| Hyperphagia and increased fat accumulation in two models of chronic CNS glucagon-like peptide-1 loss of function. | |
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MedLine Citation:
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PMID: 21389245 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Central administration of glucagon-like peptide-1 (GLP-1) causes a dose-dependent reduction in food intake, but the role of endogenous CNS GLP-1 in the regulation of energy balance remains unclear. Here, we tested the hypothesis that CNS GLP-1 activity is required for normal energy balance by using two independent methods to achieve chronic CNS GLP-1 loss of function in rats. Specifically, lentiviral-mediated expression of RNA interference was used to knock down nucleus of the solitary tract (NTS) preproglucagon (PPG), and chronic intracerebroventricular (ICV) infusion of the GLP-1 receptor (GLP-1r) antagonist exendin (9-39) (Ex9) was used to block CNS GLP-1r. NTS PPG knockdown caused hyperphagia and exacerbated high-fat diet (HFD)-induced fat accumulation and glucose intolerance. Moreover, in control virus-treated rats fed the HFD, NTS PPG expression levels correlated positively with fat mass. Chronic ICV Ex9 also caused hyperphagia; however, increased fat accumulation and glucose intolerance occurred regardless of diet. Collectively, these data provide the strongest evidence to date that CNS GLP-1 plays a physiologic role in the long-term regulation of energy balance. Moreover, they suggest that this role is distinct from that of circulating GLP-1 as a short-term satiation signal. Therefore, it may be possible to tailor GLP-1-based therapies for the prevention and/or treatment of obesity. |
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Authors:
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Jason G Barrera; Kenneth R Jones; James P Herman; David A D'Alessio; Stephen C Woods; Randy J Seeley |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural |
Journal Detail:
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Title: The Journal of neuroscience : the official journal of the Society for Neuroscience Volume: 31 ISSN: 1529-2401 ISO Abbreviation: J. Neurosci. Publication Date: 2011 Mar |
Date Detail:
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Created Date: 2011-03-10 Completed Date: 2011-05-11 Revised Date: 2012-02-15 |
Medline Journal Info:
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Nlm Unique ID: 8102140 Medline TA: J Neurosci Country: United States |
Other Details:
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Languages: eng Pagination: 3904-13 Citation Subset: IM |
Affiliation:
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Department of Internal Medicine, University of Cincinnati, Cincinnati, Ohio 45237, USA. barrerjg@mail.uc.edu |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adiposity
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drug effects,
physiology* Analysis of Variance Animals Dietary Fats Energy Metabolism / drug effects, physiology* Feeding Behavior / drug effects, physiology Fluorescent Antibody Technique Glucagon-Like Peptide 1 / antagonists & inhibitors, genetics, metabolism* Glucose Intolerance / genetics, metabolism*, physiopathology Hyperphagia / genetics, metabolism*, physiopathology In Situ Hybridization Injections, Intraventricular Islets of Langerhans / cytology, metabolism Male Motor Activity / drug effects, physiology Obesity / genetics, metabolism*, physiopathology Peptide Fragments / pharmacology Proglucagon / metabolism RNA Interference RNA, Messenger / genetics, metabolism Rats Rats, Long-Evans Reverse Transcriptase Polymerase Chain Reaction Tissue Culture Techniques |
| Grant Support | |
ID/Acronym/Agency:
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R01 DK017844-35/DK/NIDDK NIH HHS; R01 DK057900-10/DK/NIDDK NIH HHS; R01 DK54890/DK/NIDDK NIH HHS; R01 MH069860-07/MH/NIMH NIH HHS; R01 MH069860-08/MH/NIMH NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Dietary Fats; 0/Peptide Fragments; 0/RNA, Messenger; 133514-43-9/exendin (9-39); 55963-74-1/Proglucagon; 89750-14-1/Glucagon-Like Peptide 1 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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