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The Journal of Neuroscience, May 6, 2009, 29(18):5916-5925; doi:10.1523/JNEUROSCI.5977-08.2009
Previous Article | Next Article
Behavioral/Systems/Cognitive
Direct Control of Peripheral Lipid Deposition by CNS GLP-1 Receptor Signaling Is Mediated by the Sympathetic Nervous System and Blunted in Diet-Induced Obesity
Ruben Nogueiras,1,2,3 Diego Pérez-Tilve,1 Christelle Veyrat-Durebex,4 Donald A. Morgan,5 Luis Varela,2,3 William G. Haynes,5 James T. Patterson,6 Emmanuel Disse,4 Paul T. Pfluger,1 Miguel López,2,3 Stephen C. Woods,1 Richard DiMarchi,6 Carlos Diéguez,2,3 Kamal Rahmouni,5 Françoise Rohner-Jeanrenaud,4 andMatthias H. Tschöp1,7 1Department of Psychiatry, Obesity Research Centre, University of Cincinnati, Cincinnati, Ohio 45226, 2Department of Physiology, University of Santiago de Compostela–Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain, 3Centro de Investigación Biomédica en Red (CIBERobn), Fisiopatologia de la Obesidad y Nutrición, Institudo de Salud Carlos III, 15782, Spain, 4Laboratory of Metabolism, Division of Endocrinology, Diabetology and Nutrition, Department of Internal Medicine, Faculty of Medicine, University of Geneva, Geneva 12114, Switzerland, 5Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, 6Department of Chemistry, Indiana University, Bloomington, Indiana 47405, and 7Department of Pharmacology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal 14558, Germany
Correspondence should be addressed to either of the following: Dr. Ruben Nogueiras, Department of Physiology, School of Medicine, University of Santiago de Compostela, San Francisco s/n, Santiago de Compostela 15782, A Coru
a, Spain, Email: ruben.nogueiras{at}usc.es; or Dr. Matthias H. Tschöp, Department of Psychiatry, Obesity Research Center, University of Cincinnati–Genome Research Institute, 2170 East Galbraith Road, Cincinnati, OH 45237, E-mail: Email: tschoemh{at}ucmail.uc.edu
We investigated a possible role of the central glucagon-like peptide (GLP-1) receptor system as an essential brain circuit regulating adiposity through effects on nutrient partitioning and lipid metabolism independent from feeding behavior. Both lean and diet-induced obesity mice were used for our experiments. GLP-1 (7–36) amide was infused in the brain for 2 or 7 d. The expression of key enzymes involved in lipid metabolism was measured by real-time PCR or Western blot. To test the hypothesis that the sympathetic nervous system may be responsible for informing adipocytes about changes in CNS GLP-1 tone, we have performed direct recording of sympathetic nerve activity combined with experiments in genetically manipulated mice lacking β-adrenergic receptors. Intracerebroventricular infusion of GLP-1 in mice directly and potently decreases lipid storage in white adipose tissue. These effects are independent from nutrient intake. Such CNS control of adipocyte metabolism was found to depend partially on a functional sympathetic nervous system. Furthermore, the effects of CNS GLP-1 on adipocyte metabolism were blunted in diet-induced obese mice. The CNS GLP-1 system decreases fat storage via direct modulation of adipocyte metabolism. This CNS GLP-1 control of adipocyte lipid metabolism appears to be mediated at least in part by the sympathetic nervous system and is independent of parallel changes in food intake and body weight. Importantly, the CNS GLP-1 system loses the capacity to modulate adipocyte metabolism in obese states, suggesting an obesity-induced adipocyte resistance to CNS GLP-1.
Received Dec. 16, 2008; revised March 20, 2009; accepted March 30, 2009.
Correspondence should be addressed to either of the following: Dr. Ruben Nogueiras, Department of Physiology, School of Medicine, University of Santiago de Compostela, San Francisco s/n, Santiago de Compostela 15782, A Coru
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