Metabolism and potency of xenin and of its reduced hexapseudopeptide Ψ fragment in the dog

Feurle, Gerhard E.; Meyer, Helmut E.; Hamscher, Gerd

doi:10.1016/j.lfs.2003.05.009

Cited by 15 publications

(17 citation statements)

References 24 publications

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“…The kinetics were similar to those seen with intracerebroventricular administration, with potent inhibition of feeding for the first 2 h. Thus, the robust anorectic effect was observed during the 1st and 2nd hour after intraperitoneal injection. This is consistent with a short half-life of exogenously administered xenin (21). It is often observed that the short-lasting anorectic effect is reversed by a rebound hyperphagia.…”

Section: Discussionsupporting

confidence: 86%

Xenin, a Gastrointestinal Peptide, Regulates Feeding Independent of the Melanocortin Signaling Pathway

et al. 2009

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OBJECTIVE-Xenin, a 25-amino acid peptide, was initially isolated from human gastric mucosa. Plasma levels of xenin rise after a meal in humans, and administration of xenin inhibits feeding in rats and chicks. However, little is known about the mechanism by which xenin regulates food intake. Signaling pathways including leptin and melanocortins play a pivotal role in the regulation of energy balance. Therefore, we addressed the hypothesis that xenin functions as a satiety factor by acting through the melanocortin system or by interacting with leptin. RESEARCH DESIGN AND METHODS-The effect of intracerebroventricular and intraperitoneal administration of xenin on food intake was examined in wild-type, agouti, and ob/ob mice. The effect of intracerebroventricular injection of SHU9119, a melanocortin receptor antagonist, on xenin-induced anorexia was also examined in wild-type mice. To determine whether the hypothalamus mediates the anorectic effect of xenin, we examined the effect of intraperitoneal xenin on hypothalamic Fos expression. RESULTS-Both intracerebroventricular and intraperitoneal administration of xenin inhibited fasting-induced hyperphagia inwild-type mice in a dose-dependent manner. The intraperitoneal injection of xenin also reduced nocturnal intake in ad libitum-fed wild-type mice. The intraperitoneal injection of xenin increased Fos immunoreactivity in hypothalamic nuclei, including the paraventricular nucleus and the arcuate nucleus. Xenin reduced food intake in agouti and ob/ob mice. SHU9119 did not block xenin-induced anorexia.CONCLUSIONS-Our data suggest that xenin reduces food intake partly by acting through the hypothalamus but via signaling pathways that are independent of those used by leptin or melanocortins. Diabetes 58:87-94, 2009

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Section: Discussionsupporting

confidence: 86%

Xenin, a Gastrointestinal Peptide, Regulates Feeding Independent of the Melanocortin Signaling Pathway

et al. 2009

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“…Exogenously administered Xen delays gastric emptying (29), reduces food intake (1,8,9,28,36), induces gall bladder contractions (27), increases gut motility (13), augments secretion from the exocrine pancreas (12,17,46), and amplifies the effects of GIP on insulin and glucagon release (41,56,57). In mice, the effects of exogenously administered Xen on insulin release are indirectly mediated by a cholinergic relay that does not appear to utilize parasympathetic neurons (57).…”

Section: Discussionmentioning

confidence: 99%

“…Animal studies from a number of laboratories have demonstrated that exogenously administered Xen delays gastric emptying (29), reduces food intake (1,8,9,28,36), induces gall bladder contractions (27), increases gut motility (13), and augments secretion from the exocrine pancreas (12,17,46). The effects of Xen on gut motility were indirect because they were abolished in cholecystectomized dogs (27). Our laboratory generated and characterized transgenic mice that lack K cells, and thus K cell products, by expressing an attenuated diphtheria toxin A chain using regulatory elements from the GIP promoter and gene (2, 57).…”

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confidence: 99%

Xenin-25 increases cytosolic free calcium levels and acetylcholine release from a subset of myenteric neurons

Zhang

Hyrc

Wang³

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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Xenin-25 (Xen) is a 25 amino acid neurotensin-related peptide reportedly produced with glucose-dependent insulinotropic polypeptide (GIP) by a subset of K cells in the proximal gut. We previously showed exogenously administered Xen, with GIP but not alone, increases insulin secretion in humans and mice. In mice, this effect is indirectly mediated via a central nervous system-independent cholinergic relay in the periphery. Xen also delays gastric emptying, reduces food intake, induces gall bladder contractions, and increases gut motility and secretion from the exocrine pancreas, suggesting that some effects of Xen could be mediated by myenteric neurons (MENs). To determine whether Xen activates these neurons, MENs were isolated from guinea pig proximal small intestines. Cells expressed neuronal markers and exhibited typical neuron-like morphology with extensive outgrowths emanating from cell bodies. Cytosolic free Ca(2+) levels ([Ca(2+)](i)) were measured using Fura-2. ATP/UTP, KCl, and forskolin increased [Ca(2+)](i) in 99.6%, 92%, and 23% of the MENs imaged, respectively, indicating that they are functional and activated by nucleotide receptor signaling, direct depolarization, and cAMP. [Ca(2+)](i) increased in only 12.7% of MENs treated with Xen. This rise was blocked by pretreatment with EGTA, diazoxide, SR48692, and neurotensin. Thus the Xen-mediated increase in [Ca(2+)](i) involves influx of extracellular Ca(2+) and activation of neurotensin receptor-1 (NTSR1). Xen also increased acetylcholine release from MENs. Amylin, produced by β-and enteroendocrine cells, delays gastric emptying and increased [Ca(2+)](i) almost exclusively in Xen-responsive MENs. Immunohistochemistry demonstrated NTSR1 expression in human duodenal MENs. Thus myenteric rather than central neurons could mediate some effects of Xen and amylin.

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“…Whilst further studies are necessary for complete functional characterisation of (D‐Ala 2 )GIP/xenin‐8‐Gln, initial observations are favourable. Furthermore, xenin‐6 (xenin 20‐25) has also been characterised as a biologically active fragment of xenin‐25, possessing notable insulinotropic actions (Table ) . Interestingly, introduction of a reduced pseudopeptide bond between the Lys and Arg amino acid residues in xenin‐6, further enhanced bioactivity .…”

Section: Xenin‐25 Fragment Peptidesmentioning

confidence: 99%

Emerging therapeutic potential for xenin and related peptides in obesity and diabetes

Craig

Gault

Irwin

2018

Diabetes Metabolism Res

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Xenin-25 is a 25-amino acid peptide hormone co-secreted from the same enteroendocrine K-cell as the incretin peptide glucose-dependent insulinotropic polypeptide. There is no known specific receptor for xenin-25, but studies suggest that at least some biological actions may be mediated through interaction with the neurotensin receptor. Original investigation into the physiological significance of xenin-25 focussed on effects related to gastrointestinal transit and satiety. However, xenin-25 has been demonstrated in pancreatic islets and recently shown to possess actions in relation to the regulation of insulin and glucagon secretion, as well as promoting beta-cell survival. Accordingly, the beneficial impact of xenin-25, and related analogues, has been assessed in animal models of diabetes-obesity. In addition, studies have demonstrated that metabolically active fragment peptides of xenin-25, particularly xenin-8, possess independent therapeutic promise for diabetes, as well as serving as bioactive components for the generation of multi-acting hybrid peptides with antidiabetic potential. This review focuses on continuing developments with xenin compounds in relation to new therapeutic approaches for diabetes-obesity.

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Metabolism and potency of xenin and of its reduced hexapseudopeptide Ψ fragment in the dog

Cited by 15 publications

References 24 publications

Xenin, a Gastrointestinal Peptide, Regulates Feeding Independent of the Melanocortin Signaling Pathway

Xenin, a Gastrointestinal Peptide, Regulates Feeding Independent of the Melanocortin Signaling Pathway

Xenin-25 increases cytosolic free calcium levels and acetylcholine release from a subset of myenteric neurons

Emerging therapeutic potential for xenin and related peptides in obesity and diabetes

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