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

Abstract

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

Evaluation of the degradation and metabolic effects of the gut peptide xenin on insulin secretion, glycaemic control and satiety

“…Consistent with earlier reports (Cline et al 2007, Nandar et al 2008, Cooke et al 2009, Leckstrom et al 2009 we were able to demonstrate a satiety effect of xenin in normal mice. The dose required to induce such effects was high (500 nmol/kg), but this is in agreement with others (Leckstrom et al 2009).…”

“…In addition, xenin is now thought to be involved in the regulation of calorie intake (Leckstrom et al 2009) and possibly insulin secretion (Silvestre et al 2003). Thus, the aim of the current study was to evaluate the effects and role of xenin in food intake, glucose homoeostasis and insulin secretion.…”

“…and i.p. xenin injection has been shown to reduce food intake in mice (Leckstrom et al 2009). Similar to other anorectic gastrointestinal peptides, levels of circulating xenin appear to increase after a meal, suggesting that xenin may regulate food intake by acting as a satiety factor (Feurle et al 2003).…”

“…Furthermore, the same study also reported that acute, but not chronic, peripheral administration of xenin reduced food intake in mice and rats (Cooke et al 2009). Indeed, it has recently been shown that xenin reduces feeding in part by acting through signalling pathways in the hypothalamus, which are independent of those used by leptin or melanocortin (Leckstrom et al 2009). …”

Characterisation of the biological activity of xenin-25 degradation fragment peptides

“…This lack of in vivo biological action of the fragment peptides was mirrored by studies examining feeding behaviour, as we were unable to demonstrate any satiety effects in normal mice. Consistent with earlier reports (Cline et al 2007, Cooke et al 2009, Leckstrom et al 2009), a mild satiating effect of native xenin-25 was observed in vivo, corroborating use of this model to investigate the biological actions of xenin-25 fragment peptides. Indeed, it has recently been shown that xenin-25 induces appetite-suppressive effects through delayed gastric emptying and activation of cells in the nucleus of the solitary tract (Kim & Mizuno 2010).…”