دورية أكاديمية
Lorcaserin improves glycemic control via a melanocortin neurocircuit.
| العنوان: | Lorcaserin improves glycemic control via a melanocortin neurocircuit. |
|---|---|
| المؤلفون: | Burke LK; Department of Pharmacology, University of Cambridge, Cambridge, UK; Department of Medicine and Wellcome Trust/MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK., Ogunnowo-Bada E; Department of Medicine and Wellcome Trust/MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK., Georgescu T; The Rowett Institute, University of Aberdeen, Aberdeen, UK., Cristiano C; The Rowett Institute, University of Aberdeen, Aberdeen, UK., de Morentin PBM; The Rowett Institute, University of Aberdeen, Aberdeen, UK., Valencia Torres L; Department of Pharmacology, University of Cambridge, Cambridge, UK; The Rowett Institute, University of Aberdeen, Aberdeen, UK., D'Agostino G; Department of Pharmacology, University of Cambridge, Cambridge, UK; The Rowett Institute, University of Aberdeen, Aberdeen, UK., Riches C; Department of Medicine and Wellcome Trust/MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK., Heeley N; Department of Medicine and Wellcome Trust/MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK., Ruan Y; Department of Medicine and Wellcome Trust/MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK., Rubinstein M; Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, Consejo Nacional de Investigaciones Científicas y Técnicas, 1428 Buenos Aires, Argentina., Low MJ; Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA., Myers MG; Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA., Rochford JJ; The Rowett Institute, University of Aberdeen, Aberdeen, UK., Evans ML; Department of Medicine and Wellcome Trust/MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK. Electronic address: mle24@cam.ac.uk., Heisler LK; Department of Pharmacology, University of Cambridge, Cambridge, UK; The Rowett Institute, University of Aberdeen, Aberdeen, UK. Electronic address: lora.heisler@abdn.ac.uk. |
| المصدر: | Molecular metabolism [Mol Metab] 2017 Oct; Vol. 6 (10), pp. 1092-1102. Date of Electronic Publication: 2017 Jul 21. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier GmbH Country of Publication: Germany NLM ID: 101605730 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2212-8778 (Electronic) Linking ISSN: 22128778 NLM ISO Abbreviation: Mol Metab Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: [München] : Elsevier GmbH, 2012- |
| مواضيع طبية MeSH: | Benzazepines/*pharmacology , Blood Glucose/*drug effects , Receptor, Serotonin, 5-HT2C/*drug effects, Animals ; Benzazepines/metabolism ; Body Weight/drug effects ; Diabetes Mellitus, Type 2/drug therapy ; Disease Models, Animal ; Eating/drug effects ; Energy Metabolism/drug effects ; Glucose/metabolism ; Glucose Tolerance Test ; Homeostasis/physiology ; Humans ; Insulin Resistance/physiology ; Melanocortins/pharmacology ; Mice ; Mice, Transgenic ; Obesity/drug therapy ; Receptors, Melanocortin/drug effects ; Weight Loss/drug effects |
| مستخلص: | Objective: The increasing prevalence of type 2 diabetes (T2D) and associated morbidity and mortality emphasizes the need for a more complete understanding of the mechanisms mediating glucose homeostasis to accelerate the identification of new medications. Recent reports indicate that the obesity medication lorcaserin, a 5-hydroxytryptamine (5-HT, serotonin) 2C receptor (5-HT Methods: Murine models of common and genetic T2D were utilized to probe the direct effect of lorcaserin on glycemic control. Results: Lorcaserin dose-dependently improves glycemic control in mouse models of T2D in the absence of reductions in food intake or body weight. Examining the mechanism of this effect, we reveal a necessary and sufficient neurochemical mediator of lorcaserin's glucoregulatory effects, brain pro-opiomelanocortin (POMC) peptides. To clarify further lorcaserin's therapeutic brain circuit, we examined the receptor target of POMC peptides. We demonstrate that lorcaserin requires functional melanocortin4 receptors on cholinergic preganglionic neurons (MC4R ChAT ) to exert its effects on glucose homeostasis. In contrast, MC4R ChAT signaling did not impact lorcaserin's effects on feeding, indicating a divergence in the neurocircuitry underpinning lorcaserin's therapeutic glycemic and anorectic effects. Hyperinsulinemic-euglycemic clamp studies reveal that lorcaserin reduces hepatic glucose production, increases glucose disposal and improves insulin sensitivity. Conclusions: These data suggest that lorcaserin's action within the brain represents a mechanistically novel treatment for T2D: findings of significance to a prevalent global disease. (Copyright © 2017 The Authors. Published by Elsevier GmbH.. All rights reserved.) |
| References: | Pharmacogenet Genomics. 2008 Feb;18(2):153-9. (PMID: 18192901) J Neurosci. 2013 Jun 5;33(23):9800-4. (PMID: 23739976) Cell. 1997 Jan 10;88(1):131-41. (PMID: 9019399) Obesity (Silver Spring). 2012 Jul;20(7):1426-36. (PMID: 22421927) J Clin Invest. 2013 Dec;123(12):5061-70. (PMID: 24177424) Nat Neurosci. 2014 Dec;17 (12 ):1744-1750. (PMID: 25383904) Trends Neurosci. 2013 Sep;36(9):504-12. (PMID: 23790727) Nat Genet. 1998 Oct;20(2):111-2. (PMID: 9771698) Neuron. 2011 Aug 11;71(3):488-97. (PMID: 21835345) Endocrinology. 2016 Dec;157(12 ):4669-4676. (PMID: 27740870) Diabetes. 2012 Feb;61(2):321-8. (PMID: 22210318) Lancet. 1998 Sep 12;352(9131):854-65. (PMID: 9742977) Lancet. 1998 Sep 12;352(9131):837-53. (PMID: 9742976) Proc Natl Acad Sci U S A. 1989 Sep;86(17):6793-7. (PMID: 2771958) Diabetes. 2016 Mar;65(3):660-72. (PMID: 26467632) J Mol Endocrinol. 2016 May;56(4):T157-74. (PMID: 26939593) Cell Metab. 2014 Dec 2;20(6):1030-7. (PMID: 25470549) Handb Exp Pharmacol. 2016;233:437-59. (PMID: 25903416) Postgrad Med. 2016 May;128(4):364-70. (PMID: 27116910) Obesity (Silver Spring). 2009 Mar;17(3):494-503. (PMID: 19057523) Nat Neurosci. 2010 Dec;13(12):1457-9. (PMID: 21037584) Neuron. 2008 Nov 26;60(4):582-9. (PMID: 19038216) Diabetes. 2001 Nov;50(11):2585-90. (PMID: 11679438) Postgrad Med. 2016 Aug;128(6):591-7. (PMID: 27389084) Endocrinology. 2006 Jun;147(6):2619-30. (PMID: 16513827) Trends Endocrinol Metab. 2009 Jul;20(5):203-15. (PMID: 19541496) N Engl J Med. 2010 Jul 15;363(3):245-56. (PMID: 20647200) J Neurosci. 2010 Nov 3;30(44):14630-4. (PMID: 21048120) Cell. 2005 Nov 4;123(3):493-505. (PMID: 16269339) Cell Metab. 2011 Feb 2;13(2):195-204. (PMID: 21284986) J Clin Endocrinol Metab. 2011 Jan;96(1):E181-8. (PMID: 21047921) Endocrinology. 2008 Mar;149(3):1323-8. (PMID: 18039773) J Clin Invest. 2010 Jul;120(7):2355-69. (PMID: 20577053) Mol Metab. 2016 Jan 22;5(3):245-52. (PMID: 26977396) Cell Metab. 2007 Nov;6(5):398-405. (PMID: 17983585) Cell Rep. 2015 Apr 21;11(3):335-43. (PMID: 25865886) Cell Rep. 2017 Jan 17;18(3):583-592. (PMID: 28099839) J Neuroendocrinol. 2015 Jun;27(6):389-98. (PMID: 25925636) Nat Neurosci. 2014 Jul;17(7):911-3. (PMID: 24908101) Am J Physiol. 1979 Jun;236(6):E667-77. (PMID: 443421) Nat Med. 1998 Oct;4(10):1152-6. (PMID: 9771748) J Clin Invest. 2012 Nov;122(11):4203-12. (PMID: 23093774) Science. 2002 Jul 26;297(5581):609-11. (PMID: 12142539) Postgrad Med. 2016 Nov;128(8):740-746. (PMID: 27659698) Cell. 2013 Jan 31;152(3):612-9. (PMID: 23374353) J Clin Invest. 2012 Mar;122(3):1000-9. (PMID: 22326958) J Clin Endocrinol Metab. 2011 Mar;96(3):837-45. (PMID: 21190985) Endocrinology. 2012 Apr;153(4):1908-14. (PMID: 22396449) PLoS Biol. 2009 Oct;7(10 ):e1000229. (PMID: 19859528) Diabetes Obes Metab. 2014 Sep;16 Suppl 1:33-40. (PMID: 25200294) |
| معلومات مُعتمدة: | WT098012 United Kingdom WT_ Wellcome Trust; R01 DK056731 United States DK NIDDK NIH HHS; R01 DK078056 United States DK NIDDK NIH HHS; R56 DK066604 United States DK NIDDK NIH HHS; 100574/Z/12/Z United Kingdom WT_ Wellcome Trust; MR/P009824/1 United Kingdom MRC_ Medical Research Council; BB/K001418/1 United Kingdom BB_ Biotechnology and Biological Sciences Research Council; BB/NO17838/1 United Kingdom BB_ Biotechnology and Biological Sciences Research Council; 093566/Z/10/A United Kingdom WT_ Wellcome Trust; R01 DK066604 United States DK NIDDK NIH HHS; MR/L002620/1 United Kingdom MRC_ Medical Research Council; R37 DK056731 United States DK NIDDK NIH HHS; MC/PC/15077 United Kingdom MRC_ Medical Research Council; WT081713 United Kingdom WT_ Wellcome Trust; R01 DK068400 United States DK NIDDK NIH HHS; BB/K017772/1 United Kingdom BB_ Biotechnology and Biological Sciences Research Council; P30 DK020572 United States DK NIDDK NIH HHS; MC_PC_15077 United Kingdom MRC_ Medical Research Council; United Kingdom WT_ Wellcome Trust |
| فهرسة مساهمة: | Keywords: 5-HT2c receptor; Hypothalamus; Lorcaserin; Melanocortin4 receptor (Mc4r); Pro-opiomelanocortin (POMC); Type 2 diabetes |
| المشرفين على المادة: | 0 (Benzazepines) 0 (Blood Glucose) 0 (Melanocortins) 0 (Receptor, Serotonin, 5-HT2C) 0 (Receptors, Melanocortin) 637E494O0Z (lorcaserin) IY9XDZ35W2 (Glucose) |
| تواريخ الأحداث: | Date Created: 20171017 Date Completed: 20181212 Latest Revision: 20220330 |
| رمز التحديث: | 20231215 |
| مُعرف محوري في PubMed: | PMC5641625 |
| DOI: | 10.1016/j.molmet.2017.07.004 |
| PMID: | 29031711 |
| قاعدة البيانات: | MEDLINE |
Full Text via ClinicalKey 
Full Text Finder | تدمد: | 2212-8778 |
|---|---|
| DOI: | 10.1016/j.molmet.2017.07.004 |