Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P61278 (somatostatin)
 22,083 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cortistatin (CST) is a neuropeptide, which binds with high affinity all somatostatin (SS) receptor subtypes and shows high structural homology with SS itself. A receptor specific for CST only, i.e., not recognized by SS, has been recently described in agreement with data reporting that not all CST actions are shared by SS. Interestingly, CST but not SS also binds ghrelin receptor (GHS-R1a) in vitro, suggesting a potential interplay between CST and ghrelin system. The aim of this study was to investigate in humans the endocrine and metabolic activities of human CST-17 in comparison with rat CST-14 that has previously been shown to exert the same endocrine actions of SS in healthy volunteers. To this aim, in six healthy male volunteers (age [median, 3rd-97th centiles]: 28.5; 23.6-34.3 years; Body Mass Index: 23.5; 21.0-25.1 kg/m(2)), we studied the effects of human CST-17 (2.0 microg/kg/h iv over 120 min), rat CST-14 (2.0 microg/kg/h iv over 120 min) and SS-14 (2.0 microg/kg/h iv over 120 min) on: (a) spontaneous GH, ACTH, PRL, cortisol, insulin and glucose levels; (b) the GH responses to GHRH (1.0 microg/kg iv at 0 min); (c) the GH, PRL, ACTH, cortisol, insulin and glucose responses to ghrelin (1.0 microg/kg iv at 0 min). CST-17 inhibited (p < 0.01) basal GH secretion to the same extent of CST-14 and SS-14. Spontaneous PRL, ACTH and cortisol secretion were not significantly modified by CST-17, CST-14 or SS-14. CST-17 as well as CST-14 and SS-14 also inhibited (p < 0.05) spontaneous insulin secretion to a similar extent. None of these peptides modified glucose levels. The GH response to GHRH was inhibited to the same extent by CST-17 (p < 0.01), CST-14 (p < 0.01) and SS-14 (p < 0.05 ). The ghrelin-induced GH response was higher than that elicited by GHRH (p < 0.01) and inhibited by CST-17 (p < 0.05) as well as by CST-14 (p < 0.05) and SS-14 (p < 0.01). The PRL, ACTH and cortisol responses to ghrelin were unaffected by CST-17, CST-14 or SS-14. On the other hand, the inhibitory effect of ghrelin on insulin levels was abolished by CST-17, CST-14 or SS-14 (p < 0.05) that, in turn, did not modify the ghrelin-induced increase in glucose levels. In conclusion, this study demonstrates that human CST-17 and rat CST-14 exert the same endocrine activities of SS in humans. The endocrine actions of human and rat CST therefore are likely to reflect activation of classical SS receptors.
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PMID:Cortistatin-17 and -14 exert the same endocrine activities as somatostatin in humans. 1533 31

Ghrelin, the 28 amino acid peptide recently identified as the natural ligand for the growth hormone (GH) secretagogue (GHS) receptor, has multiple activities in addition to stimulation of GH secretion, including stimulation of feeding and weight gain. To utilize these actions for potential therapeutic benefit, we have produced analogs of human ghrelin with enhanced metabolic stability, affinity for the GHS receptor, and efficacy in stimulating weight gain. We have also discovered an analog of ghrelin, BIM-28163, that is an antagonist at the GHS receptor and that fully inhibits GHS receptor activation induced by native ghrelin. In vivo, BIM-28163 does not increase GH secretion but fully blocks ghrelin-induced GH secretion. In contrast, BIM-28163 acts as a full agonist with regard to the ghrelin actions of stimulating weight gain and food intake. These results suggest that a receptor other than the GHS receptor mediates the actions of ghrelin on feeding and weight gain. This concept is strengthened by our observation that at certain hypothalamic sites, BIM-28163 acts as an antagonist of ghrelin-induced neuronal activation, while at other sites, both ghrelin and BIM-28163 induce neuronal activation via the same receptor. Collectively, these results indicate the existence of a novel ghrelin receptor that may regulate the feeding activity of ghrelin. Using BIM-28163 as a tool to define the endogenous role of ghrelin in normal GH secretion, we have demonstrated that antagonism of the GHS receptor in normal rats does not impair the pulsatility of GH secretion but lowers the pulse amplitude and mean GH level. These results demonstrate that endogenous ghrelin acts to amplify the basic pattern of GH secretion established by the interplay of hypothalamic GH-releasing hormone and somatostatin. These studies demonstrate the feasibility of creating ghrelin analogs that are selective for specific activities, as well as their utility in dissecting the role of ghrelin in both normal physiology and specific pathologies.
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PMID:Novel analogs of ghrelin: physiological and clinical implications. 1533 48

There is a negative relationship between obesity and GH. However, it is not known how metabolic changes, associated with obesity, lead to a reduction in GH output. This study examined the GH axis of two mouse models of obesity, the leptin-deficient (ob/ob) mouse and the diet-induced obese (DIO; high-fat fed) mouse. Both models displayed hyperglycemia and hyperinsulinemia with reduced expression of GH as well as reduced expression of pituitary receptors important for GH synthesis and release [GHRH receptor (DIO only) and the ghrelin receptor (ob/ob and DIO)]. These pituitary changes were not accompanied by changes in hypothalamic expression of GHRH or somatostatin; suggesting that alterations in pituitary function may be precipitated in part by direct effects of systemic signals. Of the metabolic and hormonal parameters examined (insulin, glucose, corticosterone, free fatty acids, ghrelin, and IGF-I), only insulin/glucose showed a significant, and negative, correlation with pituitary expression. Pituitaries of DIO mice remained responsive to the acute in vivo actions of insulin, as assessed by phosphorylation of Akt, despite systemic (skeletal muscle and fat) insulin resistance. In addition, treating primary pituitary cell cultures from lean mice with insulin reduced GH release as well as GH, GHRH receptor, and ghrelin receptor mRNA levels compared with vehicle-treated controls, where the magnitude of suppression of pituitary mRNA levels was similar to that observed in the DIO mouse. These results coupled with the fact that the pituitary expresses the insulin receptor at levels comparable to tissues classically considered insulin sensitive, indicates high circulating insulin levels can directly contribute to the suppression of GH synthesis and release in the obese state.
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PMID:Impact of obesity on the growth hormone axis: evidence for a direct inhibitory effect of hyperinsulinemia on pituitary function. 1651 28

At first sight, the title is confusing as it seems to try to merge four unrelated topics into a single presentation. Somatostatin, cortistatin (CST) and ghrelin display broad biological activities, including metabolic effects. However, although apparently unrelated, these peptides entities have more in common than it might be expected and their reciprocal interactions give a new perspective to the hormonal regulation of glucose metabolism. Let's analyze the ghrelin receptor subtype GH secretagogue (GHS)-receptor 1a (R1a). Taking into account the GHS-R1a as receptor of reference, acylated ghrelin is one of its natural ligands. Interestingly, it has been demonstrated that also CST, a neuropeptide, binds with high affinity to the GHS-R1a in human hypothalamus and pituitary tissues. CST is a recently described neuropeptide showing high structural homology with somatostatin that binds to all somatostatin receptor subtypes (SSTRs) with an affinity (1-2 nM). In fact, CST and somatostatin exhibit the same endocrine activities. The existence of specific receptors which selectively bind somatostatin or CST has been hypothesized, based on evidence that CST possesses an action profile different from somatostatin and that CST and somatostatin are often co-expressed in the same neurons but are regulated by different stimuli. Given these findings, the ability of CST to bind the GHS-R1a is of particular relevance because somatostatin and its fragments do not bind the same receptor. Interestingly, the classical synthetic somatostatin analogs, i.e. octreotide, lanreotide and vapreotide bind the GHS-R1a with an affinity lower than that of CST. These findings have generated the hypothesis that CST, because of its ability to bind both SSTRs and GHSRs, would represent the link between ghrelin and "somatostatin/CST" system that had not previously been demonstrated. On the other hand, the GHS-R1a is unlikely to be the only GHS-R. It has been already demonstrated that a GHS-R subtype able to bind non-acylated as well as acylated ghrelin exists and likely mediates biological activities. Another GHS-R subtype likely mediates the influence of unacylated ghrelin on glucose metabolism, since it does not bind nor activates the GHS-R1a. Given this complexity, it is clear that further studies are required to clarify whether ghrelin is the sole ligand or one of a number of ligands activating the GHS-R 1a and whether that receptor used for ghrelin isolation is the sole receptor or one of a group of receptors for such ligands.
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PMID:Somatostatin, cortistatin, ghrelin and glucose metabolism. 1662 61

Obesity is a major public health concern and environmental factors are involved in its development. The hypothalamus is a primary site for the integration of signals for the regulation of energy homeostasis. Dysregulation of these pathways can lead to weight loss or gain. Some drugs in development can have favourable effects on body weight, acting on some of these pathways and leading to responses resulting in weight loss. Strategies for the management of weight reduction include exercise, diet, behavioural therapy, drug therapy and surgery. Investigational antiobesity medications can modulate energy homeostasis by stimulating catabolic or inhibiting anabolic pathways. Investigational drugs stimulating catabolic pathways consist of leptin, agonists of melanocortin receptor-4, 5-HT and dopamine; bupropion, growth hormone fragments, cholecystokinin subtype 1 receptor agonist, peptide YY3-36, oxyntomodulin, ciliary neurotrophic factor analogue, beta3-adrenergic receptor agonists, adiponectin derivatives and glucagon-like peptide-1. On the other hand, investigational drugs inhibiting anabolic pathways consist of the ghrelin receptor, neuropeptide Y receptor and melanin-concentrating hormone-1 antagonists; somatostatin analogues, peroxisome proliferator-activated receptor-gamma and -beta/delta antagonists, gastric emptying retardation agents, pancreatic lipase inhibitors, topiramate and cannabinoid-1 receptor antagonists. These differing approaches are reviewed and commented on in this article.
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PMID:Investigational therapies in the treatment of obesity. 1685 93

To determine whether the severity of the catabolic condition differentially regulates the GH axis, male mice were either fed ad libitum or fasted for 12, 24, and 48 h. Hypothalami, pituitaries, and stomachs were collected for assessment of mRNA levels by quantitative real-time RT-PCR, and blood collected for measurement of plasma hormone and metabolite levels by commercial assay kits. Overnight (12 h) fasting resulted in a significant suppression of circulating glucose, insulin, IGF-I, and leptin levels and an increase in corticosterone, free fatty acids, and n-octanoyl ghrelin levels, and these directional changes were maintained at the 24- and 48-h time points. Fasting (24 h) also increased circulating GH levels, which was associated with an increase in pituitary mRNA levels for GHRH receptor and ghrelin receptor and a decrease in mRNA levels for somatostatin (SST) receptor (SSTR) subtypes, SSTR2, SSTR3, and SSTR5, where the changes in ghrelin receptor and SSTR expression persisted after 48 h fasting. Hypothalamic SST mRNA levels were not altered by fasting, whereas there was a transient rise in stomach SST mRNA levels 24 h after food withdrawal. In contrast, there was a biphasic effect of fasting on GHRH expression. GHRH mRNA levels were significantly elevated at 12 and 24 h but fell to approximately 50% of fed controls 48 h after food withdrawal. A sequential rise in hypothalamic neuropeptide Y (NPY) and CRH mRNA levels preceded the fall in GHRH expression, where fasting-induced changes in CRH and GHRH mRNA levels were not observed in 48-h-fasted NPY knockout mice. These observations, in light of previous reports showing both NPY and CRH can inhibit GHRH expression and GH release, suggest that these neuronal systems may work in concert to control the ultimate impact of fasting on GH axis function.
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PMID:Severity of the catabolic condition differentially modulates hypothalamic expression of growth hormone-releasing hormone in the fasted mouse: potential role of neuropeptide Y and corticotropin-releasing hormone. 1703 58

Leptin-deficient obese mice (ob/ob) have decreased circulating growth hormone (GH) and pituitary GH and ghrelin receptor (GHS-R) mRNA levels, whereas hypothalamic GH-releasing hormone (GHRH) and somatostatin (SST) expression do not differ from lean controls. Given the fact that GH is suppressed in diet-induced obesity (a state of hyperleptinemia), it remains to be determined whether the absence of leptin contributes to changes in the GH axis of ob/ob mice. Therefore, to study the impact of leptin replacement on the hypothalamic-pituitary GH axis of ob/ob mice, leptin was infused for 7 days (sc), resulting in circulating leptin levels that were similar to wild-type controls (approximately 1 ng/ml). Leptin treatment reduced food intake, body weight, and circulating insulin while elevating circulating n-octanoyl ghrelin concentrations. Leptin treatment did not alter hypothalamic GHRH, SST, or GHS-R mRNA levels compared with vehicle-treated controls. However, leptin significantly increased pituitary GH and GHRH-R expression and tended to enhance circulating GH levels, but this latter effect did not reach statistical significance. In vitro, leptin (1 ng/ml, 24 h) did not affect pituitary GH, GHRH-R, or GHS-R mRNA but did enhance GH release. The in vivo effects of leptin on circulating hormone and pituitary mRNA levels were not replicated by pair feeding ob/ob mice to match the food intake of leptin-treated mice. However, leptin did prevent the fall in hypothalamic GHRH mRNA and circulating IGF-I levels observed in pair-fed mice. These results demonstrate that leptin replacement has positive effects on multiple levels of GH axis function in ob/ob mice.
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PMID:Effects of leptin replacement on hypothalamic-pituitary growth hormone axis function and circulating ghrelin levels in ob/ob mice. 1712 91

Cortistatin (CST), a neuropeptide with high structural homology with somatostatin (SST), binds all SST receptor (SST-R) subtypes but, unlike SST, also shows high binding affinity to ghrelin receptor (GHS-R1a). CST exerts the same endocrine activities of SST in humans, suggesting that the activation of the SST-R might mask the potential interaction with ghrelin system. CST-8, a synthetic CST-analogue devoid of any binding affinity to SST-R but capable to bind the GHS-R1a, has been reported able to exert antagonistic effects on ghrelin actions either in vitro or in vivo in animals. We studied the effects of CST-8 (2.0 microg/kg i.v. as a bolus or 2.0 microg/kg/h i.v. as infusion) on both spontaneous and ghrelin- or hexarelin- (1.0 microg/kg i.v. as bolus) stimulated GH, PRL, ACTH and cortisol secretion in 6 normal volunteers. During saline, no change occurred in GH and PRL levels while a spontaneous ACTH and cortisol decrease was observed. As expected, both ghrelin and hexarelin stimulated GH, PRL, ACTH and cortisol secretion (p<0.05). CST-8, administered either as bolus or as continuous infusion, did not modify both spontaneous and ghrelin- or hexarelin-stimulated GH, PRL, ACTH and cortisol secretion. In conclusion, CST-8 seems devoid of any modulatory action on either spontaneous or ghrelin-stimulated somatotroph, lactotroph and corticotroph secretion in humans in vivo. These negative results do not per se exclude that, even at these doses, CST-8 might have some neuroendocrine effects after prolonged treatment or that, at higher doses, may be able to effectively antagonize ghrelin action in humans. However, these data strongly suggest that CST-8 is not a promising candidate as GHS-R1a antagonist for human studies to explore the functional interaction between ghrelin and cortistatin systems.
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PMID:Cortistatin-8, a synthetic cortistatin-derived ghrelin receptor ligand, does not modify the endocrine responses to acylated ghrelin or hexarelin in humans. 1806 63

Somatostatin (SRIF) and cortistatin (CST) are two cyclic peptides sharing remarkable structural, pharmacological and functional similarities. Both peptides bind all somatostatin receptors subtypes (sst1-5) with comparable affinities, which may explain the considerable similitude between their actions, particularly on endocrine targets. However, the expression patterns of both peptides do not overlap in human tissues, and they are regulated by different stimuli, suggesting that SRIF and CST can exert unique roles. In fact, CST can bind other receptors, different to ssts (e.g. ghrelin receptor, GHS-R and the MrgX2 receptor), which may be involved in those differential actions. In this review, we have summarized the limited knowledge gathered so far regarding the in vitro actions exerted by CST in different endocrine systems under normal and pathophysiological conditions, and have compared them with the well established functions known for SRIF on these systems. Available data suggests that CST substantially reproduces, but not fully mimics the "in vitro" effects of SRIF on pituitary secretions of human and animal models. Conversely, the functions of CST in the majority of peripheral endocrine (and non-endocrine) tissues are still unknown. Notwithstanding this, the differential tissue expression pattern of SRIF, CST and their receptors suggests that CST may act as a mere natural SRIF analogue in a number of tissues but in some endocrine tissues it may play a predominant, unique regulatory role with potential pathophysiological relevance. The challenge is now to find the genuine differences between these seemingly identical endocrine siblings.
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PMID:Are somatostatin and cortistatin two siblings in regulating endocrine secretions? In vitro work ahead. 1821 56

Somatostatin (SS) and its synthetic analogs have a role in the treatment of neuroendocrine tumours both in terms of symptoms control and antiproliferative activities. These effects are mediated by five SS receptors, widely expressed in both human neuroendocrine and non-neuroendocrine tumours, which were demonstrated to be diagnostically and therapeutically valuable targets. Cortistatin (CST), a brain cortex peptide, partially homologous to SS and having similar functions is also expressed in peripheral tissues and tumours. CST binds all SS receptors, and, differently from SS, also the ghrelin receptor GHSR1a and the CST specific receptor MrgX2. The expression profile of CST is mostly restricted to neuroendocrine tumours (gastrointestinal, pancreas, lung, parathyroid, thyroid, adrenal). In these tumours, CST probably acts via the SS or ghrelin receptor, the MrgX2 receptor being absent. Thus, in comparison to SS analogs, CST synthetic analogs may represent additional diagnostic/therapeutic tools in those tumours expressing the receptors for SS, for ghrelin or for both peptides.
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PMID:Somatostatin, cortistatin and their receptors in tumours. 1824 80


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