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Peripheral, but not central, CB1 antagonism provides food intake independent metabolic benefits in diet-induced obese rats

¹Department of Psychiatry, Obesity Research Centre-Genome Research Institute, University of Cincinnati, Cincinnati, OH 45226, USA
²Laboratory of Metabolism, Division of Endocrinology, Diabetology and Nutrition, Department of Internal Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland
³Procter & Gamble Pharmaceuticals, Inc., Mason, Ohio
⁴The Laboratory of Trauma, Sepsis & Inflammation Research, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
⁵Department of Endocrine Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, 43 Szigony Street, 1083 Budapest, Hungary
⁶Department of Anatomy, Hokkaido University School of Medicine, Sapporo 060-8638, Japan
⁷Tupper Research Institute and Department of Medicine, Division of Endocrinology, Diabetes, Metabolism and Molecular Medicine, New England Medical Center, 750 Washington St, Boston, MA, 02111
⁸Department of Cell Biology, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, NC10, Cleveland, OH 44195, USA
⁹Department of Physiology, School of Medicine, University of Santiago de Compostela, Santiago de Compostela, Spain
¹⁰CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Spain

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, lipid and glucose metabolism in rats with diet-induced obesity (DIO).

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 (WAT) and cellular glucose uptake. Insulin sensitivity and skeletal muscle glucose uptake were enhanced while hepatic glucose production was decreased during peripheral infusion of 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.

Correspondence: tschoemh{at}ucmail.uc.edu

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