xenin-25 and Body-Weight

Xenin is a gastrointestinal hormone that reduces food intake when administered centrally and it has been hypothesized that central action of xenin participates in the regulation of whole-body metabolism. The present study was performed to address this hypothesis by investigating the central effect of xenin on the expression of genes and proteins that are involved in the regulation of lipid metabolism in white adipose tissue (WAT). Male obese ob/ob mice received intracerebroventricular (i.c.v.) injections of xenin (5μg) twice 12h apart. Food intake and body weight change during a 24-h period after the first injection were measured. Epididymal WAT was collected at the end of the 24-h treatment period and levels of lipid metabolism-related genes and proteins were measured. Xenin treatment caused significant reductions in food intake and body weight compared to control vehicle treatment. Levels of fatty acid synthase (FASN) protein were significantly reduced by xenin treatment, while levels of adipose triglyceride lipase (Atgl) and beta-3 adrenergic receptor (Adrb3) mRNA and phosphorylated hormone sensitive lipase (Ser

Topics: Adipose Tissue, White; Animals; Body Weight; Eating; Fatty Acid Synthases; Fatty Acids, Nonesterified; Gene Expression; Glycerol; Lipase; Lipid Metabolism; Male; Mice; Neurotensin; Obesity; Phosphorylation; Receptors, Adrenergic, beta-3

Xenin is a peptide that is co-secreted with the incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), from intestinal K-cells in response to feeding. Studies demonstrate that xenin has appetite suppressive effects and modulates glucose-induced insulin secretion. The present study was undertaken to determine the bioactivity and antidiabetic properties of two C-terminal fragment xenin peptides, namely xenin 18-25 and xenin 18-25 Gln. In BRIN-BD11 cells, both xenin fragment peptides concentration-dependently stimulated insulin secretion, with similar efficacy as the parent peptide. Neither fragment peptide had any effect on acute feeding behaviour at elevated doses of 500 nmol/kg bw. When administered together with glucose to normal mice at 25 nmol/kg bw, the overall insulin secretory effect was significantly enhanced in both xenin 18-25 and xenin 18-25 Gln treated mice, with better moderation of blood glucose levels. Twice daily administration of xenin 18-25 or xenin 18-25 Gln for 21 days in high fat fed mice did not affect energy intake, body weight, circulating blood glucose or body fat stores. However, circulating plasma insulin concentrations had a tendency to be elevated, particularly in xenin 18-25 Gln mice. Both treatment regimens significantly improved insulin sensitivity by the end of the treatment period. In addition, sustained treatment with xenin 18-25 Gln significantly reduced the overall glycaemic excursion and augmented the insulinotropic response to an exogenous glucose challenge on day 21. In harmony with this, GIP-mediated glucose-lowering and insulin-releasing effects were substantially improved by twice daily xenin 18-25 Gln treatment. Overall, these data provide evidence that C-terminal octapeptide fragments of xenin, such as xenin 18-25 Gln, have potential therapeutic utility for type 2 diabetes.

Topics: Amino Acid Sequence; Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Diet, High-Fat; Energy Intake; Gastrointestinal Hormones; Glucose Tolerance Test; Hypoglycemic Agents; Insulin; Insulin Resistance; Male; Mice; Molecular Sequence Data; Neurotensin

Central administration of neuromedins and neuromedin-related peptides suppresses food intake in rodents. Neurotensin- and neuromedin U (NMU)-induced anorexia is mainly mediated through neurotensin receptor 1 (Ntsr1) and NMU receptor 2, respectively. Xenin belongs to the neurotensin family and suppresses food intake via an unknown receptor. It has been suggested that Ntsr1 also mediates biological actions of xenin and NMU. Therefore, we examined the effect of intracerebroventricular injection of xenin and NMU on food intake and body weight in wild-type and Ntsr1-deficient mice. The feeding-suppressing and weight gain-inhibiting effects of xenin were abolished in Ntsr1-deficient mice, but NMU reduced food intake and body weight gain in both wild-type and Ntsr1-deficient mice. These findings support the role for Ntsr1 in the mediation of the metabolic effect of xenin as well as neurotensin. Therefore, enhancement of signaling through the Ntsr1 receptor is a potential strategy to reduce appetite and ameliorate obesity.

Topics: Animals; Body Weight; Eating; Male; Mice; Mice, Knockout; Neuropeptides; Neurotensin; Receptors, Neurotensin

Xenin is a 25-amino acid peptide highly homologous to neurotensin. Xenin and neurotensin are reported to have similar biological effects. Both reduce food intake when administered centrally to fasted rats. We aimed to clarify and compare the effects of these peptides on food intake and behavior. We confirm that intracerebroventricular (ICV) administration of xenin or neurotensin reduces food intake in fasted rats, and demonstrate that both reduce food intake in satiated rats during the dark phase. Xenin reduced food intake more potently than neurotensin following ICV administration. ICV injection of either peptide in the dark phase increased resting behavior. Xenin and neurotensin stimulated the release of corticotrophin-releasing hormone (CRH) from ex vivo hypothalamic explants, and administration of alpha-helical CRH attenuated their effects on food intake. Intraperitoneal (IP) administration of xenin or neurotensin acutely reduced food intake in fasted mice and ad libitum fed mice in the dark phase. However, chronic continuous or twice daily peripheral administration of xenin or neurotensin to mice had no significant effect on daily food intake or body weight. These studies confirm that ICV xenin or neurotensin can acutely reduce food intake and demonstrate that peripheral administration of xenin and neurotensin also reduces food intake. This may be partly mediated by changes in hypothalamic CRH release. The lack of chronic effects on body weight observed in our experiments suggests that xenin and neurotensin are unlikely to be useful as obesity therapies.

Topics: Animals; Body Weight; Corticotropin-Releasing Hormone; Eating; Fasting; Feeding Behavior; Hypothalamus; Infusion Pumps, Implantable; Infusions, Subcutaneous; Injections, Intraperitoneal; Injections, Intraventricular; Male; Mice; Mice, Inbred C57BL; Neurotensin; Organ Culture Techniques; Peptides; Rats; Rats, Wistar; Time Factors