title: Peripheral, but not central, CB1 antagonism provides food intake-independent metabolic benefits in diet-induced obese rats.
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.
  
  
  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.
authors: Department of Psychiatry, Obesity Research Centre, Genome Research Institute, University of Cincinnati, Cincinnati, Ohio, USA. ruben.nogueiras@usc.es
authors: Ruben
authors: R
authors: Nogueiras
authors: Christelle
authors: C
authors: Veyrat-Durebex
authors: Paula M
authors: PM
authors: Suchanek
authors: Marcella
authors: M
authors: Klein
authors: Johannes
authors: J
authors: Tschöp
authors: Charles
authors: C
authors: Caldwell
authors: Stephen C
authors: SC
authors: Woods
authors: Gabor
authors: G
authors: Wittmann
authors: Masahiko
authors: M
authors: Watanabe
authors: Zsolt
authors: Z
authors: Liposits
authors: Csaba
authors: C
authors: Fekete
authors: Ofer
authors: O
authors: Reizes
authors: Francoise
authors: F
authors: Rohner-Jeanrenaud
authors: Matthias H
authors: MH
authors: Tschöp
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000235:genetics / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D002853:Chromatography, Liquid; D004041:Dietary Fats / Q000008:administration & dosage; D004435:Eating / Q000187:drug effects / Q000502:physiology*; D064429:Fatty Acid Synthases / Q000235:genetics / Q000378:metabolism; D015309:Glucose Clamp Technique; D050356:Lipid Metabolism / Q000187:drug effects; D008071:Lipoprotein Lipase / Q000235:genetics / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D009765:Obesity / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077285:Rimonabant; D014280:Triglycerides / Q000378:metabolism
chemical_list: D004041:Dietary Fats; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D014280:Triglycerides; D064429:Fatty Acid Synthases; D008071:Lipoprotein Lipase; D000103:Acetyl-CoA Carboxylase; D000077285:Rimonabant