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Peripherally Administered Y(2)-Receptor Antagonist BIIE0246 Prevents Diet-Induced Obesity in Mice With Excess Neuropeptide Y, but Enhances Obesity in Control Mice

Neuropeptide Y (NPY) plays an important role in the regulation of energy homeostasis in the level of central and sympathetic nervous systems (SNSs). Genetic silencing of peripheral Y(2)-receptors have anti-obesity effects, but it is not known whether pharmacological blocking of peripheral Y(2)-recep...

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Autores principales: Ailanen, Liisa, Vähätalo, Laura H., Salomäki-Myftari, Henriikka, Mäkelä, Satu, Orpana, Wendy, Ruohonen, Suvi T., Savontaus, Eriika
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5895854/
https://www.ncbi.nlm.nih.gov/pubmed/29674968
http://dx.doi.org/10.3389/fphar.2018.00319
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author Ailanen, Liisa
Vähätalo, Laura H.
Salomäki-Myftari, Henriikka
Mäkelä, Satu
Orpana, Wendy
Ruohonen, Suvi T.
Savontaus, Eriika
author_facet Ailanen, Liisa
Vähätalo, Laura H.
Salomäki-Myftari, Henriikka
Mäkelä, Satu
Orpana, Wendy
Ruohonen, Suvi T.
Savontaus, Eriika
author_sort Ailanen, Liisa
collection PubMed
description Neuropeptide Y (NPY) plays an important role in the regulation of energy homeostasis in the level of central and sympathetic nervous systems (SNSs). Genetic silencing of peripheral Y(2)-receptors have anti-obesity effects, but it is not known whether pharmacological blocking of peripheral Y(2)-receptors would similarly benefit energy homeostasis. The effects of a peripherally administered Y(2)-receptor antagonist were studied in healthy and energy-rich conditions with or without excess NPY. Genetically obese mice overexpressing NPY in brain noradrenergic nerves and SNS (OE-NPY(DβH)) represented the situation of elevated NPY levels, while wildtype (WT) mice represented the normal NPY levels. Specific Y(2)-receptor antagonist, BIIE0246, was administered (1.3 mg/kg/day, i.p.) for 2 or 4.5 weeks to OE-NPY(DβH) and WT mice feeding on chow or Western diet. Treatment with Y(2)-receptor antagonist increased body weight gain in both genotypes on chow diet and caused metabolic disturbances (e.g., hyperinsulinemia and hypercholesterolemia), especially in WT mice. During energy surplus (i.e., on Western diet), blocking of Y(2)-receptors induced obesity in WT mice, whereas OE-NPY(DβH) mice showed reduced fat mass gain, hepatic glycogen and serum cholesterol levels relative to body adiposity. Thus, it can be concluded that with normal NPY levels, peripheral Y(2)-receptor antagonist has no potential for treating obesity, but oppositely may even induce metabolic disorders. However, when energy-rich diet is combined with elevated NPY levels, e.g., stress combined with an unhealthy diet, Y(2)-receptor antagonism has beneficial effects on metabolic status.
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spelling pubmed-58958542018-04-19 Peripherally Administered Y(2)-Receptor Antagonist BIIE0246 Prevents Diet-Induced Obesity in Mice With Excess Neuropeptide Y, but Enhances Obesity in Control Mice Ailanen, Liisa Vähätalo, Laura H. Salomäki-Myftari, Henriikka Mäkelä, Satu Orpana, Wendy Ruohonen, Suvi T. Savontaus, Eriika Front Pharmacol Pharmacology Neuropeptide Y (NPY) plays an important role in the regulation of energy homeostasis in the level of central and sympathetic nervous systems (SNSs). Genetic silencing of peripheral Y(2)-receptors have anti-obesity effects, but it is not known whether pharmacological blocking of peripheral Y(2)-receptors would similarly benefit energy homeostasis. The effects of a peripherally administered Y(2)-receptor antagonist were studied in healthy and energy-rich conditions with or without excess NPY. Genetically obese mice overexpressing NPY in brain noradrenergic nerves and SNS (OE-NPY(DβH)) represented the situation of elevated NPY levels, while wildtype (WT) mice represented the normal NPY levels. Specific Y(2)-receptor antagonist, BIIE0246, was administered (1.3 mg/kg/day, i.p.) for 2 or 4.5 weeks to OE-NPY(DβH) and WT mice feeding on chow or Western diet. Treatment with Y(2)-receptor antagonist increased body weight gain in both genotypes on chow diet and caused metabolic disturbances (e.g., hyperinsulinemia and hypercholesterolemia), especially in WT mice. During energy surplus (i.e., on Western diet), blocking of Y(2)-receptors induced obesity in WT mice, whereas OE-NPY(DβH) mice showed reduced fat mass gain, hepatic glycogen and serum cholesterol levels relative to body adiposity. Thus, it can be concluded that with normal NPY levels, peripheral Y(2)-receptor antagonist has no potential for treating obesity, but oppositely may even induce metabolic disorders. However, when energy-rich diet is combined with elevated NPY levels, e.g., stress combined with an unhealthy diet, Y(2)-receptor antagonism has beneficial effects on metabolic status. Frontiers Media S.A. 2018-04-05 /pmc/articles/PMC5895854/ /pubmed/29674968 http://dx.doi.org/10.3389/fphar.2018.00319 Text en Copyright © 2018 Ailanen, Vähätalo, Salomäki-Myftari, Mäkelä, Orpana, Ruohonen and Savontaus. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Ailanen, Liisa
Vähätalo, Laura H.
Salomäki-Myftari, Henriikka
Mäkelä, Satu
Orpana, Wendy
Ruohonen, Suvi T.
Savontaus, Eriika
Peripherally Administered Y(2)-Receptor Antagonist BIIE0246 Prevents Diet-Induced Obesity in Mice With Excess Neuropeptide Y, but Enhances Obesity in Control Mice
title Peripherally Administered Y(2)-Receptor Antagonist BIIE0246 Prevents Diet-Induced Obesity in Mice With Excess Neuropeptide Y, but Enhances Obesity in Control Mice
title_full Peripherally Administered Y(2)-Receptor Antagonist BIIE0246 Prevents Diet-Induced Obesity in Mice With Excess Neuropeptide Y, but Enhances Obesity in Control Mice
title_fullStr Peripherally Administered Y(2)-Receptor Antagonist BIIE0246 Prevents Diet-Induced Obesity in Mice With Excess Neuropeptide Y, but Enhances Obesity in Control Mice
title_full_unstemmed Peripherally Administered Y(2)-Receptor Antagonist BIIE0246 Prevents Diet-Induced Obesity in Mice With Excess Neuropeptide Y, but Enhances Obesity in Control Mice
title_short Peripherally Administered Y(2)-Receptor Antagonist BIIE0246 Prevents Diet-Induced Obesity in Mice With Excess Neuropeptide Y, but Enhances Obesity in Control Mice
title_sort peripherally administered y(2)-receptor antagonist biie0246 prevents diet-induced obesity in mice with excess neuropeptide y, but enhances obesity in control mice
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5895854/
https://www.ncbi.nlm.nih.gov/pubmed/29674968
http://dx.doi.org/10.3389/fphar.2018.00319
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