Xenin, a gastrointestinal peptide, is structurally similar to neurotensin which functions as a satiety factor via neurotensin receptor 1 (Ntsr1). Metabolic effect of the adipocyte hormone leptin is partially mediated through the Ntsr1 and interleukin 1 type I receptor (IL-1RI) in the central nervous system (CNS). Xenin reduces food intake when administered centrally and peripherally. Apart from its acute feeding-suppressing effect, the distinct metabolic action of xenin and the mechanism of xenin-induced anorexia remain to be elucidated. We hypothesized that prolonged xenin treatment reduces food intake and body weight and increases energy expenditure. We also hypothesized that xenin reduces food intake by activating CNS signalling pathways including Ntsr1 and IL-1RI and by interacting with leptin. To address these hypotheses, we examined (1) the effect of xenin treatment on food intake, energy expenditure and body weight in wild-type, Ntsr1-deficient and IL-1RI-deficient mice, (2) the effect of xenin on hypothalamic Fos and interleukin 1β (IL-1β) expression in wild-type mice, and (3) the effect of co-injection of xenin and leptin on food intake and body weight in wild-type mice. Daily intraperitoneal (i.p.) or intracerebroventricular (i.c.v.) xenin treatment (6-10 days) significantly reduced body weight gain and adiposity with a transient reduction in food intake in wild-type mice. Xenin treatment (i.p.) caused a significant reduction in respiratory quotient without changes in energy expenditure. Xenin treatment increased hormone sensitive lipase (HSL) mRNA levels and reduced acyl-coenzyme A: diacylglycerol acyltransferase 2 (DGAT2) mRNA levels in white adipose tissue. Xenin (i.p.) increased the number of Fos-immunoreactive cells in the hypothalamus and the brainstem and increased hypothalamic IL-1β mRNA levels. The anorectic effects of xenin and leptin were abolished or attenuated in mice lacking Ntsr1 or IL-1RI. I.p. co-administration of xenin and leptin caused greater reductions in food intake and body weight compared to leptin alone and xenin alone. These data suggest that long-term xenin treatment reduces body weight by reducing food intake and increasing fat oxidization. Xenin reduces food intake by activating CNS signalling pathways involving Ntsr1 and IL-1 possibly through the interaction with leptin. These findings implicate xenin and its downstream mediators as potential targets for anti-obesity drugs.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:MWU.1993/5006 |
| Date | 30 August 2010 |
| Creators | Kim, Eun Ran |
| Contributors | Mizuno, Tooru (Physiology), Pierce, Grant (Physiology) Shiu, Robert (Physiology) Bergen, Hugo ( Human anatomy and cell science) Havel, Peter J(University of California, Davis) |
| Publisher | Elsevier, American diabetes association |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Detected Language | English |
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