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      Hyperphagia and increased fat accumulation in two models of chronic CNS glucagon-like peptide-1 loss of function.

      The Journal of neuroscience : the official journal of the Society for Neuroscience
      Adiposity, drug effects, physiology, Analysis of Variance, Animals, Dietary Fats, Energy Metabolism, Feeding Behavior, Fluorescent Antibody Technique, Glucagon-Like Peptide 1, antagonists & inhibitors, genetics, metabolism, Glucose Intolerance, physiopathology, Hyperphagia, In Situ Hybridization, Injections, Intraventricular, Islets of Langerhans, cytology, Male, Motor Activity, Obesity, Peptide Fragments, pharmacology, Proglucagon, RNA Interference, RNA, Messenger, Rats, Rats, Long-Evans, Reverse Transcriptase Polymerase Chain Reaction, Tissue Culture Techniques

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          Abstract

          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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