracisternally (ic) in rats accelerated gastric emptying of a liquid non-nutrient solution. This effect is mimicked by somatostatin-28 and the sst5 preferring agonist, BIM-23052 but not somatostatin-14 or the agonists preferring sst1, CH-275, sst2, DC-32-87, sst3, BIM-23056, and sst4, L-803,087 (Martinez et al., 2000) indicating a prominent role of brain sst5 activation to induce a gastroprokinetic effect. This contention is further corroborated by the prominent mRNA expression of

sst5 in the dorsal motor nucleus of the vagus nerve (Thoss etal., 1995). Since sst receptors are also expressed in hypothalamic brain nuclei regulating colonic functions (Mönnikes etal., 1993; Mön-nikes et al., 1994; Tebbe et al., 2005) including the arcuate (sst1 -5; Fehlmann etal., 2000; Schulz etal., 2000) and paraventricular nucleus of the hypothalamus (sst2-4; Fehlmann et al., 2000; Schulz et al., 2000) and the locus coeruleus (sst2-4; Fehlmann et al., 2000; Schulz etal., 2000), several studies investigated whether activation of central somatostatin signaling influences colonic motor functions. Stressing mice by short exposure to anesthesia vapor and icv injection of vehicle robustly stimulated propulsive colonic motor function shown by a 99% increase in fecal pellet output (Stengel et al., 2011a). This effect was completely abolished by icv pretreatment with ODT8-SST, somatostatin-28 and the selective sst1 agonist, whereas sst2 or sst4 agonists or octreotide (Table 1) had no effect. These data suggest that activation of brain sst1 can prevent the stress-related stimulation of colonic propulsive motor function in mice (Stengel et al., 2011a).

Central somatostatin alters food intake with a divergent action depending on the doses used: an increase is induced by icv injection of lower (picomolar) doses and a decrease following high (nanomolar) in rats (Feifel and Vaccarino, 1990). The stable pan-somatostatin agonist, ODT8-SST (Erchegyi etal., 2008) icv stimulated food intake in rats under basal as well as already stimulated conditions during the dark phase with a rapid onset (during the first hour) and a long duration of action (lasting for 4 h; Stengel etal., 2010a). ODT8-SST's orexigenic action is sst2 mediated as it is reproduced by icv injection of the selective peptide sst2 agonist (Stengel etal., 2010d) and blocked by the selective peptide sst2 antagonist (Stengel et al., 2010a). This represents a central action since injected intraperitoneally at a 30-fold higher dose, the peptide did not influence food intake (Stengel etal., 2010d). The orexigenic effect of central sst2 stimulation observed in rats has been recently expanded to mice (Stengel etal., 2010c). A detailed analysis of the food intake microstructure using an automated food intake monitoring device showed that icv injection of the sst2 agonist increased the number of meals, shortened inter-meal intervals, and induced a higher rate of ingestion, whereas meal sizes were not altered (Stengel etal., 2010c). Collectively, these data indicate that brain activation of sst2 signaling pathways in rodents induces a rapid orexigenic response by decreasing satiety (number of meals), without influencing satiation indicated by normal meal sizes (Stengel et al., 2010c). The physiological role of brain sst2 signaling in modulating food intake is also supported by the decrease of nocturnal food intake induced by the peptide sst2 antagonist injected icv at the beginning of the dark phase (Stengel etal., 2010d). In addition, hypothalamic somatostatin shows a circadian rhythm with a peak in the early dark phase and a nadir in the early light phase (Gardi et al., 1999). Moreover, food restriction increases pituitary somatostatin release (Ishikawa etal., 1997) which could increase the drive to eat under these conditions.

PERIPHERAL ACTIONS OF SOMATOSTATIN

Contrasting to the central effects, somatostatin's actions in the periphery are largely inhibitory. In the stomach, somatostatin delays emptying of the food (Smedh etal., 1999) and inhibits

gastric acid secretion which is mediated directly by an interaction with acid producing parietal cells but also via the reduced release of histamine from ECL cells and gastrin from G cells (Walsh, 1994). The acid-antisecretory action of somatostatin is no longer observed in sst2 knockout mice, indicative of a primary role of the sst2 (Piqueras et al., 2003). Similarly, in the small intestine somatostatin reduces intestinal peristalsis in cats, rabbits and rats, while stimulating the duodenal, jejunal, and ileal contractile response in dogs (Tansy et al., 1979). In line with the findings in rodents, somatostatin increases gastrointestinal transit time in humans (Gregersen etal., 2011). The effects on colonic motility are likely mediated by the sst1 and sst2 based on in vitro studies using circular and longitudinal human colonic smooth muscle cells (Corleto etal., 2006). In addition, somatostatin reduces visceral sensitivity with the sst2 playing a key role as indicated by visceral hypersensitivity to both mechanical and chemical stimulation in the jejunum of sst2 knockout mice (Rong etal., 2007). This finding is likely to be relevant in humans as well. Patients with irritable bowel syndrome injected subcutaneously with octreotide display an anti-hyperalgesic response as shown by the increased threshold of discomfort and pain using rectal barostat manome-try compared to injection of placebo (Bradette et al., 1994; Schwetz et al., 2004).

GHRELIN AND ITS RECEPTOR: EXPRESSION AND PHYSIOLOGICAL OREXIGENIC AND PROKINETIC ACTIONS EXPRESSION AND REGULATION OF GHRELIN AND GHRELIN RECEPTOR

Ghrelin bears a unique fatty acid (n-octanoyl) residue on the third amino acid which is essential for affinity and binding to the GRLN-R (Kojima etal., 1999; Kojima and Kangawa, 2005). Other dietary fatty acids of medium length can also serve as a direct source for the acylation of ghrelin (Nishi etal., 2005). The enzyme catalyzing the acylation of ghrelin was unknown for several years and just recently identified in mouse and human as a member of the membrane-bound O-acyltransferases (MBOATs), namely MBOAT4 which was subsequently renamed ghrelin-O-acyltransferase (GOAT; Gutierrez etal., 2008; Yang etal., 2008). GOAT mRNA and protein are prominently expressed in rodent and human gastric mucosa in ghrelin expressing cells (Sakata et al., 2009; Stengel etal., 2010f). In addition, GOAT protein has been detected in rodent and human intestine, pancreatic duct, gallbladder, hypothalamus and pituitary gland (Gahete etal., 2010b; Lim et al., 2011; Kang et al., 2012), rodent plasma (Stengel et al., 2010f) and human visceral and subcutaneous adipocytes (Rodriguez et al., 2012) leading to the speculation of additional acylation sites of ghrelin.

Unlike ghrelin, desacyl ghrelin, which does not bear the hydrophobic residue on the third amino acid, is the main circulating form. The acyl:desacyl ghrelin ratio is 1:3 as recently reported using an optimized blood processing protocol to improve the yield of acylated ghrelin in rats (Stengel etal., 2009). Although desacyl ghrelin does not bind to and activate the GRLN-R (Kojima etal., 1999), recent studies indicate that the peptide exerts several biological actions to influence food intake (Stengel et al., 2010e), reduce inflammatory somatic pain (Sibilia etal., 2012), muscle cachexia produced by injury in rats (Sheriffetal.,2012) and basal autophagy

in human visceral adipocytes (Rodriguez etal., 2012). However, the understanding of the physiological function of this peptide is hampered by the fact that the desacyl ghrelin receptor mediating its effects is still to be identified.

Blood levels of ghrelin vary in relation with the meal pattern with an increase before meals and a decrease thereafter (Cum-mings etal., 2001; Tschöp etal., 2001a). In addition, fasting also increases ghrelin mRNA expression (Toshinai etal., 2001; Kim etal., 2003; Xu etal., 2009) and reduces ghrelin peptide content in the stomach (Toshinai etal., 2001; Kim etal., 2003) indicative of a stimulated production and release under conditions of food deprivation. Ghrelin levels are not only regulated by short-term variations in energy status associated with meal patterns but also by long-term changes in body weight. Ghrelin plasma levels are elevated under conditions of reduced body weight such as anorexia nervosa or tumor cachexia and reduced in obesity (Tschöp etal., 2000, 2001b; Cummings etal., 2002). Similar to the ligand, the ghrelin acylating enzyme, GOAT is regulated by the metabolic status with an increased GOAT mRNA and protein expression in rodent gastric mucosa, hypothalamus, and pituitary following a 12- or 24-h fast (Gonzalez etal., 2008; Gahete etal., 2010b; Stengel etal., 2010f). Under conditions of obesity induced by high fat diet or leptin deficiency in ob/ob mice, a down-regulation of GOAT mRNA occurred in the mouse pituitary, unlike the stomach or hypothalamus (Gahete et al., 2010b), while patients with obesity-associated type 2 diabetes showed higher levels of GOAT in visceral adipose tissue (Rodriguez et al., 2012). This indicates a tissue specific regulation of GOAT under conditions of obesity.

OREXIGENIC AND PROKINETIC EFFECTS OF GHRELIN

Ghrelin is well established to stimulate food intake in line with its regulation by changes in energy status in many species including humans (Wren et al., 2000; Tang-Christensen et al., 2004; Druce etal., 2005). It is so far the only known peripherally produced and centrally acting orexigenic peptide, contrasting with the numerous anorexigenic peptides in the gut (Suzuki et al., 2011). Ghrelin's action is blocked by pharmacological or genetic approaches using GRLN-R antagonists (Salome et al., 2009) and GRLN-R knockout mice (Sun et al., 2004; Zigman et al., 2005) indicating a key role of ghrelin-GRLN-R interaction in mediating the orexigenic response. The food intake stimulatory action can result from ghrelin crossing the blood-brain barrier and binding to GRLN-R expressed on food intake regulatory brain nuclei (Banks et al., 2002; Pan et al., 2006) or acting directly on vagal afferents which also bear the ghrelin receptor (Date etal., 2002; Sakata etal., 2003). The respective role of these pathways under nutritional changes is still to be delineated. In addition to the stimulation of food intake, ghrelin is also involved in the regulation of body weight inducing an increase of body weight following chronic infusion of the pep-tide. This occurs through combined actions of stimulating appetite along with increasing fat storage and reducing lipid mobilization (Tschöp etal., 2000; Strassburg etal., 2008; Davies etal., 2009). Further corroborating these findings, ghrelin and GRLN-R double knockout mice display an increased energy expenditure leading to a reduction of body weight (Pfluger etal., 2008) which, however, could not be reproduced with a single genetic deletion of

either ghrelin (Sun et al., 2003; Pfluger et al., 2008) or the GRLN-R (Pfluger etal., 2008). These differential phenotypes may reflect the functional relevance of the high constitutive activity of the GRLN-R (Damian etal., 2012) and also give rise to the speculation that additional ligands for the receptor may exist (Deghenghi etal., 2001a).

DIFFERENTIAL MODULATION OF GH RELEASE BY GHRELIN AND SOMATOSTATIN

Ghrelin exerts endocrine actions opposite to somatostatin by stimulating anterior pituitary release of GH (Kojima etal., 1999; Yamazaki etal., 2002; Kojima and Kangawa, 2011), prolactin, and ACTH (Lanfranco et al., 2010). Somatostatin's GH inhibitory effect is mediated by the sst2 (Briard etal., 1997), sst5 (Saveanu et al., 2001) and also sst1 (Kreienkamp et al., 1999). The GH releasing effect of ghrelin is blunted by intravenous (iv) infusion of somatostatin in healthy volunteers (Di Vito etal., 2002) and was completely blocked in pig pituitary cells in vitro (Malagon etal., 2003). The GH releasing action of ghrelin is likely to not only result from inhibiting somatostatin release (Feng etal., 2011) but also from direct activation of GH release (Veldhuis etal., 2006). In addition, ghrelin and somatostatin antagonistically interact on hypothalamic arcuate cells to regulate the release of GHRH with an activation of these neurons following ghrelin and a reduction after application of somatostatin in vitro (Mori etal., 2010).

ACTIVATION OF BRAIN sst2 SIGNALING INCREASES BASAL AND PREVENTS VISCERAL STRESS-INDUCED SUPPRESSION OF CIRCULATING GHRELIN

Based on the established centrally sst2-mediated orexigenic action of somatostatin (Stengel etal., 2010a,d), we further investigated whether changes in circulating ghrelin may play a role. We found that the pan-somatostatin peptide, ODT8-SST (Table 1 ) injected icv increased basal plasma acyl ghrelin levels in ad libitum fed rats (Stengel etal., 2010a). However, the rise was observed at 3 h postinjection and therefore unlikely to underlie the initial increase in food intake response to central ODT8-SST which occurred within the first hour. However, it may contribute to the sustained significant increase in cumulative food intake still maintained at 4 h after icv injection of ODT8-SST (Stengel et al., 2010a). Other studies showed that activation of brain sst2 receptor prevents the decline in circulating ghrelin induced by visceral stress. Abdominal surgery reproducibly decreased the fasting plasma levels of acyl and desacyl ghrelin with a rapid onset and long lasting effect in rats (Stengel etal., 2010b, 2011b,c). Such a response was completely prevented by the ic injection of ODT8-SST as monitored 50 min postsurgery at a time where the peptide induces a 31 and 46% rise in fasting circulating acyl and desacyl ghrelin, respectively in sham animals (Stengel et al., 2011b). In addition, the sst2 selective peptide agonist injected ic also prevented the postoperative decline in plasma levels of acyl ghrelin, whereas sst1 and sst4 agonists (Table 1 ) did not when tested under the same conditions (Stengeletal., 2011b).

Of interest was the demonstration that ic ODT8-SST or sst2 agonist in addition to preventing the decline in acyl ghrelin induced by abdominal surgery also blunted the postoperative suppression of food intake (Stengel etal., 2011b). However, the

observed prevention of declining circulating ghrelin levels is not the main factor for the restoration of the orexigenic response postsurgically. The peripheral blockade of the GRLN-R using the GRLN-R antagonist ([D-Lys3]-GHRP-6) injected intraperi-toneally did not modify the food intake stimulating effect of ic ODT8-SST (Stengel etal., 2011b). ODT8-SST injected icv also restored gastric emptying inhibited by abdominal surgery to levels observed under basal conditions, an effect mimicked by the sst5 but not the sst1, sst2, and sst4 agonists in rats (Stengel etal., 2011b). Similar to the effect on food intake, this action was not mediated by acyl ghrelin as the intraperitoneal injection of the GRLN-R antagonist did not influence the gastroprokinetic action of ODT8-SST postsurgery (Stengel etal., 2011b).

Taken together, these data indicate that the central activation of sst2 increases basal or prevents the surgical inhibition of circulating levels of ghrelin and food intake while activation of sst5 restores postoperative gastric ileus in rats. It also points to a differential role of brain sst subtypes 2 and 5 in preventing the stress-related suppression of ghrelin release/food intake and gastric emptying, respectively. In addition, the restoration of suppressed circulating acyl ghrelin levels after surgery does not play a major role as underlying mechanisms through which ODT8-SST injected into the brain exerts its prokinetic and orexigenic effects. Other studies showed that activation of sst2 and sst5 receptors in the brain inhibits stimulated CRF release in the hypothalamus and acute stress-related CRF mediated ACTH release (Brown et al., 1984; Tiz-abi and Calogero, 1992; Saegusa etal., 2011; Tringali etal., 2012). Brain CRF acting on CRF receptors is involved in the stress-related decrease in feeding behavior, ghrelin secretion, and gastric emptying (Hotta et al., 1999; Sekino et al., 2004; Taché and Bonaz, 2007; Yakabi etal., 2011). Therefore, it may be speculated that central activation of sst2 and/or sst5 dampens hypothalamic CRF activated by abdominal surgery (Wang et al., 2011) which may have a bearing with preventing the reduction in feeding, gastric emptying, and circulating ghrelin induced by abdominal surgery (Stengel etal., 2011b).

ACTIVATION OF PERIPHERAL sst2 SIGNALING INHIBITS CIRCULATING GHRELIN

In contrast to the rise in circulating ghrelin induced by central administration of somatostatin agonists, convergent in vivo and in vitro rodent studies established that somatostatin or the stable agonists octreotide and SOM230 act peripherally through the sst2 to reduce ghrelin release (Seoane etal., 2007; Iwakura etal., 2010; Lu etal., 2012) resulting in lower circulating levels (Shi-mada etal., 2003; Silva etal., 2005; de la Cour etal., 2007). Such a response is in line with the inhibitory effects of somatostatin-sst2 on the endocrine secretion of other intestinal hormones (Pederson etal., 1975; Marco etal., 1983; Rokaeus, 1984; Shiratori etal., 1991; Strowski etal., 2000). Likewise, in humans, peripherally injected somatostatin (Broglio etal., 2002; Norre-lund etal., 2002) and somatostatin agonists such as octreotide (Barkan et al., 2003) reduce circulating ghrelin in healthy subjects. Of relevance, chronic subcutaneous infusion of the sst2/sst3/sst5 agonist octreotide-induced suppression of ghrelin plasma levels is not subject to rapid desensitization in rats and is likely to be sst2 mediated based on the prominent sst2 mRNA expression in

the rat stomach (Silva etal., 2005). Further support for a role of sst2 came from immunofluorescent double labeling studies detecting the protein expression of sst2 on ghrelin-producing X/A-like cells of the rat stomach (Stengel etal., 2011c) and similarly on human ghrelin-producing gastric mucosal P/D1 cells (Fischer etal., 2008). Moreover, the selective peptide sst2 agonist (Table 1 ) injected intravenously decreased circulating levels of acyl and desacyl ghrelin with a rapid onset (0.5 h) and a long duration of action (still visible at 2 h; Stengel etal., 2011c). Lastly, the selective peptide sst2 antagonist (Table 1 ) injected intravenously prevents the decline in circulating ghrelin induced by the stimulation of endogenous peripheral somatostatin in rats (Stengel etal., 2011c).

The physiological role of peripheral somatostatin-sst2 signaling in the regulation of ghrelin was investigated under conditions of stimulation of endogenous gastric somatostatin. Urethane is well established to stimulate gastric somatostatin mRNA expression and peptide release in rats (Yang etal., 1990). Under these conditions, plasma ghrelin levels are decreased and the selective peptide sst2 antagonist (Table 1 ) injected intravenously prevents the decline in circulating ghrelin induced by urethane (Stengel et al., 2011c). Convergent reports showed that abdominal surgery induces a rapid and sustained inhibition of circulating levels of ghrelin in rats (Stengel etal., 2010b, 2011b,c). Likewise, iv injection of the selective peptide sst2 antagonist (Table 1 ) blocked the abdominal surgery-induced decrease of plasma ghrelin at 0.5 h postsurgery (Stengel etal., 2011c). The peptide is likely to act through paracrine transmission since somatostatin positive D cells directly contact ghrelin immunoreactive X/A-like cells in the rat stomach (Shimada etal., 2003). Interestingly, following abdominal surgery, acyl ghrelin was reduced more rapidly compared to desacyl ghrelin which was associated with a reduction of gastric as well as plasma concentrations of GOAT (Stengel etal., 2011c). Since blockade of peripheral sst2 signaling restores circulating levels of ghrelin (Stengel et al., 2011c), these data collectively suggest that peripheral somatostatin may blunt gastric GOAT mRNA expression and thereby negatively affect the acylation of ghrelin. In primary pituitary cell cultures somatostatin was reported to reduce GOAT mRNA expression and somatostatin knockout mice showed higher GOAT mRNA expression in the pituitary gland than the wild type (Gahete etal., 2010b). Based on these findings, somatostatin may influence ghrelin signaling not only via a direct inhibition of secretion but also by modulating the ghre-lin activating enzyme GOAT. Further support for a physiological inhibitory action of peripheral somatostatin on ghrelin signaling came from somatostatin knockout mice that displayed an increased gastric ghrelin expression and higher circulating ghrelin levels compared to their wild type littermates (Luque etal., 2006a). These data indicate that endogenous somatostatin exerts a physiological inhibitory tone on gastric ghrelin synthesis and release.

During the past years, several clinical studies described ghrelin-producing NETs (Papotti etal., 2001; Volante etal., 2002; Taal and Visser, 2004) including six insulinomas, gastrinomas, vasoactive intestinal polypeptide (VIP)omas, non-functioning tumors (Volante et al., 2002) and as part of the multiple endocrine neo-plasia type 1 (MEN-1; Iwakura etal., 2002; Raffel etal., 2005;

Ekeblad et al., 2007). Moreover, ghrelinomas have been identified to originate from the stomach or pancreas and were associated with very high ghrelin levels (Corbetta et al., 2003; Tsolakis et al., 2004). Growing evidence from clinical reports indicates that in addition to the surgical, chemotherapeutic, alpha-interferon, and local radiation treatments, the use of somatostatin or somatostatin analog is an established treatment option for gastroenteropancre-atic NETs (Pavel and Wiedenmann, 2011). Based on the evidence described above, the determination of the sst subtype expressed on those ghrelinoma tumor cells followed by the use of peripherally acting selective sst compounds may result in an even more targeted approach.

INTERACTION OF CORTISTATIN WITH GHRELIN SIGNALING

In 1996, the discovery of a new peptide sharing 11 of its 14 amino acids with somatostatin-14 was named cortistatin based on its predominant cortical expression and ability to depress cortical activity (de Lecea et al., 1996). Despite the chemical structure homology with somatostatin, both peptides are derived from distinct genes (de Lecea etal., 1997b). Similar to pro-somatostatin, processing of cortistatin precursor generated two mature products, cortistatin-14 and -29 in rodents and cortistatin-17 and -29 in humans (Fukusumi etal., 1997; Spier and de Lecea, 2000). Cortistatin is widely expressed in the brain, namely in the cortex and hippocampus, and although regional overlap exists, the distribution pattern differs from that of somatostatin (de Lecea et al., 1997a). Likewise, the peripheral expression pattern of cortis-tatin (e.g., in adrenal, thyroid, and parathyroid gland, testis, pancreas, kidney, lung, liver, stomach, ileum, jejunum, colon, endothelial, and immune cells) does not fully match that of somatostatin (Papotti et al., 2003; Dalm et al., 2004; Xidakis et al., 2007). Consistent with being a close somatostatin endogenous analog, cortistatin contains the FWKT tetramer crucial for sst binding, and therefore displays high-affinity (1-2 nM) to all five sst subtypes where the peptide acts as an agonist (Fukusumi etal., 1997; Siehler etal., 2008). However, emerging evidence indicates that cortistatin induces distinct central and peripheral effects that differ from those exerted by the somatostatin-sst interaction such as central acetylcholine release, reduction of locomotor activity, depression of cortical activity, induction of slow wave sleep, anti-inflammatory and immunomodulatory effects, and reduction of vascular calcium deposition (for review, see Spier and de Lecea, 2000; Broglio etal., 2007; Gonzalez-Rey and Delgado, 2008).

The existence of a specific cortistatin receptor has not been identified yet but differential actions between somatostatin and cortistatin may possibly reside in the ability of cortistatin to bind and to activate the GRLN-R, whereas somatostatin does not (Deghenghi etal., 2001b; Muccioli etal., 2001). Divergent from native somatostatin, however, synthetic somatostatin agonists, lanreotide, octreotide, and vapreotide bind to the GRLN-R in human pituitary tissue (Deghenghi etal., 2001c) in addition to their selective affinity for sst2 > sst5 > sst3 (Bauer etal., 1982; Reichlin, 1983; Redding and Schally, 1984). In addition to binding studies, few functional findings also support the possibility that cortistatin maybe another endogenous high-affinity ligand of the

GRLN-R. Cortistatin has been reported to inhibit vascular calcification induced experimentally in rats through activation of the GRLN-R receptor rather than sst or Mrg X2 (Liu et al., 2010). Of interest was the demonstration that cortistatin selectively upreg-ulates the GRLN-R mRNA expression in cultured rat vascular smooth muscle cells, further indicative of an interaction between cortistatin and ghrelin signaling (Liu etal., 2010). Other studies in primates and mice demonstrated that endogenous cortistatin, unlike somatostatin, is involved in the stimulation of pituitary prolactin release, an effect that is blocked in vitro by the GRLN-R antagonist (Cordoba-Chacon etal., 2011). However, most of the endocrine studies performed in vivo or in vitro showed parallel inhibitory responses between cortistatin and somatostatin consistent with the activation of classical sst subtypes (Broglio etal., 2008) with some exceptions (Prodam etal., 2008). This is further corroborated by the finding that cortistatin knockout mice display elevated circulating acyl ghrelin levels associated with an upregu-lated gastric ghrelin and GOAT expression (Cordoba-Chacon et al., 2011) indicating an inhibitory tone of endogenous cortistatin on ghrelin signaling.

To further delineate the actions of cortistatin mediated via the GRLN-R another peptide, cortistatin-8, has been shown to bind to the GRLN-R while being devoid of affinity to the sst subtypes (Luque etal., 2006b). However, in one clinical study cortistatin-8 did not influence spontaneous pituitary hormone secretion (GH, prolactin, and ACTH) and did not interfere with ghrelin's endocrine responses when given in equimolar dose ratios in healthy human subjects (Prodam et al., 2008). Therefore,

additional specific tools may be needed to characterize a possible direct link between the ghrelin and somatostatin signaling system via interaction on the GRLN-R.

SUMMARY

In summary, somatostatin robustly affects circulating levels of ghrelin through interaction with the sst2. However, alterations vary with the site of action. Central somatostatin elevates plasma levels of acyl and desacyl ghrelin via interaction with brain sst2 and counteracts the visceral stress-related decrease in circulating ghrelin through pathways still to be elucidated in rodents. By contrast, the activation of peripheral somatostatin-sst2 inhibits circulating ghrelin levels in experimental and clinical studies and mediates the decline in circulating ghrelin induced by abdominal surgery in rodents likely via a paracrine action of somatostatin on sst2-bearing ghrelin cells in the stomach. Of interest, cortistatin, the other member of the somatostatin family, in addition to binding to sst1-5, also binds to and activates the GRLN-R. There is evidence that the peptide can exert a dual influence on ghrelin, by inhibiting its release through interaction with sst2 located on gastric ghrelin cells while activating GRLN-R at ghrelin's tissue targets.

ACKNOWLEDGMENTS

This work was supported by NIH R01 DK-33061, NIH Center Grant DK-41301 (Animal Core), VA Research Career Scientist and VA Merit grant (to Yvette Taché), German Research Foundation STE 1765/3-1 (to Andreas Stengel), and Charité University Funding UFF 89-441-176 (to Andreas Stengel).

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Conflict of Interest Statement: The

authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Received: 11 October 2012; paper pending published: 01 November 2012; accepted: 17 December 2012; published online: 11 January 2013.

Citation: Stengel A and Taché Y (2013) Activation of somatostatin 2 receptors in the brain and the periphery induces opposite changes in circulating ghrelin levels: functional implications. Front. Endocrin. 3:178. doi: 10.3389/fendo.2012.00178 This article was submitted to Frontiers in Neuroendocrine Science, a specialty of Frontiers in Endocrinology. Copyright © 2013 Stengel and Taché. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.

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