REVIEW ARTICLE published: 11 January 2013 doi: 10.3389/fendo.2012.00178 Activation of 2 receptors in the brain and the periphery induces opposite changes in circulating ghrelin levels: functional implications

Andreas Stengel 1* andYvetteTaché 2* 1 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: Somatostatin is an important modulator of neurotransmission in the central nervous sys- Hubert Vaudry, University of Rouen, tem and acts as a potent inhibitor of and exocrine secretion and regulator of cell France proliferation in the periphery.These pleiotropic actions occur through interaction with five G Reviewed by: protein-coupled somatostatin receptor subtypes (sst − ) that are widely expressed in the Rafael Vazquez-Martinez, University of 1 5 Cordoba, Spain brain and peripheral organs. The characterization of somatostatin’s effects can be inves- Francisco Gracia-Navarro, University tigated by pharmacological or genetic approaches using newly developed selective sst of Cordoba, Spain agonists and antagonists and mice lacking specific sst subtypes. Recent evidence points *Correspondence: toward a divergent action of somatostatin in the brain and in the periphery to regulate cir- Andreas Stengel, Division culating levels of ghrelin, an orexigenic hormone produced by the endocrine X/A-like cells Psychosomatic Medicine and Psychotherapy, Department of in the rat gastric mucosa. Somatostatin interacts with the sst2 in the brain to induce an Medicine, Obesity Center Berlin, increase in basal ghrelin plasma levels and counteracts the visceral stress-related decrease Charité, Universitätsmedizin Berlin, in circulating ghrelin. By contrast, stimulation of peripheral somatostatin-sst2 signaling Luisenstr. 13a, 10117 Berlin, Germany. e-mail: [email protected]; results in the inhibition of basal ghrelin release and mediates the postoperative decrease Yvette Taché, Digestive Diseases in circulating ghrelin. The peripheral sst2-mediated reduction of plasma ghrelin is likely Division, CURE: Digestive Diseases to involve a paracrine action of D cell-derived somatostatin acting on sst2 bearing X/A- Research Center, Center for like ghrelin cells in the gastric mucosa. The other member of the somatostatin family, Neurobiology of Stress and Women’s Health, Department of Medicine, VA named cortistatin, in addition to binding to sst1−5 also directly interacts with the ghrelin Greater Los Angeles Health Care receptor and therefore may simultaneously modulate ghrelin release and actions at target System, University of California at Los sites bearing ghrelin receptors representing a link between the ghrelin and somatostatin Angeles, CURE Building 115, Room systems. 117, 11301 Wilshire Boulevard, Los Angeles, CA 90073, USA. Keywords: X/A-like cell, somatostatin receptor subtypes, ghrelin cell, somatostatin receptor agonists and e-mail: [email protected] antagonist, cortistatin

INTRODUCTION “superfamily” of membrane G protein-coupled (GPC) receptors. In 1972, Guillemin’s group – while searching for additional The sst1−5 have distinct as well as overlapping patterns of distribu- releasing factors in hypothalamic extracts after their identifi- tion in the brain (Fehlmann et al., 2000; Spary et al., 2008) and gut cation of thyrotropin-releasing hormone (TRH) – identified a (Schafer and Meyerhof, 1999; Ludvigsen et al., 2004; Corleto et al., novel negative regulator of pituitary somatotropic cells releasing 2006) with a prominent expression of sst2 in the gastrointestinal (GH; Brazeau et al., 1973). The cyclo peptide tract (Sternini et al., 1997). Studies using new pharmacological was named somatostatin (somatotropin release-inhibiting factor, tools, namely selective sst subtype agonists and antagonists (Grace SRIF), in keeping with its hypophysiotropic action (Guillemin, et al., 2006; Cescato et al., 2008; Erchegyi et al., 2008, 2009; Table 1) 2011). Somatostatin was found to be expressed in two biologically point toward the role of different sst1−5 in mediating the large active isoforms: the tetradecapeptide somatostatin-14 (Brazeau spectrum of somatostatin biological actions, mostly inhibitory in et al., 1973) and the amino terminally extended octacosapep- nature. Multiple effects of somatostatin can also result from the tide somatostatin-28 generated by differential post-translational ability of sst to form both homodimers or heterodimers (sst5 with processing from a common precursor molecule (Pradayrol et al., sst1 or dopamine D2 receptor, sst2a with sst3,D2 or μ opioid 1980). Thereafter, a flow of articles in rodents and humans estab- receptor subtype 1) resulting in the activation of different intra- lished the ubiquitous distribution of somatostatin in various brain cellular signaling cascades (Rocheville et al., 2000; Baragli et al., areas (Finley et al., 1981; Johansson et al., 1984; Uhl et al., 1985) 2007; Siehler et al., 2008). and peripheral organs including the gastrointestinal tract (Costa Of interest to neuroendocrinologists, somatostatin’s inhibitory et al., 1977; Walsh, 1994). This was followed by the identifica- action on pituitary GH release was soon extended to a wide tion and characterization of five distinct, high-affinity, specific range of hypophyseal including prolactin, thyrotropin somatostatin receptors (sst) encoded by five distinct genes (Gahete (thyroid-stimulating hormone, TSH), and adrenocorticotropic et al., 2010a). Structurally, these receptors belong to the so-called hormone (ACTH; Brown et al., 1984; Bertherat et al., 1995;

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

a Peptide Structure Receptor binding affinity (IC50, nM)

sst1 sst2 sst3 sst4 sst5

Somatostatin-14 Ala-Gly-c[Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser- 0.1–1.5 1.7 1.7 1.0–1.6 0.2–2.2 (Viollet et al., 1995) Cys]-OH Somatostatin-28 Ser-Ala-Asn-Ser-Asn-Pro-Ala-Met-Ala-Pro-Arg-Glu-Arg- 0.1–4.7 0.4–5.2 0.2 0.3–1.1 0.05–0.19 (Viollet et al., 1995) Lys-Ala-Gly-c[Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe- Thr-Ser-Cys]-OH Octreotide H-(D)-Phe2-c[Cys3-Phe7-DTrp8-Lys9-Thr10 -Cys14 ]- >1K 1.9 ± 0.3 39 ± 14 >1K 5.1 ± 1. 1 (Grace et al., 2008) Thr15 (ol) ODT8-SST des-AA1,2,4,5,12,13-(DTrp8)-SST 27.0 ± 3.4 41.0 ± 8.7 13.0 ± 3.2 1.8 ± 0.7 46.0 ± 27.0 (Erchegyi et al., 2008) Cortistatin-17 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 (Fukusumi et al., 1997) Thr-Phe-Ser-Ser-Cys]Lys 1,4−6,10,12,13 2 8 sst1 agonist des-AA -[DTyr ,D-Agl(NMe,2naphtoyl) , 0.19 ± 0.04 >1K 158.0 ± 14.0 27.0 ± 7. 5 >1K 9 (Erchegyi et al., 2009) IAmp ]-SST-Thr-NH2 1,4−6,11−13 2 7 8 sst2 agonist des-AA -[DPhe ,Aph (Cbm),DTrp ]-Cbm- >1K 7.5–20 942–1094 872–957 109–260

(Grace et al., 2006) SST-Thr-NH2 1,4−6,11−13 sst2 antagonist des-AA -[pNO2- >1K 2.6 ± 0.7 384.0 ± 97.0 >1K >1K 2 3 7 8 (Cescato et al., 2008) Phe ,DCys ,Tyr ,DAph(Cbm) ]-SST-2Nal-NH2

Receptor affinities were derived from competitive radioligand displacement assays in cells stably expressing the cloned human receptor using 125 I-[Leu8DTrp22Tyr 25] SST-28 (Grace et al., 2006, 2008; Cescato et al., 2008; Erchegyi et al., 2008, 2009) except for somatostatin-14 (Viollet et al., 1995), somatostatin-28 (Viollet et al., 1995), and cortistatin (Fukusumi et al., 1997).

Shimon et al., 1997) as well as a large number of hormones somatostatin (Kojima et al., 2001; Malagon et al., 2003; Kineman secreted from endocrine cells of the gastrointestinal tract including and Luque, 2007). gastrin (Lloyd et al., 1997), cholecystokinin (CCK; Shiratori et al., Consistent with ghrelin, being predominantly produced by the 1991), secretin (Shiratori et al., 1991), gastric inhibitory peptide endocrine cells of the stomach (Ariyasu et al., 2001), recent stud- (GIP; Pederson et al., 1975), and neurotensin (Rokaeus, 1984), ies also documented that gastrointestinal NETs released ghrelin and from the (Marco et al., 1983; Strowski (Corbetta et al., 2003; Tsolakis et al., 2004). Therefore the regula- et al., 2000), (Pederson et al., 1975; Marco et al., 1983; tion of ghrelin release by somatostatin will be of clinical relevance. Strowski et al., 2000), and pancreatic polypeptide (PP; Marco The present review focuses on recent evidence that somatostatin et al., 1983). Studies to characterize the somatostatin receptor signaling in the brain and the periphery exerts opposite influence subtypes established that sst2 is primarily involved and, to a on circulating ghrelin levels. The sst receptor subtype(s) involved smaller extent, sst5 in the broad inhibitory effects of somato- and functional relevance of somatostatin-induced altered ghrelin statin on endocrine secretion (Lloyd et al., 1997; Strowski et al., plasma levels in the context of orexigenic and gastric prokinetic 2000; de Heer et al., 2008). Of clinical relevance was also the actions of the peptide (Kojima and Kangawa, 2005) will also be compelling evidence that the majority of neuroendocrine tumors addressed. (NETs) expressed increased levels of sst2 leading to the develop- ment of radiolabeled peptides and peptide receptor radionuclides SOMATOSTATIN AND ITS RECEPTORS: EXPRESSION AND as diagnostic and therapeutic tools respectively for NETs (van MODULATION OF FEEDING BEHAVIOR AND der Hoek et al., 2010; Culler et al., 2011; Giovacchini et al., 2012; GASTROINTESTINAL MOTILITY Jawiarczyk et al., 2012). EXPRESSION OF SOMATOSTATIN AND sst In the past decade, a significant breakthrough came from the Somatostatin is expressed throughout the brain except in the identification of a 28-amino-acid octanoylated peptide, ghrelin in cerebellum (Finley et al., 1981; Johansson et al., 1984). Peptide the endocrine cells of the gastric mucosa as the cognate ligand distribution has been investigated by immunohistochemistry indi- for the GH-secretagogue receptor 1a (GHS-R1a, later renamed cating the expression in the cortex, limbic system, central nucleus ghrelin receptor, GRLN-R; Kojima et al., 2001; Davenport et al., of the amygdala, sensory structures, hypothalamus (including the 2005). Ghrelin’s interaction with the GRLN-R represents a third arcuate, ventromedial, and paraventricular nucleus), and the peri- independent regulatory pathway controlling the pulsatile release aqueductal central gray (Finley et al., 1981; Johansson et al., 1984; of pituitary GH besides the GH-releasing hormone (GHRH) and Moga and Gray, 1985). Similarly, sst receptor mRNA expression

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is widely detected in the rat brain including the deep layers of sst5 in the dorsal motor nucleus of the vagus nerve (Thoss et al., the cerebral cortex, bed nucleus of the stria terminalis, basolateral 1995). Since sst receptors are also expressed in hypothalamic brain amygdaloid nucleus, medial amygdaloid nucleus, paraventricu- nuclei regulating colonic functions (Mönnikes et al., 1993; Mön- lar thalamic nucleus, medial preoptic nucleus, dorsomedial and nikes et al., 1994; Tebbe et al., 2005) including the arcuate (sst1−5; ventromedial hypothalamic nucleus, arcuate and paraventricu- Fehlmann et al., 2000; Schulz et al., 2000) and paraventricular lar nucleus of the hypothalamus, substantia nigra, dorsal raphe nucleus of the hypothalamus (sst2−4; Fehlmann et al.,2000; Schulz nucleus, granular layer of the cerebellum, locus coeruleus, nucleus et al., 2000) and the locus coeruleus (sst2−4; Fehlmann et al., 2000; of the solitary tract, and the dorsal motor nucleus of the vagus Schulz et al., 2000), several studies investigated whether activa- nerve (Fehlmann et al., 2000; Spary et al., 2008). The wide distri- tion of central somatostatin signaling influences colonic motor bution of the ligand along with the receptors is consistent with the functions. Stressing mice by short exposure to anesthesia vapor pleiotropic action of the sst signaling systems. and icv injection of vehicle robustly stimulated propulsive colonic Somatostatin is widely expressed in the gastrointestinal tract motor function shown by a 99% increase in fecal pellet output and the pancreas, namely in endocrine mucosal D cells scattered (Stengel et al., 2011a). This effect was completely abolished by icv within the stomach, small and large intestine, and in δ-cells of pretreatment with ODT8-SST, somatostatin-28 and the selective the pancreatic islets of Langerhans (Walsh, 1994). In addition, sst1 agonist, whereas sst2 or sst4 agonists or octreotide (Table 1) somatostatin is also detected in neurons of the gut enteric nervous had no effect. These data suggest that activation of brain sst1 can system within both the submucosal and myenteric plexus (Costa prevent the stress-related stimulation of colonic propulsive motor et al., 1977). Similar to the ligand, sst receptor subtypes are widely function in mice (Stengel et al., 2011a). expressed in the gastrointestinal tract. In rats, mRNA expression Central somatostatin alters food intake with a divergent action of sst1, sst2, sst3, and sst4 is detected in the small and large intes- depending on the doses used: an increase is induced by icv injec- tine without any clear predominance to one segment (Schafer and tion of lower (picomolar) doses and a decrease following high Meyerhof, 1999). The sst1 is the predominant form in gastroin- (nanomolar) in rats (Feifel and Vaccarino, 1990). The stable testinal tract of mice, whereas the sst5 was almost undetectable pan-somatostatin agonist, ODT8-SST (Erchegyi et al., 2008) icv (Schafer and Meyerhof, 1999). In human colon, a differential stimulated food intake in rats under basal as well as already stimu- expression has been reported with sst2 mRNA expression on circu- lated conditions during the dark phase with a rapid onset (during lar smooth muscle cells and sst1−3 mRNA on longitudinal muscle the first hour) and a long duration of action (lasting for 4 h; Sten- layer cells (Corleto et al., 2006). Interestingly, in the pancreas pro- gel et al., 2010a). ODT8-SST’s orexigenic action is sst2 mediated tein expression of all sst1−5 receptor subtypes has been identified as it is reproduced by icv injection of the selective peptide sst2 on every major endocrine cell type, namely α, β, δ, and PP cells agonist (Stengel et al., 2010d) and blocked by the selective pep- with a differential expression pattern between species (Ludvigsen tide sst2 antagonist (Stengel et al., 2010a). This represents a central et al., 2004). action since injected intraperitoneally at a 30-fold higher dose, the peptide did not influence food intake (Stengel et al., 2010d). The BRAIN ACTIONS OF SOMATOSTATIN orexigenic effect of central sst2 stimulation observed in rats has The first function assigned to somatostatin was the inhibition been recently expanded to mice (Stengel et al., 2010c). A detailed of GH release (Brazeau et al., 1973). Now somatostatin is rec- analysis of the food intake microstructure using an automated ognized to exert several central extrapituitary actions such as food intake monitoring device showed that icv injection of the the regulation of other pituitary endocrine hormones especially sst2 agonist increased the number of meals, shortened inter-meal those responsive to stress, parasympathetic and sympathetic out- intervals, and induced a higher rate of ingestion, whereas meal flow, thermogenesis, visceral functions, and behaviors. Namely, sizes were not altered (Stengel et al., 2010c). Collectively, these intracerebroventricular (icv) injection of somatostatin-28 inhib- data indicate that brain activation of sst2 signaling pathways in ited the tail suspension stress-induced rise of circulating ACTH rodents induces a rapid orexigenic response by decreasing sati- (Brown et al., 1984). This effect was mimicked by the stable ety (number of meals), without influencing satiation indicated by pan-somatostatin agonist, ODT8-SST but not by somatostatin- normal meal sizes (Stengel et al., 2010c). The physiological role of 14 (Brown et al., 1984). The sst2 seems to play a pivotal role in brain sst2 signaling in modulating food intake is also supported these regulatory processes as sst2 receptor knockout mice display by the decrease of nocturnal food intake induced by the peptide an increased ACTH release compared to their wild type littermates sst2 antagonist injected icv at the beginning of the dark phase (Viollet et al., 2000). (Stengel et al., 2010d). In addition, hypothalamic somatostatin With regard to the central actions of somatostatin to affect vis- shows a circadian rhythm with a peak in the early dark phase ceral functions, recent studies have focused on the gastrointestinal and a nadir in the early light phase (Gardi et al., 1999). Moreover, tract. ODT8-SST injected intracisternally (ic) in rats accelerated food restriction increases pituitary somatostatin release (Ishikawa gastric emptying of a liquid non-nutrient solution. This effect et al., 1997) which could increase the drive to eat under these is mimicked by somatostatin-28 and the sst5 preferring agonist, conditions. 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 PERIPHERAL ACTIONS OF SOMATOSTATIN (Martinez et al., 2000) indicating a prominent role of brain sst5 Contrasting to the central effects, somatostatin’s actions in the activation to induce a gastroprokinetic effect. This contention periphery are largely inhibitory. In the stomach, somatostatin is further corroborated by the prominent mRNA expression of delays emptying of the food (Smedh et al., 1999) and inhibits

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gastric acid secretion which is mediated directly by an interac- in human visceral adipocytes (Rodriguez et al., 2012). However, tion with acid producing parietal cells but also via the reduced the understanding of the physiological function of this peptide is release of histamine from ECL cells and gastrin from G cells hampered by the fact that the desacyl ghrelin receptor mediating (Walsh, 1994). The acid-antisecretory action of somatostatin is its effects is still to be identified. no longer observed in sst2 knockout mice, indicative of a primary Blood levels of ghrelin vary in relation with the meal pattern role of the sst2 (Piqueras et al., 2003). Similarly, in the small intes- with an increase before meals and a decrease thereafter (Cum- tine somatostatin reduces intestinal peristalsis in cats, rabbits and mings et al., 2001; Tschöp et al., 2001a). In addition, fasting also rats, while stimulating the duodenal, jejunal, and ileal contrac- increases ghrelin mRNA expression (Toshinai et al., 2001; Kim tile response in dogs (Tansy et al., 1979). In line with the findings et al., 2003; Xu et al., 2009) and reduces ghrelin peptide content in rodents, somatostatin increases gastrointestinal transit time in in the stomach (Toshinai et al., 2001; Kim et al., 2003) indica- humans (Gregersen et al., 2011). The effects on colonic motility tive of a stimulated production and release under conditions of are likely mediated by the sst1 and sst2 based on in vitro stud- food deprivation. Ghrelin levels are not only regulated by short- ies using circular and longitudinal human colonic smooth muscle term variations in energy status associated with meal patterns but cells (Corleto et al., 2006). In addition, somatostatin reduces vis- also by long-term changes in body weight. Ghrelin plasma lev- ceral sensitivity with the sst2 playing a key role as indicated by els are elevated under conditions of reduced body weight such visceral hypersensitivity to both mechanical and chemical stim- as anorexia nervosa or tumor cachexia and reduced in obesity ulation in the jejunum of sst2 knockout mice (Rong et al., 2007). (Tschöp et al., 2000, 2001b; Cummings et al., 2002). Similar to This finding is likely to be relevant in humans as well. Patients with the ligand, the ghrelin acylating enzyme, GOAT is regulated by irritable bowel syndrome injected subcutaneously with octreotide the metabolic status with an increased GOAT mRNA and protein display an anti-hyperalgesic response as shown by the increased expression in rodent gastric mucosa, hypothalamus, and pitu- threshold of discomfort and pain using rectal barostat manome- itary following a 12- or 24-h fast (Gonzalez et al., 2008; Gahete try compared to injection of placebo (Bradette et al., 1994; Schwetz et al., 2010b; Stengel et al., 2010f). Under conditions of obesity et al., 2004). induced by high fat diet or leptin deficiency in ob/ob mice, a down-regulation of GOATmRNA occurred in the mouse pituitary, GHRELIN AND ITS RECEPTOR: EXPRESSION AND unlike the stomach or hypothalamus (Gahete et al., 2010b), while PHYSIOLOGICAL OREXIGENIC AND PROKINETIC ACTIONS patients with obesity-associated type 2 diabetes showed higher lev- EXPRESSION AND REGULATION OF GHRELIN AND GHRELIN els of GOAT in visceral adipose tissue (Rodriguez et al., 2012). This RECEPTOR indicates a tissue specific regulation of GOAT under conditions of Ghrelin bears a unique fatty acid (n-octanoyl) residue on the obesity. third amino acid which is essential for affinity and binding to the GRLN-R (Kojima et al., 1999; Kojima and Kangawa, 2005). OREXIGENIC AND PROKINETIC EFFECTS OF GHRELIN Other dietary fatty acids of medium length can also serve as a Ghrelin is well established to stimulate food intake in line with its direct source for the acylation of ghrelin (Nishi et al., 2005). The regulation by changes in energy status in many species including enzyme catalyzing the acylation of ghrelin was unknown for sev- humans (Wren et al., 2000; Tang-Christensen et al., 2004; Druce eral years and just recently identified in mouse and human as a et al., 2005). It is so far the only known peripherally produced and member of the membrane-bound O-acyltransferases (MBOATs), centrally acting orexigenic peptide, contrasting with the numer- namely MBOAT4 which was subsequently renamed ghrelin-O- ous anorexigenic peptides in the gut (Suzuki et al., 2011). Ghrelin’s acyltransferase (GOAT; Gutierrez et al., 2008; Yang et al., 2008). action is blocked by pharmacological or genetic approaches using GOAT mRNA and protein are prominently expressed in rodent GRLN-R antagonists (Salome et al., 2009) and GRLN-R knockout and human gastric mucosa in ghrelin expressing cells (Sakata et al., mice (Sun et al., 2004; Zigman et al., 2005) indicating a key role of 2009; Stengel et al., 2010f). In addition, GOAT protein has been ghrelin-GRLN-R interaction in mediating the orexigenic response. detected in rodent and human intestine, pancreatic duct, gallblad- The food intake stimulatory action can result from ghrelin cross- der, hypothalamus and (Gahete et al., 2010b; Lim ing the blood–brain barrier and binding to GRLN-R expressed et al., 2011; Kang et al., 2012), rodent plasma (Stengel et al., 2010f) on food intake regulatory brain nuclei (Banks et al., 2002; Pan and human visceral and subcutaneous adipocytes (Rodriguez et al., 2006) or acting directly on vagal afferents which also bear et al., 2012) leading to the speculation of additional acylation sites the ghrelin receptor (Date et al., 2002; Sakata et al., 2003). The of ghrelin. respective role of these pathways under nutritional changes is still Unlike ghrelin, desacyl ghrelin, which does not bear the to be delineated. In addition to the stimulation of food intake, hydrophobic residue on the third amino acid, is the main circulat- ghrelin is also involved in the regulation of body weight inducing ing form. The acyl:desacyl ghrelin ratio is 1:3 as recently reported an increase of body weight following chronic infusion of the pep- using an optimized blood processing protocol to improve the yield tide. This occurs through combined actions of stimulating appetite of acylated ghrelin in rats (Stengel et al., 2009). Although desacyl along with increasing fat storage and reducing lipid mobilization ghrelin does not bind to and activate the GRLN-R (Kojima et al., (Tschöp et al., 2000; Strassburg et al., 2008; Davies et al., 2009). 1999), recent studies indicate that the peptide exerts several biolog- Further corroborating these findings, ghrelin and GRLN-R dou- ical actions to influence food intake (Stengel et al., 2010e), reduce ble knockout mice display an increased energy expenditure leading inflammatory somatic pain (Sibilia et al., 2012), muscle cachexia toareductionofbodyweight(Pfluger et al., 2008) which, how- produced by injury in rats (Sheriff et al.,2012) and basal autophagy ever, could not be reproduced with a single genetic deletion of

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either ghrelin (Sun et al., 2003; Pfluger et al., 2008) or the GRLN- observed prevention of declining circulating ghrelin levels is not R(Pfluger et al., 2008). These differential phenotypes may reflect the main factor for the restoration of the orexigenic response the functional relevance of the high constitutive activity of the postsurgically. The peripheral blockade of the GRLN-R using GRLN-R (Damian et al., 2012) and also give rise to the specula- the GRLN-R antagonist ([D-Lys3]-GHRP-6) injected intraperi- tion that additional ligands for the receptor may exist (Deghenghi toneally did not modify the food intake stimulating effect of ic et al., 2001a). ODT8-SST (Stengel et al., 2011b). ODT8-SST injected icv also restored gastric emptying inhibited by abdominal surgery to lev- DIFFERENTIAL MODULATION OF GH RELEASE BY GHRELIN els observed under basal conditions, an effect mimicked by the AND SOMATOSTATIN sst5 but not the sst1, sst2, and sst4 agonists in rats (Stengel et al., Ghrelin exerts endocrine actions opposite to somatostatin by 2011b). Similar to the effect on food intake, this action was not stimulating anterior pituitary release of GH (Kojima et al., 1999; mediated by acyl ghrelin as the intraperitoneal injection of the Yamazaki et al., 2002; Kojima and Kangawa, 2011), prolactin, GRLN-R antagonist did not influence the gastroprokinetic action and ACTH (Lanfranco et al., 2010). Somatostatin’s GH inhibitory of ODT8-SST postsurgery (Stengel et al., 2011b). effect is mediated by the sst2 (Briard et al., 1997), sst5 (Saveanu Taken together, these data indicate that the central activation of et al., 2001) and also sst1 (Kreienkamp et al., 1999). The GH releas- sst2 increases basal or prevents the surgical inhibition of circulating ing effect of ghrelin is blunted by intravenous (iv) infusion of levels of ghrelin and food intake while activation of sst5 restores somatostatin in healthy volunteers (Di Vito et al., 2002) and was postoperative gastric ileus in rats. It also points to a differential completely blocked in pig pituitary cells in vitro (Malagon et al., role of brain sst subtypes 2 and 5 in preventing the stress-related 2003). The GH releasing action of ghrelin is likely to not only suppression of ghrelin release/food intake and gastric emptying, result from inhibiting somatostatin release (Feng et al., 2011) but respectively. In addition, the restoration of suppressed circulat- also from direct activation of GH release (Veldhuis et al., 2006). ing acyl ghrelin levels after surgery does not play a major role as In addition, ghrelin and somatostatin antagonistically interact on underlying mechanisms through which ODT8-SST injected into hypothalamic arcuate cells to regulate the release of GHRH with the brain exerts its prokinetic and orexigenic effects. Other stud- an activation of these neurons following ghrelin and a reduction ies showed that activation of sst2 and sst5 receptors in the brain after application of somatostatin in vitro (Mori et al., 2010). inhibits stimulated CRF release in the hypothalamus and acute stress-related CRF mediatedACTH release (Brown et al.,1984; Tiz- ACTIVATION OF BRAIN sst2 SIGNALING INCREASES BASAL abi and Calogero, 1992; Saegusa et al., 2011; Tringali et al., 2012). AND PREVENTS VISCERAL STRESS-INDUCED SUPPRESSION Brain CRF acting on CRF receptors is involved in the stress-related OF CIRCULATING GHRELIN decrease in feeding behavior, ghrelin secretion, and gastric empty- Based on the established centrally sst2-mediated orexigenic action ing (Hotta et al., 1999; Sekino et al., 2004; Taché and Bonaz, 2007; of somatostatin (Stengel et al., 2010a,d), we further investigated Yakabi et al., 2011). Therefore, it may be speculated that central whether changes in circulating ghrelin may play a role. We found activation of sst2 and/or sst5 dampens hypothalamic CRF acti- that the pan-somatostatin peptide, ODT8-SST (Table 1) injected vated by abdominal surgery (Wang et al., 2011) which may have a icv increased basal plasma acyl ghrelin levels in ad libitum fed bearing with preventing the reduction in feeding, gastric empty- rats (Stengel et al., 2010a). However, the rise was observed at 3 h ing, and circulating ghrelin induced by abdominal surgery (Stengel postinjection and therefore unlikely to underlie the initial increase et al., 2011b). in food intake response to central ODT8-SST which occurred within the first hour. However, it may contribute to the sustained ACTIVATION OF PERIPHERAL sst2 SIGNALING INHIBITS significant increase in cumulative food intake still maintained at CIRCULATING GHRELIN 4 h after icv injection of ODT8-SST (Stengel et al., 2010a). Other In contrast to the rise in circulating ghrelin induced by central studies showed that activation of brain sst2 receptor prevents the administration of somatostatin agonists, convergent in vivo and decline in circulating ghrelin induced by visceral stress. Abdom- in vitro rodent studies established that somatostatin or the sta- inal surgery reproducibly decreased the fasting plasma levels of ble agonists octreotide and SOM230 act peripherally through the acyl and desacyl ghrelin with a rapid onset and long lasting effect sst2 to reduce ghrelin release (Seoane et al., 2007; Iwakura et al., in rats (Stengel et al., 2010b, 2011b,c). Such a response was com- 2010; Lu et al., 2012) resulting in lower circulating levels (Shi- pletely prevented by the ic injection of ODT8-SST as monitored mada et al., 2003; Silva et al., 2005; de la Cour et al., 2007). Such 50 min postsurgery at a time where the peptide induces a 31 and a response is in line with the inhibitory effects of somatostatin- 46% rise in fasting circulating acyl and desacyl ghrelin, respec- sst2 on the endocrine secretion of other intestinal hormones tively in sham animals (Stengel et al., 2011b). In addition, the sst2 (Pederson et al., 1975; Marco et al., 1983; Rokaeus, 1984; Shi- selective peptide agonist injected ic also prevented the postopera- ratori et al., 1991; Strowski et al., 2000). Likewise, in humans, tive decline in plasma levels of acyl ghrelin, whereas sst1 and sst4 peripherally injected somatostatin (Broglio et al., 2002; Norre- agonists (Table 1) did not when tested under the same conditions lund et al., 2002) and somatostatin agonists such as octreotide (Stengel et al., 2011b). (Barkan et al., 2003) reduce circulating ghrelin in healthy subjects. Of interest was the demonstration that ic ODT8-SST or sst2 Of relevance, chronic subcutaneous infusion of the sst2/sst3/sst5 agonist in addition to preventing the decline in acyl ghrelin agonist octreotide-induced suppression of ghrelin plasma levels induced by abdominal surgery also blunted the postoperative is not subject to rapid desensitization in rats and is likely to be suppression of food intake (Stengel et al., 2011b). However, the sst2 mediated based on the prominent sst2 mRNA expression in

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the rat stomach (Silva et al., 2005). Further support for a role Ekeblad et al., 2007). Moreover, ghrelinomas have been identified of sst2 came from immunofluorescent double labeling studies to originate from the stomach or pancreas and were associated detecting the protein expression of sst2 on ghrelin-producing with very high ghrelin levels (Corbetta et al., 2003; Tsolakis et al., X/A-like cells of the rat stomach (Stengel et al., 2011c) and sim- 2004). Growing evidence from clinical reports indicates that in ilarly on human ghrelin-producing gastric mucosal P/D1 cells addition to the surgical, chemotherapeutic, alpha-interferon, and (Fischer et al., 2008). Moreover, the selective peptide sst2 ago- local radiation treatments, the use of somatostatin or somatostatin nist (Table 1) injected intravenously decreased circulating levels analog is an established treatment option for gastroenteropancre- of acyl and desacyl ghrelin with a rapid onset (0.5 h) and a atic NETs (Pavel and Wiedenmann, 2011). Based on the evidence long duration of action (still visible at 2 h; Stengel et al., 2011c). described above, the determination of the sst subtype expressed Lastly, the selective peptide sst2 antagonist (Table 1) injected intra- on those ghrelinoma tumor cells followed by the use of periph- venously prevents the decline in circulating ghrelin induced by the erally acting selective sst compounds may result in an even more stimulation of endogenous peripheral somatostatin in rats (Sten- targeted approach. gel et al., 2011c). The physiological role of peripheral somatostatin-sst2 signal- INTERACTION OF CORTISTATIN WITH GHRELIN ing in the regulation of ghrelin was investigated under conditions SIGNALING of stimulation of endogenous gastric somatostatin. Urethane is In 1996, the discovery of a new peptide sharing 11 of its 14 well established to stimulate gastric somatostatin mRNA expres- amino acids with somatostatin-14 was named cortistatin based sion and peptide release in rats (Yang et al., 1990). Under these on its predominant cortical expression and ability to depress cor- conditions, plasma ghrelin levels are decreased and the selective tical activity (de Lecea et al., 1996). Despite the chemical structure peptide sst2 antagonist (Table 1) injected intravenously prevents homology with somatostatin, both peptides are derived from dis- the decline in circulating ghrelin induced by urethane (Stengel tinct genes (de Lecea et al., 1997b). Similar to pro-somatostatin, et al., 2011c). Convergent reports showed that abdominal surgery processing of cortistatin precursor generated two mature prod- induces a rapid and sustained inhibition of circulating levels of ucts, cortistatin-14 and -29 in rodents and cortistatin-17 and -29 ghrelin in rats (Stengel et al., 2010b, 2011b,c). Likewise, iv injec- in humans (Fukusumi et al., 1997; Spier and de Lecea, 2000). tion of the selective peptide sst2 antagonist (Table 1) blocked the Cortistatin is widely expressed in the brain, namely in the cor- abdominal surgery-induced decrease of plasma ghrelin at 0.5 h tex and hippocampus, and although regional overlap exists, the postsurgery (Stengel et al., 2011c). The peptide is likely to act distribution pattern differs from that of somatostatin (de Lecea through paracrine transmission since somatostatin positive D cells et al., 1997a). Likewise, the peripheral expression pattern of cortis- directly contact ghrelin immunoreactive X/A-like cells in the rat tatin (e.g., in adrenal, thyroid, and parathyroid gland, testis, stomach (Shimada et al., 2003). Interestingly, following abdomi- pancreas, kidney, lung, liver, stomach, ileum, jejunum, colon, nal surgery, acyl ghrelin was reduced more rapidly compared to endothelial, and immune cells) does not fully match that of desacyl ghrelin which was associated with a reduction of gastric somatostatin (Papotti et al., 2003; Dalm et al., 2004; Xidakis et al., as well as plasma concentrations of GOAT (Stengel et al., 2011c). 2007). Consistent with being a close somatostatin endogenous Since blockade of peripheral sst2 signaling restores circulating analog, cortistatin contains the FWKT tetramer crucial for sst levels of ghrelin (Stengel et al., 2011c), these data collectively sug- binding, and therefore displays high-affinity (1–2 nM) to all five gest that peripheral somatostatin may blunt gastric GOAT mRNA sst subtypes where the peptide acts as an agonist (Fukusumi expression and thereby negatively affect the acylation of ghrelin. et al., 1997; Siehler et al., 2008). However, emerging evidence In primary pituitary cell cultures somatostatin was reported to indicates that cortistatin induces distinct central and peripheral reduce GOAT mRNA expression and somatostatin knockout mice effects that differ from those exerted by the somatostatin-sst showed higher GOAT mRNA expression in the pituitary gland interaction such as central acetylcholine release, reduction of loco- than the wild type (Gahete et al., 2010b). Based on these find- motor activity, depression of cortical activity, induction of slow ings, somatostatin may influence ghrelin signaling not only via wave sleep, anti-inflammatory and immunomodulatory effects, a direct inhibition of secretion but also by modulating the ghre- and reduction of vascular calcium deposition (for review, see lin activating enzyme GOAT. Further support for a physiological Spier and de Lecea, 2000; Broglio et al., 2007; Gonzalez-Rey and inhibitory action of peripheral somatostatin on ghrelin signal- Delgado, 2008). ing came from somatostatin knockout mice that displayed an The existence of a specific cortistatin receptor has not been increased gastric ghrelin expression and higher circulating ghre- identified yet but differential actions between somatostatin and lin levels compared to their wild type littermates (Luque et al., cortistatin may possibly reside in the ability of cortistatin to 2006a). These data indicate that endogenous somatostatin exerts bind and to activate the GRLN-R, whereas somatostatin does a physiological inhibitory tone on gastric ghrelin synthesis and not (Deghenghi et al., 2001b; Muccioli et al., 2001). Divergent release. from native somatostatin, however, synthetic somatostatin ago- During the past years, several clinical studies described ghrelin- nists, lanreotide, octreotide, and vapreotide bind to the GRLN-R producing NETs (Papotti et al., 2001; Volante et al., 2002; Taal in human pituitary tissue (Deghenghi et al., 2001c) in addition and Visser, 2004) including six insulinomas, gastrinomas, vasoac- to their selective affinity for sst2 > sst5 > sst3 (Bauer et al., 1982; tive intestinal polypeptide (VIP)omas, non-functioning tumors Reichlin, 1983; Redding and Schally, 1984). In addition to binding (Volante et al., 2002) and as part of the multiple endocrine neo- studies, few functional findings also support the possibility that plasia type 1 (MEN-1; Iwakura et al., 2002; Raffel et al., 2005; cortistatin may be another endogenous high-affinity ligand of the

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GRLN-R. Cortistatin has been reported to inhibit vascular calci- additional specific tools may be needed to characterize a possible fication induced experimentally in rats through activation of the direct link between the ghrelin and somatostatin signaling system GRLN-R receptor rather than sst or Mrg X2 (Liu et al., 2010). Of via interaction on the GRLN-R. interest was the demonstration that cortistatin selectively upreg- ulates the GRLN-R mRNA expression in cultured rat vascular SUMMARY smooth muscle cells, further indicative of an interaction between In summary, somatostatin robustly affects circulating levels of cortistatin and ghrelin signaling (Liu et al., 2010). Other studies ghrelin through interaction with the sst2. However, alterations in primates and mice demonstrated that endogenous cortistatin, vary with the site of action. Central somatostatin elevates plasma unlike somatostatin, is involved in the stimulation of pituitary levels of acyl and desacyl ghrelin via interaction with brain sst2 and prolactin release, an effect that is blocked in vitro by the GRLN-R counteracts the visceral stress-related decrease in circulating ghre- antagonist (Cordoba-Chacon et al., 2011). However, most of the lin through pathways still to be elucidated in rodents. By contrast, endocrine studies performed in vivo or in vitro showed parallel the activation of peripheral somatostatin-sst2 inhibits circulating inhibitory responses between cortistatin and somatostatin con- ghrelin levels in experimental and clinical studies and mediates sistent with the activation of classical sst subtypes (Broglio et al., the decline in circulating ghrelin induced by abdominal surgery 2008) with some exceptions (Prodam et al., 2008). This is further in rodents likely via a paracrine action of somatostatin on sst2- corroborated by the finding that cortistatin knockout mice display bearing ghrelin cells in the stomach. Of interest, cortistatin, the elevated circulating acyl ghrelin levels associated with an upregu- other member of the somatostatin family, in addition to binding to lated gastric ghrelin and GOATexpression (Cordoba-Chacon et al., sst1−5, also binds to and activates the GRLN-R. There is evidence 2011) indicating an inhibitory tone of endogenous cortistatin on that the peptide can exert a dual influence on ghrelin, by inhibiting ghrelin signaling. its release through interaction with sst2 located on gastric ghrelin To further delineate the actions of cortistatin mediated via cells while activating GRLN-R at ghrelin’s tissue targets. the GRLN-R another peptide, cortistatin-8, has been shown to bind to the GRLN-R while being devoid of affinity to the sst ACKNOWLEDGMENTS subtypes (Luque et al., 2006b). However, in one clinical study This work was supported by NIH R01 DK-33061, NIH Center cortistatin-8 did not influence spontaneous pituitary hormone Grant DK-41301 (Animal Core), VA Research Career Scientist secretion (GH, prolactin, and ACTH) and did not interfere and VA Merit grant (to Yvette Taché), German Research Foun- with ghrelin’s endocrine responses when given in equimolar dose dation STE 1765/3-1 (to Andreas Stengel), and Charité University ratios in healthy human subjects (Prodam et al., 2008). Therefore, Funding UFF 89-441-176 (to Andreas Stengel).

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