Peripherally Administered Y2-Receptor Antagonist BIIE0246 Prevents Diet-Induced Obesity in Mice With Excess Neuropeptide Y, but Enhances Obesity in Control Mice.
| Title: | Peripherally Administered Y2-Receptor Antagonist BIIE0246 Prevents Diet-Induced Obesity in Mice With Excess Neuropeptide Y, but Enhances Obesity in Control Mice. |
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| Authors: | Ailanen L; Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, Turku Center for Disease Modeling, University of Turku, Turku, Finland.; Drug Research Doctoral Program, University of Turku, Turku, Finland.; Vähätalo LH; Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, Turku Center for Disease Modeling, University of Turku, Turku, Finland.; Salomäki-Myftari H; Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, Turku Center for Disease Modeling, University of Turku, Turku, Finland.; Drug Research Doctoral Program, University of Turku, Turku, Finland.; Mäkelä S; Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, Turku Center for Disease Modeling, University of Turku, Turku, Finland.; Orpana W; Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, Turku Center for Disease Modeling, University of Turku, Turku, Finland.; Ruohonen ST; Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, Turku Center for Disease Modeling, University of Turku, Turku, Finland.; Savontaus E; Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, Turku Center for Disease Modeling, University of Turku, Turku, Finland.; Unit of Clinical Pharmacology, Turku University Hospital, Turku, Finland. |
| Source: | Frontiers in pharmacology [Front Pharmacol] 2018 Apr 05; Vol. 9, pp. 319. Date of Electronic Publication: 2018 Apr 05 (Print Publication: 2018). |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Frontiers Media] Country of Publication: Switzerland NLM ID: 101548923 Publication Model: eCollection Cited Medium: Print ISSN: 1663-9812 (Print) Linking ISSN: 16639812 NLM ISO Abbreviation: Front Pharmacol Subsets: PubMed not MEDLINE |
| Imprint Name(s): | Original Publication: [Lausanne : Frontiers Media] |
| Abstract: | 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 Y2-receptors have anti-obesity effects, but it is not known whether pharmacological blocking of peripheral Y2-receptors would similarly benefit energy homeostasis. The effects of a peripherally administered Y2-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-NPYDβH) represented the situation of elevated NPY levels, while wildtype (WT) mice represented the normal NPY levels. Specific Y2-receptor antagonist, BIIE0246, was administered (1.3 mg/kg/day, i.p.) for 2 or 4.5 weeks to OE-NPYDβH and WT mice feeding on chow or Western diet. Treatment with Y2-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 Y2-receptors induced obesity in WT mice, whereas OE-NPYDβH 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 Y2-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, Y2-receptor antagonism has beneficial effects on metabolic status. |
| References: | Peptides. 2010 Apr;31(4):757-76. (PMID: 20093161); Obesity (Silver Spring). 2011 Nov;19(11):2241-7. (PMID: 21818152); Obes Res. 2005 Apr;13(4):653-61. (PMID: 15897473); Diabetologia. 2007 Mar;50(3):574-84. (PMID: 17235527); Nature. 2002 Aug 8;418(6898):650-4. (PMID: 12167864); Cell Physiol Biochem. 2013;31(2-3):421-31. (PMID: 23548582); Diabetes. 2002 Dec;51(12):3420-7. (PMID: 12453895); Regul Pept. 2005 Apr 15;127(1-3):45-53. (PMID: 15680469); Br J Pharmacol. 2012 Aug;166(8):2307-16. (PMID: 22404240); Peptides. 2002 Jun;23(6):1087-91. (PMID: 12126735); Diabetes. 2008 Jun;57(6):1517-25. (PMID: 18276767); Peptides. 2014 Apr;54:33-8. (PMID: 24462552); Mol Pharmacol. 2010 Jan;77(1):46-57. (PMID: 19837904); Am J Physiol Regul Integr Comp Physiol. 2004 Jun;286(6):R1167-75. (PMID: 15142857); Regul Pept. 1984 Apr;8(3):225-35. (PMID: 6379758); Angiology. 2013 Jan;64(1):40-5. (PMID: 22308535); Clin Chim Acta. 2002 Dec;326(1-2):3-25. (PMID: 12417094); Int J Pept. 2012;2012:452524. (PMID: 23118773); Cell Metab. 2014 Jan 7;19(1):58-72. (PMID: 24411939); Cell Metab. 2013 Feb 5;17 (2):236-48. (PMID: 23395170); Am J Physiol. 1991 Feb;260(2 Pt 2):R321-7. (PMID: 1996719); PLoS One. 2010 Jun 29;5(6):e11361. (PMID: 20613867); Diabetologia. 1997 Nov;40(11):1269-77. (PMID: 9389418); Mol Endocrinol. 1997 Jan;11(1):27-38. (PMID: 8994185); Obesity (Silver Spring). 2011 Nov;19(11):2137-48. (PMID: 21546930); Endocrinology. 1993 Oct;133(4):1753-8. (PMID: 8404618); Diabetes. 2006 Jan;55(1):19-26. (PMID: 16380472); Brain Res. 2004 Apr 23;1006(1):100-6. (PMID: 15047028); Regul Pept. 1998 Sep 25;75-76:231-8. (PMID: 9802414); Mol Metab. 2014 May 14;3(5):581-91. (PMID: 25061562); Neuropeptides. 2012 Dec;46(6):359-66. (PMID: 22981159); J Endocrinol. 2017 Jul;234(1):57-72. (PMID: 28468933); Nat Med. 2007 Jul;13(7):803-11. (PMID: 17603492); Neuroscience. 1985 Aug;15(4):1159-81. (PMID: 3900805); J Clin Endocrinol Metab. 2011 Dec;96(12):E2055-62. (PMID: 21937627); Eur J Pharmacol. 1999 Nov 19;384(2-3):R3-5. (PMID: 10611450); Nat Med. 1998 Dec;4(12):1434-7. (PMID: 9846584); Diabetologia. 2006 Nov;49(11):2653-8. (PMID: 17019604); Int J Obes (Lond). 2006 Mar;30(3):453-9. (PMID: 16331299); FASEB J. 2001 May;15(7):1242-4. (PMID: 11344101); Acta Physiol (Oxf). 2015 Apr;213(4):902-19. (PMID: 25482272); Brain Res. 2005 May 10;1043(1-2):139-44. (PMID: 15862527); Neurochem Res. 2008 Oct;33(10):2035-43. (PMID: 18373195) |
| Contributed Indexing: | Keywords: BIIE0246; Y2-receptor; neuropeptide Y; obesity; the metabolic syndrome |
| Entry Date(s): | Date Created: 20180421 Latest Revision: 20201001 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC5895854 |
| DOI: | 10.3389/fphar.2018.00319 |
| PMID: | 29674968 |
| Database: | MEDLINE |
Journal Article