Peripheral, but Not Central, CB1 Antagonism Provides Food Intake–Independent Metabolic Benefits in Diet-Induced Obese Rats
- Ruben Nogueiras123,
- Christelle Veyrat-Durebex4,
- Paula M. Suchanek5,
- Marcella Klein4,
- Johannes Tschöp6,
- Charles Caldwell6,
- Stephen C. Woods1,
- Gabor Wittmann7,
- Masahiko Watanabe8,
- Zsolt Liposits7,
- Csaba Fekete79,
- Ofer Reizes10,
- Francoise Rohner-Jeanrenaud4 and
- Matthias H. Tschöp1
- 1Department of Psychiatry, Obesity Research Centre, Genome Research Institute, University of Cincinnati, Cincinnati, Ohio
- 2Department of Physiology, School of Medicine, University of Santiago de Compostela, Santiago de Compostela, Spain
- 3CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain
- 4Laboratory of Metabolism, Division of Endocrinology, Diabetology, and Nutrition, Department of Internal Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- 5Procter and Gamble Pharmaceuticals, Mason, Ohio
- 6Laboratory of Trauma, Sepsis and Inflammation Research, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio
- 7Department of Endocrine Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary
- 8Department of Anatomy, Hokkaido University School of Medicine, Sapporo, Japan
- 9Tupper Research Institute and Department of Medicine, Division of Endocrinology, Diabetes, Metabolism, and Molecular Medicine, New England Medical Center, Boston, Massachusetts
- 10Department of Cell Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio
- Corresponding authors: Ruben Nogueiras, ruben.nogueiras{at}usc.es, and Matthias H. Tschöp, tschoemh{at}ucmail.uc.edu
Abstract
OBJECTIVE—Blockade of the CB1 receptor is one of the promising strategies for the treatment of obesity. Although antagonists suppress food intake and reduce body weight, the role of central versus peripheral CB1 activation on weight loss and related metabolic parameters remains to be elucidated. We therefore specifically assessed and compared the respective potential relevance of central nervous system (CNS) versus peripheral CB1 receptors in the regulation of energy homeostasis and lipid and glucose metabolism in diet-induced obese (DIO) rats.
RESEARCH DESIGN AND METHODS—Both lean and DIO rats were used for our experiments. The expression of key enzymes involved in lipid metabolism was measured by real-time PCR, and euglycemic-hyperinsulinemic clamps were used for insulin sensitivity and glucose metabolism studies.
RESULTS—Specific CNS-CB1 blockade decreased body weight and food intake but, independent of those effects, had no beneficial influence on peripheral lipid and glucose metabolism. Peripheral treatment with CB1 antagonist (Rimonabant) also reduced food intake and body weight but, in addition, independently triggered lipid mobilization pathways in white adipose tissue and cellular glucose uptake. Insulin sensitivity and skeletal muscle glucose uptake were enhanced, while hepatic glucose production was decreased during peripheral infusion of the CB1 antagonist. However, these effects depended on the antagonist-elicited reduction of food intake.
CONCLUSIONS—Several relevant metabolic processes appear to independently benefit from peripheral blockade of CB1, while CNS-CB1 blockade alone predominantly affects food intake and body weight.
Footnotes
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Published ahead of print at http://diabetes.diabetesjournals.org on 20 August 2008.
R.N. and C.V.-D. contributed equally to this article.
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- Accepted August 8, 2008.
- Received February 5, 2008.
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